Schauer ´ Becker ´ Reiser ´ Possinger: The Sentinel Lymph Node Concept
A. J. Schauer ´ W. Becker M. Reiser ´ K. Possinger
The Sentinel Lymph Node Concept
With 329 Figures in 420 Separate Illustrations, Mostly in Color, and 228 Tables
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ISBN 3-540-41041-4 Springer Berlin Heidelberg New York Library of Congress Control Number: 2004106520 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springeronline.com ° Springer-Verlag Berlin Heidelberg 2005 Printed in Germany The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about the application of operative techniques and medications contained in this book. In every individual case the user must check such information by consulting the relevant literature. Editor: Dr. Ute Heilmann, Heidelberg Desk editor: Wilma McHugh, Heidelberg Production editor: Ute Pfaff, Heidelberg Cover design: Erich Kirchner, Heidelberg Typesetting: K+V Fotosatz GmbH, Beerfelden Reproduction of the figures: AM-productions GmbH, Wiesloch Printing and bookbinding: Stçrtz AG, Wçrzburg Printed on acid-free paper
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Sadly, just as we were embarking on the preparation of this book we suffered a heavy blow when our colleague and co-editor, Professor Dr. Wolfgang Becker died unexpectedly. He was held in high esteem, both as a scientist and doctor and on the personal level, by all who knew and worked with him. We hope this work will be seen as a memorial to him as a valued member of the scientific and medical community.
Preface
Development of the sentinel node concept started at the beginning of the 1990s with evaluation and comparison of the procedures that could be used to detect the sentinel node(s). This involved the use of different dye solutions, mostly blue dyes, such as patent blue, and/or labeling of the first regional node(s), mostly by administration of 99mTc-colloid solutions, the colloid particles selected being of an adequate size to keep ªspilloverº to a minimum. The main goals were to localize the so-called sentinel nodes exactly, to allow subsequent removal and histopathological and immunohistochemical examination of cancer cells, and also to detect any atypically localized sentinel nodes so as to avoid unnecessarily extensive lymphadenectomies with nodes removed from regional basins or from connected lymph node chains. Investigations of breast cancer and malignant melanoma patients, initially carried out mainly in the United States of America and also in Italy and England, contributed most to the development of the new sentinel lymph node concept. After the initial learning phases in all the centers actively involved, safety in handling the sophisticated techniques involved improved and with growing experience of the interdisciplinary working groups the false-negative rates decreased to less than 3%. In recent years the sentinel node concept has been extended to other tumor entities, such as head and neck cancers, thyroid cancers, various cancer types affecting the gastrointestinal and urogenital tracts, and some neuroendocrine cancer subtypes. Investigations evaluating the practicability and usefulness of the sentinel lymph node concept are in progress. In the coming years, increasing use of sentinel node labeling will make it possible to recognize the cancer types and the localizations of primaries in which the sentinel node concept can be used to advantage to minimize locoregional surgical tissue injury and attain complete clearance of primarily locoregional cancer on the one hand, while limiting the extension of lymphadenectomy on the other. In a second series of investigations, a prospective comparative analysis of survival rates among patients in whom the sentinel lymph node concept has been applied and survival rates derived from historical data will show whether real survival benefits accrue when the sentinel node concept is followed. The aims of this book are to provide all relevant information about locoregional lymphatic drainage linked to the different tumor types, to present the current status of the techniques used in sentinel lymph node labeling, and to discuss the preoperative and intraoperative options available for histopathological, cytopathological, and immunopathological cancer characterization. The important preoperative N- and M-staging procedures based on
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Preface
radioimaging and nuclear medical imaging techniques are evaluated, and in some cases compared, with reference to different tumor types and sites. As the sentinel lymph node concept has now been extended to different tumor categories, the ± often preliminary ± current status of knowledge and experience in these fields has also been included. Since any adjuvant and neoadjuvant therapies are based mainly on the estimated nodal status of the patient concerned, some reflections on chemotherapy and radiotherapy regimens are added at the end of the book. We are grateful to Mrs. Silke Kreisch, Department of Nuclear Medicine, University Clinics of Gættingen, for preparation of the manuscript and to Mr. Klaus Zander in the Department of Photo-Reprography and Mr. Klaus Mçller, Department of Pathology, University of Gættingen for photography and computer-supported preparation of illustrations. We also wish to record our gratitude to all the co-authors, whose names appear at the appropriate points in the book. A. Schauer Gættingen
Adresses
Authors
Contributors
Schauer, Alfred J., Prof. Dr. med. Emeritus of Department of Pathology Medical Faculty of Georg August University Gættingen Robert-Koch-Str. 40 37075 Gættingen, Germany
Avril, Norbert, Priv.-Doc. Dr. med. Clinic of Nuclear Medicine Clinicum rechts der Isar Technical University of Munich Ismaninger Str. 22 81675 Munich, Germany
Becker, Wolfgang {, Prof. Dr. med. Director of Department of Nuclear Medicine Medical Faculty of Georg August University Gættingen Robert-Koch-Str. 40 37075 Gættingen, Germany Reiser, Maximilian, Prof. Dr. med. Director of the Institute for Clinical Radiology Medical Faculty of Ludwig Maximilian University Munich Marchioninistr. 15 81377 Munich, Germany Possinger, Kurt, Prof. Dr. med. Director of the Clinic for Internal Medicine (Hematology, Oncology) Alexander v. Humboldt University Berlin (Charit) Schumannstr. 20/21 10117 Berlin, Germany
Buchmann, J., Priv.-Doc. Dr. med. Chief of Dept. of Pathology Town-Hospital Martha Maria Roentgen-Str. 1 06120 Halle-Doelau/Saale, Germany Gilbert, Fiona J., Prof. Dr. Department of Radiology Lilian Sutton Building University of Aberdeen Forester Hill AB. 252 ZD, Scotland, UK Griesinger, Frank, Univ.-Doc. Dr. med. Clinic for Internal Medicine Department for Hematology and Oncology Medical Faculty of Georg August University Gættingen Robert-Koch-Str. 40 37075 Gættingen, Germany Heywang-Kæbrunner, Sylvia H., Prof. Dr. med. Clinic for Diagnostic Radiology Medical Faculty of Technical University of Munich Ismaninger Str. 22 81675 Munich, Germany
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Adresses
Hæfler, Heinz, Prof. Dr. med. Director of the Institute of Pathology of the Clinicum rechts der Isar Technical University of Munich Ismaninger Str. 22 81675 Munich, Germany
Ritzel, Uwe, Dr. med. Clinic for Internal Medicine Department of Gastroenterology Georg August University Gættingen Robert-Koch-Str. 40 37075 Gættingen, Germany
Hupperts, Alexander, Dr. med. Institute for Radiodiagnosis Medical Faculty of Ludwig Maximilian University Munich Marchioninistr. 15 81377 Munich, Germany
Roever, Anne, Dr. med. Clinic for Internal Medicine (Hematology, Oncology) Alexander v. Humboldt University Berlin (Charit) Schumannstr. 20/21 10117 Berlin, Germany
Kamphausen, Bettina H., Dr. med. Institute of Pathology Medical Faculty of Georg August University Gættingen Robert-Koch-Str. 40 37075 Gættingen, Germany
Ruschenburg, Ilka, Dr. med. Institute of Pathology Medical Faculty of Georg August University Gættingen Robert-Koch-Str. 40 37075 Gættingen, Germany
Kopp, Jçrgen, Dipl.-Phys. Nuclear Medical Clinic Central Clinicum Augsburg Stenglinstr. 2 86156 Augsburg, Germany
Schauer, Matthias Chr., Dr. med. Clinic for Surgery University of Munich Ismaninger Str. 22 81675 Munich, Germany
Lautenschlåger, Christine, Dr. med. Department of Informatic and Biometrics Clinicum of Martin Luther University Halle-Wittenberg Magdeburger Str. 16 06097 Halle, Germany
Schauer, Verena, Dr. med. Clinic for Radiodiagnosis Clinicum rechts der Isar Technical University of Munich Ismaninger Str. 22 81675 Munich, Germany
Minnich, T., Dr. med. Internal Medicine Dept. of Nephrology Clinicum Braunschweig Salzdahumer Str. 90 38126 Braunschweig, Germany Nåhrig, Jærg, Dr. med. Institute of Pathology Medical Faculty of the Clinicum rechts der Isar Technical University Ismaninger Str. 22 81675 Munich, Germany
Schwaiger, Markus, Prof. Dr. med. Director of the Clinic for Nuclear Medicine Clinicum rechts der Isar Technical University of Munich Ismaninger Str. 22 81675 Munich, Germany Sciuk, J., Prof. Dr. med. Nuclear Medical Clinic Central Clinicum Augsburg Stenglinstr. 2 86156 Augsburg, Germany
Adresses
Stets, Constance, Dr. med. Clinic for Diagnostic Radiology Medical Faculty of Martin Luther University Halle-Wittenberg Magdeburger Str. 16 06097 Halle, Germany
Weber, Wolfgang, Dr. med. Clinic of Nuclear Medicine Clinicum rechts der Isar Technical University of Munich Ismaninger Str. 22 81675 Munich, Germany
Tællner, Thilo, Dr. med. Radiodiagnostic Clinic Dr. Hancken Harsefelder Str. 8 21680 Stade, Germany
Wengenmair, Hermann, Dipl.-Phys. Nuclear Medical Clinic Central Clinicum Augsburg Stenglinstr. 2 86156 Augsburg, Germany
Wallis, Finton, Dr. med. Department of Diagnostic Imaging Limerick Regional Hospital Complex Dooradoyle Co. Limerick, Republic of Ireland
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Contents
General Part Chapter 1 Definition of the Sentinel Lymph Node and Basic Principles of Detection . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 2 Main Techniques of Sentinel Lymph Node Labeling . . . . . . . . . . . . . . . . .
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Good Practice for Radiation Protection in the Operating Room . Radioactivity Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Good Radiation Protection Practice in the Pathology Laboratory References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 3 Different Aspects Dependent on Type and Localization of the Primary . . . .
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Male Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Female Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 4 Basic Strategies in Sentinel Node Detection and Exclusion or Verification of Cancer Metastasis into the Regional Node(s) . . . . . . . . . . . . . . . . . . . .
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Early Developments and Continuous Improvements . Possible Prescreening Methods for SLN Detection and Tracers Most Frequently Used for Detection of SLN . . Critical Points of the SLN Detection Process . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 5 Positron Emission Tomography: Significance for Preoperative N-Staging . . .
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Imaging Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Radiopharmacy . . . . . . . . . . . . . . . . . . . . . . . . . . Quantitative Measurements . . . . . . . . . . . . . . . . . Clinical Applications . . . . . . . . . . . . . . . . . . . . . . Patient Preparation . . . . . . . . . . . . . . . . . . . . . . . Diagnosis of Primary Tumors . . . . . . . . . . . . . . . Diagnosis of Lymph Node Metastases . . . . . . . . . . Staging of Disease . . . . . . . . . . . . . . . . . . . . . . . . Monitoring Effects of Therapy . . . . . . . . . . . . . . . Limitations of PET Imaging . . . . . . . . . . . . . . . . . Exclusion of Brain Metastases in Staging Programs System-immanent Properties of PET to Support the Sentinel Node Concept . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 6 Detection and Radiological Imaging of SLN . . . . . . . . . . . . . . . . . . . . . . .
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Methodical Work-up and Improvements . . . . . . . . . . . . . . . . . . . . . Techniques in Sentinel Node Detection . . . . . . . . . . . . . . . . . . . . . . Intraoperative Sentinel Node Detection by Use of the Gamma Probe Efforts at Optimization in 99mNanocolloid-Mediated Sentinel Node Localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histo- and Cytopathological Diagnosis . . . . . . . . . . . . . . . . . . . . . . MAGE-A3 Marker Function in Breast Cancer Patients Sentinel Node Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Retrospective Evaluation of the Significance of SLN Located Mediastinally or Along the Mammaria Interna by Radioimaging . Inclusion and Exclusion Criteria for Sentinel Node Investigation . . . Criteria for Clinical and Histopathological Sentinel Node Evaluation (Breast Cancer) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparative Experimental Tracer Studies . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 7 Lymphatic Drainage to the SLN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Time Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Involvement of the Regional Lymph Nodes in Breast Cancer . . . . Direct and Secondary Hematogenous Metastasis of Breast Cancer Is Intraoperative SLN Staging Possible in Breast Cancer Cases? . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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51 52 54 55 57
Tc-Colloids . . . .
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radionuclides in Conventional and Routine Nuclear Medicine Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 8 Specific Developments in Sentinel Node Labeling Using
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Quality of the Colloids Used and the Particle Size . . . . . . . . . . . . . . . . Injection Techniques Using 99mTc Nanocolloids and/or Blue Dyes in Breast Cancer Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Precision in Tracer Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . Danger of Opening of Capillaries and Venules with Increasing Risk of Hematogenous Cancer Cell Transport . . . . . . . . . . . . . . . . . . . . . Use of Liposomes for Radioimaging Within the Sentinel Node Concept References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60 62 64 65 65 69
Chapter 9 Experience with and Suggestions for Cancer of Different Types and in Different Sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Malignant Melanomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cancers of the Head and Neck and of the Upper Aerodigestive Tract Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastric and Neuroendocrine Cancers . . . . . . . . . . . . . . . . . . . . . . . Colorectal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urogenital Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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71 71 76 80 81 82 83 85 86
Chapter 10 General Techniques in Surgical Investigations . . . . . . . . . . . . . . . . . . . . .
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Initial Remarks on the Histopathology of the Lymphatic System . . . . . Significance of Labeling of the Different Cellular Compartments of the Lymph Nodes for Radiological Diagnosis . . . . . . . . . . . . . . . Critical Points in Blue Dye (Patent Blue) Mapping . . . . . . . . . . . . . . . . Timing in Blue Staining Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . Probe Guidance in Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . Practical Use and Servicing of the Gamma Probe . . . . . . . . . . . . . . . . Good Practice in Combined Use of Dye and 99mTc-labeling Procedures Determination of the SLN's Location and Procedure for Its Excision . . Pitfalls of SLN Labeling and Detection . . . . . . . . . . . . . . . . . . . . . . . . SLN Investigation by Pathologists in Cooperation with Cytopathologists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Handling of Histopathological Procedures . . . . . . . . . . . . . . . . . . . . . . Benefits of Sentinel Node Evaluation Over Primary Axillary Revision . Use of Radiodiagnostic Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . Choice of the Labeled Contrast Solution . . . . . . . . . . . . . . . . . . . . . . . Plans for Improvements to the Quality of the Contrast Media . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89 89 90 91 91 91 92 92 94 94 95 96 96 96 99 99
Chapter 11 Radiation-Detecting Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction and Steps in Development . . . . . . . . . . . . . . . . . . . . . . . Preconditions for Detector Quality . . . . . . . . . . . . . . . . . . . . . . . . . . .
101 102
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Development of the Modern Gamma Camera Systems . . . . . . . . . . . . . Set-up and Function of the Gamma Camera . . . . . . . . . . . . . . . . . . . . Operation of a Digital Gamma Camera System . . . . . . . . . . . . . . . . . . Quality Requirements for Optimal Function of Commercially Available Gamma Probes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New Developments in Gamma Camera Devices . . . . . . . . . . . . . . . . . . Operation-oriented Requirements for the Detection of the SLNs . . . . . Optimizing Gamma Ray Measurement . . . . . . . . . . . . . . . . . . . . . . . . Important Factors in Performance of the Detector . . . . . . . . . . . . . . . . Quality Criteria for Gamma Probes and Dosimetric Consequences . . . . Management of Electromedical Safety . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
105 106 106 108 109 110 110 110
Chapter 12 Quality Criteria of Gamma Probes: Requirements and Future Developments . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction . . . . . . . . . . . . . Quality Criteria . . . . . . . . . . . Radial Sensitivity Distribution Spatial Resolution . . . . . . . . . Sensitivity . . . . . . . . . . . . . . . Shielding . . . . . . . . . . . . . . . . Energy Resolution . . . . . . . . . Display and Acoustics . . . . . . Probe Shape . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . Future Developments . . . . . . . References . . . . . . . . . . . . . . .
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113 113 114 114 115 115 118 118 118 118 120 125
Chapter 13 Statistical Evaluation in Detection of the SLN(s) . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 14 Are the Technical Conditions for SLN Detection Satisfactory? . . . . . . . . . . .
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Investigations of Breast Cancer Cases As a Basic Parameter . . . . . . . . . Detection Rate and Accuracy of SLN Detection in Dependence on Tumor Diameter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
103 104 105
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Chapter 15 Breast Cancer Diagnosis Based on Histopathology and/or Cytopathology Before Sentinel Lymph Node Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . Reasons for Histology/Cytology-based Diagnosis of Breast Cancer Before Sentinel Lymph Node Labeling . . . . . . . . . . . . . . . . . . . . . Routine and Special Histopathological and Cytopathological Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basic Need for Qualified Diagnostic Methods in the Context of the ªSLN Conceptº . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MR Imaging Support of Needle Biopsy for Preoperative Detection of Multifocality and/or Multicentricity of Breast Cancer . . . . . . . . Selective Use of the Different Needle Biopsy Techniques . . . . . . . . . . Advantages of Using Combined Methods . . . . . . . . . . . . . . . . . . . . . Suitability of These Minimally Invasive Diagnostic Methods for Confirmation or Exclusion of Breast Cancer . . . . . . . . . . . . . . Comparison of the Different Needle Biopsy Techniques by Proportion of Correct Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 16 Success of Stereotactic Fine-Needle Aspiration Cytology Depending on Quality of Sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References and Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 17 Use of a Newly Developed Ultrarapid Immunohistochemical Method to Improve Security in Sentinel Node Investigation and Timing in Interdisciplinary Cooperation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Methodical Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technical Procedure for Ultrarapid Immunohistochemistry . . . . Preliminary Experience with Ultrarapid Immunohistochemistry Staining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differences in Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . Planning for the Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 18 ªMicrometastasisº Versus ªMicroinvolvementº . . . . . . . . . . . . . . . . . . . . .
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Does This Discussion Hinder Decision Making? . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
151 153
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Chapter 19 Preoperative Axillary Lymph Node Diagnosis Using Ultrasmall Particles of Iron Oxide Combined with MRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Evaluation of Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lymph Node Staging by Means of USPIO in Lung Cancer Patients . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
157 159 159
Chapter 20 New Strategies and Devices for Combined Radiological and Histological Cancer Diagnosis ± Exclusion or Confirmation . . . . . . . . . . . . . . . . . . . . .
161
Commercially Available Biopsy Systems . . . . . . . . . . . . . . Lorad MultiCare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Minimally Invasive Excision Biopsy Using the ABBI Device Background to Presentation of the Various Devices . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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162 169 169 173 174
Chapter 21 Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
177
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Special Part The Sentinel Node Concept Related to Main Tumor Types and Subtypes: Applicability in Daily Routine Work
Development of the Sentinel Lymph Node Concept (Initial Approaches) Primary- and Lymph Node-detecting Radiodiagnostic Systems Besides Mammography and Ultrasound . . . . . . . . . . . . . . . . . . . . . Role of PET in Breast Cancer Staging . . . . . . . . . . . . . . . . . . . . . . . . . Value of PET in Staging: Conclusions Derived from Positive and Negative Results in Axilla Staging . . . . . . . . . . . . . . . . . . . . . . PET Screening Investigations for Sentinel Node (Axillary) and Systemic Metastasis in Breast Cancer Patients . . . . . . . . . . . . . . Can the ACR-BI-RADS Lexicon Influence the Choice of the Most Adequate Device for Removal of the Breast Lesion? . . . . . . . . . . . . . Sentinel Node Localization in the Different Node Groups . . . . . . . . . . Warning Signals for Our Strategy in SLN Investigation of Breast Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Localization of the SLNs in Multifocal and Multicentric Breast Cancer . Ductal Carcinoma In Situ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gamma Probe Handling in the Operation Room and Sterilization Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
177 179 181 182 182 183 188 205 205 220 228 250
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Chapter 22 Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is the Sentinel Lymph Node Concept Practicable and Acceptable in the Diagnosis and Treatment of Thyroid Cancer? . . . . . . . . . . . . Is FDG-PET Helpful in T- and N-staging of Thyroid Cancer? . . . . . . . . Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter 23 Cancers of the Face, Nose, Pharynx, and Oral Cavity . . . . . . . . . . . . . . . . Head and Neck: Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Significance of PET in Head and Neck Tumor Staging . . . . . . . . . . . Cancers of the Face, Naso-pharynx and Oral Cavity and of the Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dependence of Adjuvant Therapy Regimens in SCCs of the Upper Aerodigestive Tract and the Face on SLN Status . . . . . . . . . . . . . Cancer-infiltrated Cervical Lymph Nodes as Part of a Cancer with Unknown Primary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histology and Cytology of Benign and Malignant Tumors of the Salivary Glands (Mainly of the Parotid Gland) . . . . . . . . . Special Subtypes of Ductal Salivary Gland Cancers . . . . . . . . . . . . . No Need for Discussion of SLN-Dependent Chemotherapy Strategies References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
257 257 257 258 281
283
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283 284
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293 297 298 298
Chapter 24 Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
301
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Initial Laboratory Investigations other than Radiodiagnosis and Histo-/Cytological Analysis to Assure Diagnosis and Subtype of Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Useful Serological Parameters in Confirmation of SCLC . . . . . . . . . . Is N0-status Predictable in Cases with Normal CEA Values and a Tumor Shadow Disappearance Rate of 0.8 or More? . . . . . . . . . . Elimination of Peripheral Noncancerous Lesions and Confirmation of Peripheral (Scar) Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Multicentricity of Lung Cancer: Compatibility with the SLN Concept? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Significance of PET in Staging Lung Cancer . . . . . . . . . . . . . . . . . . . T-staging Supported by FDG-PET . . . . . . . . . . . . . . . . . . . . . . . . . . . N-staging [Search for Cancer-infiltrated SLN(s)] by FDG-PET . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stage Values of PET-CT-MRI Pre-evaluation, Mediastinoscopy and SLN Search in N-staging of NSCLC . . . . . . . . . . . . . . . . . . . . Exclusion of Primary Mediastinal Neoplastic Lesions in Differential Diagnosis Against Mediastinal Metastases of Primary Lung Cancers N-level-dependent Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Skip Metastasis of NSCLC Makes N-staging More Difficult . Comparative Studies of Mediastinal Lymph Node Dissection with Systematic Node Sampling . . . . . . . . . . . . . . . . . . . Is the SLN Concept Helpful in Correct Node Staging? . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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323 327 328
Chapter 25 Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
331
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Exclusion of Nonmalignant, Nonmelanoma Lesions of the Skin . . . . . . Macroscopic Criteria for Malignant Melanoma Development in Pre-existing Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Initial Risk of Tumor Progression, Risk of Recurrence, and Definitive Risk to Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Staging of Malignant Melanoma Based on EORTC Evaluation . In Transit Metastasis, Double or Multiple Drainage, Bypass and Atypical Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interval Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morphological Stages of Development of Malignant Melanoma and Different Main Subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Historical Overview of SLN Diagnosis for Melanomas . . . . . . . . . . . . . Possible Ways of Searching for the Primary in Atypical or Nondermal Localizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Malignant Melanomas of the Anal Circle and the Rectum . . . . . . . . . . Immunohistochemical Support in the Diagnosis of Dysplastic Nevi and Early Invasive Malignant Melanomas . . . . . . . . . . . . . . . . . . . . Possibilities for Cytopathological Confirmation of the Diagnosis of Malignant Melanomas in Cancer-infiltrated Lymph Nodes in Cases with Primarily Undetected Primaries . . . . . . . . . . . . . . . . . . . . . . . Exclusion of Systemic Disease in Malignant Melanoma Cases and N-staging Supported by FDG-PET . . . . . . . . . . . . . . . . . . . . . . Accumulating Experiences in Sentinel Node Detection in Malignant Melanomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Final Version of the Staging System for Cutaneous Melanomas . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chapter 26 Esophageal and Gastrointestinal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . Current Status of International Research Activity: an Overview . . . . Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N-staging Concepts Deviating from the Common Sentinel Node Concept in Esophageal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . Relative Value of FDG-PET ± Summary . . . . . . . . . . . . . . . . . . . . . Conclusions Based on the Current Status . . . . . . . . . . . . . . . . . . . . Adenocarcinoma of the Esophagogastric Junction, Including Typical ªCardia Carcinomaº . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
331 331 331 332 333 335 336 337 339 341 342 343 343 345 347 360 362
369
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369 370 371
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Relevance of c-erb B1±3 Oncogene Overexpression for Suggestions About the Regional Lymph Node Status in Gastric Cancer Patients Colorectal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FDG-PET in Detection and Staging of Colorectal Cancer . . . . . . . . . . Up-staging by Focused Analysis of SLNs in Cancers of the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adjuvant Therapy Regimens in CRC Depending on the Sentinel and General Lymph Node(s) Status . . . . . . . . . . . . . . . . . . . . . . . FDG-PET in the Diagnosis of Pancreatic Cancer . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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380 386 387
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393
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396 396 397
Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors . . . . . . . . . . . . . . .
401
Origin, Development and Definitions Pertaining to the Neuroendocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology of Carcinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level of Malignancy of Carcinoids and Other Neuroendocrine Tumors (General Overview) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods of Confirming the Neuroendocrine Character and the Specific Subtype of these Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is the SLN Concept Generally Applicable in the Case of Neuroendocrine Tumors? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early Experience with 111In-pentetreotide . . . . . . . . . . . . . . . . . . . . . . Clinical Significance of Blood Chromogranin . . . . . . . . . . . . . . . . . . . Is PET Helpful in Preoperative N-staging of Aggressive Neuroendocrine Tumors? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preliminary Results in FDG-PET Staging of Neuroendocrine Tumors of the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is Determination of Somatostatin Receptor Subtypes (sstr 1±5) in Biopsies Helpful in Sentinel Node Search Strategies and Subsequent Therapy Planning? . . . . . . . . . . . . . . . . . . . . . . . . Special Problems in Documentation of Early Lymphatic Spread of Neuroendocrine Cancers in the Upper Abdominal Region . . . . . . Strategies to Discriminate Between Gastrointestinal, Pancreatic, and Pulmonary Carcinoids in Metastatic Tissues (Lymph Nodes, Liver) . Characteristics and Spectrum of Neuroendocrine (Carcinoid) Tumors of the Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics and Spectrum of Neuroendocrine (Carcinoid) Tumors of the Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lymphogenic Metastasis (Rough Overview) . . . . . . . . . . . . . . . . . . . . Histopathology and Immunohistochemical Confirmation of Gastric Carcinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detection of Stomach Carcinoids by Means of Somatostatin Receptor Scintigraphy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and Morphological Correlations of Gastric Carcinoids . . . . . . Localization and Spectrum of Carcinoids of Small Intestine and Colon Carcinoids of the Colon, Especially of the Rectum, and Search for Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lymphatic Basins and SLN Positions Corresponding to Carcinoids Located in Small Intestine and Colon . . . . . . . . . . . . . . . . . . . . . . .
401 401 403 404 404 404 405 405 406 406 407 407 408 409 409 409 410 411 412 412 412
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Influence of Hematogenous Spread on Survival . . . . . . . . . . . . . . . . . Treatment Strategies in Gastrointestinal Carcinoids . . . . . . . . . . . . . . Endocrine Tumors of the Pancreas and Duodenum . . . . . . . . . . . . . . Macroscopic, Histopathological and Immunohistochemical Subtyping of Pancreatic Endocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . Spectrum of Neuroendocrine Tumors of the Lung . . . . . . . . . . . . . . . Is Preoperative Sentinel Node Imaging Helpful in Increasing the Cure Rates in Neuroendocrine Lung Tumors? . . . . . . . . . . . . . Neuroendocrine Tumors of the Retroperitoneum and the Prevertebral Thoracic and Cervical Region . . . . . . . . . . . . . . . . . . . . . . . . . . . Peripheral Neuroendocrine Cancers Located Subepidermally or Deeper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroendocrine Cells in Carcinomas . . . . . . . . . . . . . . . . . . . . . . . . Search for Metastases in Neuroendocrine Tumors Before Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Developments in Detection of Neuroendocrine Cancers and their Metastases in SLNs using 111In-labeled and 123I or 131I Compounds Adjuvant Therapy Regimens in the Treatment of Neuroendocrine Tumors Related to the Sentinel and General Lymph Nodes Status . Targeting in Medullary Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . The SLN Approach in Neuroblastomas . . . . . . . . . . . . . . . . . . . . . . . Strategies in Neuroblastoma in General and in Dependence on the Lymph Node Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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413 413 414
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425 426 426
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Chapter 28 The Sentinel Node Concept in Cancers of the Female Genitalia . . . . . . . . .
431
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vulvar Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acceptance of the SLN Concept in Vulvar Cancer Treatment? Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems in Local Administration of Labeling Solutions . . . Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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431 431 434 434 435 435 437
Chapter 29 Cancers of the Male Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
439
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Sentinel Lymph Node Identification in Penile Cancers . . . . . . . . . . . . . Treatment Strategies in Premalignant and Occult Malignant Lesions . . Labeling the SLNs in Penile Cancers by Application of 99mTc-Nanocolloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Testicular Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Main Macroscopic and Microscopic Features of Malignant Testicular Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological Prognostic Factors: Implications for Risk-adjusted Therapy Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Initial, Meanwhile Obviously Abandoned, Approach to Retroperitoneal (Sentinel) Node Labeling in Testicular Cancer . . . . . . . . . . . . . . . . .
439 440 440 442 442 444 445
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Can Radiotherapy or Chemotherapy be at Least Partly Replaced by More Accurate Stage-related Surgical Treatment? . . . . . . . Is FDG-PET Helpful in N-staging of Germ Cell Tumors (SGCT and NSGCT)? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prospective Views . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Chapter 30 Prostate Cancer: an Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
449
General Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serum Values of Prostate-specific Antigen and Prostate Acid Phosphatase as Indicators for Cancer, Metastatic Spread and Cancer Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition of the Degrees of Malignancy in Gleason's Grading Scoring System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Correlations with Molecular Biological and Clinical Parameters . . . . . . Importance of Tumor Volume to Clinical Significance in Treatment of Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Relation Between Dysplasia and Cancer . . . . . . . . . . . . . . . . . . . . . . . Gleason Score (Grading) in Ultrasound-guided Biopsies Related to Results in Prostatectomy Specimens . . . . . . . . . . . . . . . . . . . . . . Simultaneous Lymphogenous and Hematogenous Metastatic Spread? . . Significance of Degree of Malignancy and Number of Biopsies Taken for N-staging and the Sentinel Lymph Node Concept . . . . . . . . . . . Is the Primary Cancer Detection Rate Higher with Twelve Biopsies than with Six? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basic Research for Complete Pelvic Lymph Node (N-) Staging . . . . . . . Is Laparoscopic Lymph Node Staging Equivalent to Open Pelvic Lymph Node Dissection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intraoperative and Postoperative Lymph Node Staging in the Treatment of Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is Whitmore's Staging Scheme Established in 1984 Still Compatible with Our Current Knowledge? . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of a SLN Concept in Relation to Tumor Stages . . . . . . . . Current Survival Rates as a Measure of Improvements in Lymph Node Staging and Clearance by the Sentinel Node Concept . . . . . . . Does Radical Prostatectomy Improve the Results in Lymph NodePositive Cases (D1)? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . In Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wawroschek's, Vogt's and Harzmann's First Approach to Detection of Sentinel Nodes in Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . Experiences of the Augsburg Research Group . . . . . . . . . . . . . . . . . . . Performance of the Labeling Procedure in Prostate Cancer Cases . . . . . Detection of the SLN(s) after 99mTc-nanocolloid Labeling . . . . . . . . . . Removal of Labeled Lymph Nodes from the Paraprostatic, Iliac, Obturator, and Retrocolic Basins . . . . . . . . . . . . . . . . . . . . . . . . . . Is FDG-PET Helpful in Detection and N-staging of Prostate Cancer? . . Can Sentinel Node Labeling be Improved According to Animal Experimental Studies? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
449 449 449 451 455 455 456 457 458 459 459 463 463 464 466 467 469 469 470 473 474 474 474 477 477 477
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Chapter 31 Cancers of the Urinary Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urinary Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . First Attempts at Detection and Clearance of Sentinel Nodes before Cystectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging by Means of Positron Emission Tomography in Urinary Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal Cell Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging before Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . Lymph Drainage of RCC Differs with Laterality . . . . . . . . . . . . . . . . Cytology of RCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lymph Node Staging in RCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ªChecklistº of Possible Methods of Lymph Node Investigation . . . . . Do Immunohistochemically Detectable Prognostic Factors have Significance for Treatment Strategies Including the Search for Sentinel Lymph Nodes? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detection of SLNs by Cancer-specific Immune Response? . . . . . . . . Is there a Benefit of Extensive Lymphadenectomy over Sampled Lymphadenectomy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is Retroperitoneal Lymphadenectomy Helpful in Extending Survival in Patients with Hematogenous Metastases from RCC? . . . . . . . . Adrenal-sparing Surgery in Cases with RCC . . . . . . . . . . . . . . . . . . Proposal for Sentinel Node Labeling in RCCs . . . . . . . . . . . . . . . . . Can FDG-PET Help in N-staging of RCC and Bladder Cancer? . . . . . Laparoscopic Retroperitoneal Partial and Radical Nephrectomy in RCCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Use of Microwaves as a Styptic in Partial Nephrectomy . . . . . . . . . . Adjuvant Therapy Regimens in Cases with Metastatic RCC . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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481 481
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491 492 492 493
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494 494 494 495
Chapter 32 Closing Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
499
Technical News . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
501 502
Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
503
Adjuvant Chemotherapy Regimens for Breast Cancer Therapy Regimens for Thyroid Cancer . . . . . . . . . . Therapy Regimens for Head and Neck Cancers . . . . Chemotherapy Regimens for Lung Cancer . . . . . . . Therapy Regimens for Esophageal Cancer . . . . . . . . Chemotherapy Regimens for Gastric Cancer . . . . . .
504 509 510 513 517 518
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Contents
Therapy Regimens for Colorectal Cancers . . . . . . . . . . . . . . . . . . Therapy Regimens for Neuroendocrine Tumors . . . . . . . . . . . . . Therapy Regimens for Neuroblastoma . . . . . . . . . . . . . . . . . . . . Therapy Regimens for Malignant Melanoma . . . . . . . . . . . . . . . . Therapy Regimens for Soft Tissue Tumors . . . . . . . . . . . . . . . . . Therapy Regimens for Renal Cell Cancer . . . . . . . . . . . . . . . . . . Therapy Regimens for Prostate Cancer . . . . . . . . . . . . . . . . . . . . Therapy Regimens for Vulvar Cancer . . . . . . . . . . . . . . . . . . . . . Therapy Regimens for Cervical Cancer . . . . . . . . . . . . . . . . . . . . Therapy Regimens for Urinary Bladder Cancer . . . . . . . . . . . . . . Adjuvant Therapy for Prevention of Severe Neutropenia, Possibly followed by Infections . . . . . . . . . . . . . . . . . . . . . . . . New Approaches to Halting Cancer Cell Spread by Immunological Blockade of Neoangiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . References and Recommended Further Reading . . . . . . . . . . . . .
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520 522 525 529 530 531 533 535 536 538
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541
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541 542
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
553
XXV
Introduction
The intention of both providing an overview and at the same time giving practical advice about how to approach the development of a ªsentinel lymph-node detecting conceptª has been concentrated to a high degree on development of the technical requirements (Keshtgar et al. 1999; Krag et al. 1993, 1998, 1999) to allow handling of this problem on a basis of interdisciplinary cooperation among surgeons (abdominal and thoracic surgeons, gynecologists, dermatological and plastic surgeons, ear, nose and throat surgeons, urologists) radiologists, specialists in nuclear medicine, and pathologists. Now, however, it is time to reflect on the experiences collected so far and, on the basis of these, on future possibilities of wider application of the concept. Sentinel node detection in breast cancer and malignant melanoma and also in various other tumor types can be seen in a positive light under the two main aspects of a) Detecting the real first station in the regional lymphatic basin b) Avoiding unnecessary extensive regional lymphadenectomy with all its unfavorable consequences in patients whose sentinel lymph nodes are tumor free. In practicing the sentinel lymph node concept and checking for delineation of its applicability it seems clear that preoperative cancer detection in a single (sentinel) node or in a node group in the regional basins by means of CT, MRI, FDG-PET, or somatostatin receptor scintigraphy makes the more difficult search for sentinel node(s) with blue stain and 99mTc unnecessary. The development of sophisticated medical concepts and devices and their applications started as long ago as the early 1990s. Therefore, the experience in many clinics is based on 7±10 years of practical work. Because the use of the classic fully developed and established systems (99mTc-nanocolloid and blue dye techniques) had already proved successful in breast cancer and melanoma treatment, developments aimed at new diagnostic approaches to other tumors have lately been initiated. In the efforts and developments of recent years the aim was not only to detect the localization of the sentinel lymph node reliably and more precisely, but also, at least for some, to find a way to evaluate whether the nodes are cancer infiltrated even before performing any surgery. Radioimmunological techniques using specific monoclonal antibodies were and are used in the development and pursuit of these aims. In order to pass on the current scientific knowledge of precise regional sentinel lymph node detection as the basis for further successful developments with the contents of this book, first of all an up-to-date overview of the methods and devices used thus far and of the special techniques used by
XXVIII Introduction
the collaborating disciplines will be given, followed by a description of applications related to the different tumor types appropriate to the various surgical disciplines. We hope that a comprehensive and up-to-date overview will be a helpful starting point for further important developments. The concepts of cancer treatment are adapted to the tumor stages (pTNMsystem) and in recent years have also been strongly influenced by evaluable prognostic factors peculiar to individual neoplasms. Therefore, besides the existing guidelines for the primary diagnostic concepts, we have to ask about the therapeutic implications of positive or negative results of the sentinel lymph nodes(s) examination. This is considered at the end of each tumor-specific chapter, and answers about changes that can be made to therapy when the sentinel lymph node(s) is/are found to be cancer infiltrated are attempted. In addition, the precise therapy regimens with dosages are summarized in tables and published in the final chapter for use in the daily practice.
References Keshtgar MRS, Waddington WA, Lakhani SR, Ell PJ (1999) The sentinel node in surgical oncology. Springer, Berlin Heidelberg New York Krag DN, Weaver DL, Alex JC, Fairband JT (1993) Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 2:335± 339; discussion 340 Krag D, Weaver D, Ashikaga T, Moffat F, Klimberg VS, Shriver C, Feldman S, Kuisminsky R, Gadd M, Kuhn J, Harlow S, Beitsch P (1998) The sentinel node in breast cancer ± a multicenter validation study. N Engl J Med 339:941±946 Krag DN, Ashikaga T, Harlow SP, Weaver DL (1999) Development of sentinel node targeting technique in breast cancer patients. Breast 4:67±74
General Part
Chapter 1
Definition of the Sentinel Lymph Node and Basic Principles of Detection
The sentinel lymph node (SLN) is defined as the first regional lymph node to receive lymphatic fluid from a malignant tumor. Therefore, this node is a ªsentinelº for second metastatic lymph node stations and for labeling regional tumor spread. (For editorials and overviews see: Veronesi et al. 1997; Dixon 1998; della Rovere and Bird 1998.) This node is useful for locoregional tumor staging and for subsequent individual related further surgical strategies. In some ways, this has been a logical development after the more or less successful use of lymphangiography by many radiologists in the 1970s. This older method has been used to detect cancer metastases or infiltration of lymph nodes, for example in cases of prostate or bladder cancer as well as in Hodgkin or non-Hodgkin lymphomas. The lymphangiographic signs indicating tumor infiltration were filling defects or distorted architecture within the lymph nodes and interruption of lymphatic vessels. Pathologic lymphangiography findings in regional or distant node groups were utilized to assess lymphatic tumor spread. Recently, labeling of the SLN or nodes for tumor staging and locoregional surgical clearance has been developed or its development has started. This means that the detection of the first node or nodes of a particular tumor may be involved in the lymphogenic spread of the primary, and if this is so more extensive regional lymphadenectomy can follow. When the SLN is negative on pathohistological examination extensive lymphadenectomy can be avoided. This staging procedure has been developed for the following tumor categories: breast cancer (already used in many clinics, but in others still in development); malignant melanomas (already well developed); lung tumors; gastrointestinal tumors and head and neck tumors (discussion and preliminary approaches in progress). In addition, new approaches for tumors of the pelvis (cervix, penis, bladder, prostate, etc.) are also under discussion, as is node labeling of neuroendocrine tumors.
Lymphatic mapping techniques have several objectives, but no generally accepted and practiced uniform concept is universally available. So far, three strategies for detection of sentinel nodes have been proposed: · Labeling of the sentinel node(s) with a dye, such as ªpatent blue,º to identify draining lymph vessels and the position(s) of the first regional lymph node(s), which are then surgically removed and examined by the techniques of histology, immunohistochemistry (IHC) and/or the polymerase chain reaction (PCR) (Min et al. 1998); · Labeling of the sentinel node(s) by 99mTc-colloid scintigraphy; · Sophisticated nuclear medicine and radiological methods: ± Increased glucose metabolism using [F18]FDG-PET (fluor-18-fluorodeoxy-d-glucose positron emission tomography) to localize increased metabolism in regional small (< 1 cm) lymph nodes (Adler et al. 1997). ± New development of radioimmunolabeling or peptide labeling with surface or cytoplasmic markers (e.g., extracellular domain of Her2/ Neu oncoprotein (p185) or EGFR; CEA, gastrin, somatostatin receptors) (Schauer et al. 1990, 1992; Marx et al. 1990; Borg et al. 1991). No systematic investigations on these lines have so far been published, and these markers can only be used when an initial aspiration biopsy has identified the tumor as positive specifically for these. ± Tissue-specific magnetic resonance imaging (MRI) contrast agents for the reticuloendothelial system, such as superparamagnetic iron oxide nanoparticles (Sinerem or AMI 227), which are presently being investigated in clinical trials for detection of lymph node metastasis (Weissleder et al. 1990 a, b, 1994) (see also chapter 19).
1
4
Chapter 1 Definition of the Sentinel Lymph Node and Basic Principles of Detection
Such investigations of SLNs can help to detect metastatic infiltration while it is still in situ before gamma probe imaging analysis. With these methods, neoplastic infiltration of the lymph nodes can even be detected in palpatory negative sentinel basins. It seems to be clear from the start that these new techniques must be measured in terms of their false-negative rates. The main questions connected with the significance of localization of a SLN are: · Can a SLN be defined so as to have significance for primaries with different localizations? · How is it possible to label the node preoperatively without influencing the primary tumor, especially by the opening of veins that can be caused by increased local pressure or necrosis, for example after the injection of contrast media, which can induce hematogenous metastatic spread? · Is biopsy of sentinel node(s) efficient in detecting occult metastases and does it have the potential for selecting patients who may benefit from sentinel node dissection alone? · Is investigation of the sentinel node really significant in avoidance, for instance, of extended axilla revision in breast cancer patients (levels I and II) in sentinel node-negative cases? · What is the best method of SLN detection and investigation? · What are the consequences of positive or negative results of investigation of the sentinel node? · Does SLN investigation, with avoidance for instance of axilla revision in negative cases, have to be included in the matters discussed with the patient and listed in the informed consent provided by the patient?
References Adler LP, Faulhaber PF, Schnur Kc, Al-Kasi NL, Shenk RR (1997) Axillary lymph node metastases: screening with (F-18)2-deoxy-2-fluoro-d-glucose (FDG) PET. Radiology 203:323, 327 Borg A, Baldetorp B, Fernæ M, Killander D, Olsson H, Sigurdson H (1991) ErbB2 amplification in breast cancer with high rate of proliferation. Oncogene 6:137±143 Borgstein PJ, Pijpers R, Comans EF, van-Diest PJ, Boom RP, Meijer S (1998) Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J AM Coll Surg 186:275± 283 Dixon M (1998) Sentinel node biopsy in breast cancer. BMJ 317:295±296 Marx D, Schauer A, Reiche C, May A, Ummenhofer L, Reles A, Rauschecker HF, Sauer R, Schumacher M (1990) cerbB2-expression in correlation to other biological parameters of breast cancer. J Cancer Res Clin Oncol 116:15± 20 Min CJ, Tafra L, Verbanac KM (1998) Identification of superior markers for polymerase chain reaction detection of breast cancer metastases in sentinel lymph nodes. Cancer Res 15(58):4581±4584 Rovere G della, Bird PA (1998) Sentinel lymph node in breast cancer. Lancet 352:421±422 Schauer A, Marx D, Ummenhofer L, Rauschecker H, Gatzemeier W, Sauer R, Schumacher M, Sauerbrei W (1990) Die Multicenter Studie ¹Kleines Mammacarcinom. Vorlåufige Ergebnisse ± Neue Aspekteª. Dtsch Ørzteblatt 87:3628±3638 Veronesi U, Paganelli G, Galimberti V, Viale G, Zurrida ST, Bodeni N, Costa A, Chicco C, Geraghty JG, Luine A, Sacchini V, Veronesi P (1997) Sentinel node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 349:1864±1867 Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH, Josephson L (1990 a) Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology 175:489±493 Weissleder R, Elizondo G, Wittenberg J, Lee AS, Josephson L, Brady TJ (1990 b) Ultrasmall superparamagnetic iron oxide: an i.v. contrast agent for assessing lymph nodes with MR imaging. Radiology 175:494±498 Weissleder R, Heautot JF, Schaffer BK, Nossiff N, Papisov M, Bogdanov AJ, Brady T (1994) MR lymphography study of a high efficiency lymphography agent. Radiology 191:225±230
Chapter 2
Main Techniques of Sentinel Lymph Node Labeling
Two main technical principles are currently followed in labeling sentinel nodes: the two techniques can be used separately, but may also be combined. · Noncarcinogenic inert blue dye (patent blue) injection. ± The blue staining method with methylene blue or patent blue or other stains shows up the paths of the lymphatics from the primaries to the nodes. However, the disadvantages, especially in the areas surrounding the primary, are the general blue staining of all regional tissues (tumors, fibrous and fat tissue). This diffuse staining disturbs the overview, especially for the pathologists (see also Bachter et al. 1996, 1998). · Radiocolloidal labeling (99mTc-nanocolloidals). ± A review of success rates as published by the Board of the New England Journal of Medicine showed that a combination of both methods provided best results (McMasters et al. 1998). Tracers have been injected peritumorally, subcutaneously or intradermally (in breast cancer) (Borgstein et al. 1997, 1998; McIntosh et al. 1998). The 99mTc-nanocolloid method is a nuclear medicine procedure which involves exposure of the patient and, principally, of the staff in the department of nuclear medicine and the operating room and of the pathologist to radiation. The radioactive tracer is normally injected in the nuclear medicine department, where all suitable facilities exist for its administration and for the safe handling and disposal of the radioactive waste produced. Sentinel node scintigraphy is a low-activity procedure for a regular nuclear medicine department. The patient's radiation exposure is about 0.32 mSv per examination. Radiation doses arising from the sentinel node technique compare with a range of natural and man-made sources and statutory dose limits (data
2
obtained from the National Radiological Protection Board (NRPB) (International Commission on Radiological Protection 1990) (Table 1).
Good Practice for Radiation Protection in the Operating Room The patient is usually scheduled for operation approximately 24 h after tracer administration. When radioactive decay is taken into account, this results in retention of between 1 and 10 MBq activity at the injection site by the time the operation is performed. As detailed earlier, with the exception of the sentinel node and other axillary lymph nodes demonstrating a similar level of tracer uptake, there will be a negligible distribution of radioactivity outside the injection site. Specifically, there is an absence of detectable radioactivity both in the general circulation and in unrelated body tissues. The possibility of radiation risk, however remote, must be considered: potentially, both internal and external radiation exposure may arise. Staff may be irradiated by virtue of their proximity to the radioactive patient and may also come into direct Table 1. Source of radiation exposure/relevant legislative limits Radiation dose (mSv) Sentinel node technique (breast carcinoma)
0.32
Return flight: London to New York (dose from cosmic rays)
0.06
Return air flight: London to Sydney (dose from cosmic rays)
0.20
One year's residence in Denver, Colorado, USA (additional radiation dose from cosmic radiation at higher altitude)
0.88
6
Chapter 2 Main Techniques of Sentinel Lymph Node Labeling Table 2. Calculations of radiation doses to the surgeon (Waddington et al. 2000)
a
Dosage of nanocolloid to breast
Performance of SLN operation 24 h after injection a
Performance of tumor and SLN operation 24 h after injection a
15 MBq
Whole body 0.21 lSv
Whole body 0.47 lSv
Finger 0.06 mSv
Finger 0.12 mSv
Increase > 4 lSv/h when the operation was performed 4 h after injection
Table 3. Values for radiation exposure of surgical staff evaluated by Institute of Physical Sciences in Medicine (1991) and Keshtgar et al. (1999) Dosage
10 MBq (unshielded)
At time of surgery Treatment at 1 m distance
Treatment at 30 cm distance
Whole body 0.21 lSv
Finger 0.06 mSv
Implication of 500 surgical SLN operations 1 mSv
Table 4. Radiation dose to the breast referred to injected volume (modified from Eshima et al. 2000) Injection volume (ml)
Dose (mGy/MBq)
0.48
160
0.96
87
1.92
44
3.85
23
5.77
15
Table 5. Radiation dose to staff (15 MBq, 24 h p.i.). (Modified from Waddington et al. 2000) Procedure
Organ
Probe
Dose Op. (nSv)
18 h (nSv)
36 h (nSv)
21.1 (1.05)
2.64 (0.13)
Immediate analysis 45'
WB
Primary SN
127 (6.33)
Processing 60'
WB
Primary SN
169 (8.44)
Close contact 15/5'
Finger
Primary SN
39.8 (6.64)
4.98 (83.0)
0.62 (10.4)
Microscope 15'
Lens
Primary SN
42.2 (2.11)
5.27 (0.26)
0.66 (0.03)
contact with the radioactive tracer in vivo, with any excised radioactive tissue specimen, or with contaminated dressings, drapes or operating room equipment (Barres et al. 1992). The maximum activity retained within the injection site at the time of operation will be approximately 10 MBq 99mTc. Exposure to an unattenuated (i.e. unshielded) radioactive source containing this activity will effect a radiation dose rate of 0.17 ´ 10±6 Sv (0.17 lSv)/h at a distance of 1 m from the source, and of 1.8 lSv/h
at 30 cm [dose rate data obtained from the Institute of Physical Sciences in Medicine (IPSM, 1991)] (vril et al. 1996, 1997). For each surgical procedure, a typical total exposure time to the tissue containing the injection site of 1 h, at the lesser distance, will result in a maximum radiation dose to the surgeon(s) involved of approximately 1.8 lSv per patient procedure. In the UK, the maximum permitted annual radiation dose to a member of the public (which also means any member of staff not formally
Radioactivity Monitoring
designated a radiation worker) was reduced to 1 mSv (ICRP 60) (International Commission) in the year 2000, allowing approximately 500 sentinel node procedures to be performed per year according to the protocol detailed in this text before the individuals exposed approach this annual dose limit. It is therefore clear that there is a very low external radiation hazard to members of staff. One circumstance requiring extra consideration may be that of the pregnant female surgeon or scrub nurse; when staff perform or assist at this procedure regularly, specifically lower dose limits have to be observed for any who are pregnant in order to minimize the radiation dose, and especially that to the fetus. Thus, personal radiation badges issued to staff would be useful in resolving the exact significance of this issue, given the individual local circumstances of both workload and surgical protocols (Keshtgar et al. 1999). Waddington et al. (2000) found that 95±99% of the tracer applied remained at the site of injection, with residual activity in the lymphatic basin even 24 h after the injection. In contrast, the systemic uptake calculated from blood measurements amounted to only 0.73% of the injected dose (Waddington et al. 2000). When 15 MBq 99mTc-nanocolloid was administered the effective dose equivalent was calculated to be 1 ´ 10±2 mSv/MBq overall to the patient and 7.2 ´ 10±1 mSv/MBq to the breast. Eshima et al. (2000) investigated the significance of the injected volume for radiation exposure of the breast. Based on the assumption that the radioactivity is retained in a distinct area of the breast without diffusion to the other parts, they showed that breast radiation exposure can be reduced to one tenth by using a tenfold volume of tracer solution. Tables 2±5 give an exact overview of exposure of the patient's breast and of medical staff to radiation doses in relation to the volume administered and the duration of exposure at different times after injection.
Radioactivity Monitoring Results of Measurements in Staff Members at the Royal Free University and Medical School, London The Royal Free Nuclear Medical Institute data resulting from control measurements have been published in a paper with Waddington (2000) as the main author, and their experience is as follows Minimal tracer migration
95% (retention at the injection site)
Dosage resulting for the patient (mean dose at the breast)
2 ´ 1 ´ 10±2 mS/MBq 7 ´ 2 ´ 10±1 mGy/MBq
Mean whole-body dose to 0.34 lSv surgical staff per procedure Mean finger dose
0.09 mSv (90 lSv)
Pathology staff, predominantly below measurable levels
Relevant doses only when a large number of cases are analyzed promptly
Observed contamination of the floor in the operating room (Waddington et al. 2000)
Up to 22% of the doses administered found in swabs!
Attempts to label cancer-infiltrated regional nodes by scintigraphy using monoclonal antibodies have had very little success, because it was not possible to detect micrometastases. Antibodies against tumor-specific antigens (SM3, mAb 170 H.82 or 99mTc-labeled anti-CEA Fab fragment) demonstrated sensitivity amounting to up to 80% in detection of cancer-infiltrated lymph nodes (Dessureault et al. 1997; Limouris et al. 1997; Britton et al. 2000; Goldenberg et al. 2000). In contrast to these results, however, 18FFDG-PET and scintigraphy with such nonspecific tracers as 99mTc-sestamibi or tetrofosmin showed promising results in advanced tumor stages, with up to 95% sensitivity, but failed to yield accurate lymph node status evaluation in pT1 stages (vril et al. 1996; Adler et al. 2000; Yutani et al. 2000).
7
8
Chapter 2 Main Techniques of Sentinel Lymph Node Labeling
Good Radiation Protection Practice in the Pathology Laboratory Histopathology staff members can also potentially be exposed to both internal and external radiation by virtue of their work practices. However, the initial sample preparation is typically very rapidly executed and should therefore present little scope for any measurable radiation exposure. Subsequent to this initial stage, preparatory fixing of the specimen in formalin for a period of not less than 48 h will lead to a reduction in the radioactive content of the specimen by a factor of approximately 250. Thus, normal histological analysis of multiple tissue samples entails negligible further exposure to radiation. After a total of 1 week's storage, all tissue specimens will have decayed so that they will now contain less than 1 Bq activity and may safely be disposed of as nonradioactive waste. New approaches to MR lymphography are in progress (Anzai et al. 1994; Vassalo et al. 1994; Bengele et al. 1994; Harika et al. 1995; Palmacci and Josephson 1996; Mussurakis et al. 1997). The new element in radiologic diagnosis is the use of Sinerem (Guerbet, France), a tissue-specific contrast agent used in MRI. This new agent, which is currently in phase III of clinical development, contains iron oxide nanoparticles surrounded by lowmolecular-weight dextran. A smaller particle size than that of the established liver-specific contrast agent Endorem (Guerbet, France), which is taken up by reticuloendothelial cells of the liver (Kupffer cells), enables Sinerem to cross the capillary wall and ultimately to be taken up by the mononuclear phagocytic system (MPS) of lymph nodes (see long-term work carried out by Weissleder's group (Weissleder et al. 1988, 1989 a, b, 1990 a, b, 1994, 1996; Jung et al. 1996). Preliminary work was also performed by Brady and Ferrucci (1987). Apart from the development of X-ray lymphangiography in the late 1970s, the new generation of MRI contrast agents targeting the MPS represents the primary approach by radiologists to examine lymph nodes in a functional, and no longer in a purely morphologic, manner. Several clinical studies have shown a significant signal increase in normal or inflammatory lymph nodes, whereas metastatic lymph nodes have shown no significant uptake of the contrast agent. Sinerem has to be administered by i.v. infusion outside of the MRI scanner after a non-contrast-enhanced baseline exami-
nation. The postcontrast images can be obtained in a time-window of 6±24 h. It must be stressed that the method of i.v. lymph node contrasting does not allow specific visualization of sentinel lymph nodes (SLN); the SLN can only be identified by staff with adequate anatomical knowledge. Trials to identify SLN and lymphatic drainage by means of the s.c. administration of ultrasmall iron oxide particles (USPIO) have been reported, but mostly in animal studies (Rogers et al. 1998). However, some clinical study programs are already in progress (see chapter 19). F-18-FDG-PET has advantages: besides the imaging of the primary tumor, PET allows localization of metastases in an acceptable proportion of cases. Small lesions, even those with a diameter of 3±5 mm, can be detected with F-18-FDG-PET. However, when lesions are smaller it gives falsenegative results. Thus, sentinel node detection and a pathological work-up are always necessary in tumors that are negative according to PET. In cases positive for FDG uptake the diagnostic accuracy is very high (see also chapter 5). Several points still require discussion with respect to the different techniques. First of all, it must be pointed out that attempts at interdisciplinary management can only be successful with optimal performance of all disciplines involved in such evaluation programs (surgeons, specialists in nuclear medicine and/or radiodiagnosis, and pathologists), because the initial locoregional operative work and the histological evaluation of lymph node material must be optimal.
References Adler LP, Faulhaber PF, Schnur KC, Al-Kasi NL, Shenk RR (2000) Axillary lymph node metastases: screening with (F-18)2-deoxy-fluoro-d-glucose (FDG) PET. Radiology 203:323±327 Anzai Y, Blackwell KE, Hirschowitz SL, Rogers JW, Sato Y, Yuh WTC, Runge VM, Morris MR, McLachlan SJ, Lufkin RB (1994) Initial clinical experience with dextran-coated superparamagnetic iron oxide for detection of lymph node metastases in patients with head and neck cancer. Radiology 192:709±715 vril N, Dose J, Jånicke F, Ziegler F, Ræmer W, Weber W, Herz M, Nathrath W, Graeff H, Schwaiger M (1996) Assessment of axillary lymph node involvement in breast cancer patients with positron emission tomography using radiolabeled 2-(fluorine-18)-fluoro-2-deoxy-d-glucose. J Natl Cancer Inst 88:1204±1209
References vril N, Bense S, Ziegler SI, Dose J, Weber W, Laubenbacher C, Ræmer W, Jånicke F, Schwaiger M (1997) Breast imaging with F-18 fluorodeoxyglucose PET: quantitative image analysis. J Nucl Med 38:1186±1191 Bachter D, Balda BR, Vogt H, Bçchels H (1996) Die ªsentinelº Lymphonodektomie mittels Scintillationsdetektor. Hautarzt 47:754±758 Bachter D, Balda BF, Vogt H, Bçchels H (1998) Primary therapy of malignant melanomas: sentinel lymphadenectomy. Int J Dermatol 37:278±282 Bares R, Mçller B, Fass, J, Buell U, Schumpelick V (1992) The radiation dose to surgical personal during intraoperative radioimmunoscintimetry. Eur J Nucl Med 19:110±112 Bengele HH, Palmacci S, Rogers J, Jung CW, Crenshaw C, Josephson L (1994) The biodistribution of the USPIO BMS 180549 by radioactive studies. Magn Reson Imaging 12:1161±1165 Borgstein PJ, Pijpers R, Comans EF, van-Diest PJ, Boom RP, Meijer S (1998) Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 186:275± 283 Brady T, Ferruci J (1987) Ferrite particles: a superparamagnetic MR contrast agent for the reticuloendothelial system. Radiology 162:211±216 Britton KE, Al-Yasi AR, Biassoni L, Carroll MJ, Granowska M (2000) Efficacy of immunoscintigraphy for detection of lymph node metastases. Recent Results Cancer Res 157:3±11 Dessureault S, Koven I, Reilly RM, Couture J, Schmocker B, Daman Kirsh J, Ichise M, Dislofsky S, McEvan AJ, Boniface G, Stern H, Gallinger S (1997) Preoperative assessment of axillary lymph node status in patients with breast adenocarcinoma using intravenous 99mtechnetium mAB170H.82 (Tru-Scint AD). Breast Cancer Res Treat 45:29±37 Eshima D, Fauconniour T, Eshima L, Thornback JR (2000) Radiopharmaceuticals for lymphoscintigraphy: including dosimetry and radiation considerations. Semin Nucl Med 30:25±32 Goldenberg DM, Abdel-Nabi H, Sullivan CI, Serafini A, Seldin D, Barron B, Lamki L, Line B, Wegener WA (2000) Carcinoembryonic antigen immunoscintigraphy complement mammography in the diagnosis of breast carcinoma. Cancer 89:104±115 Goldstone KE, Jackson PC, Myers MJ, Simpson AE (eds) (1991) Radiation protection in nuclear medicine and pathology. (Report no 63 of the Institute of Physical Sciences in Medicine.) IPSM, York Harika L, Weissleder R, Poss K, Zimmer C, Papisov M, Brady TJ (1995) MR lymphography with a T1-type MR contrast agent: 6d-DTPA-P6M. Magn Reson Med 33:88±92 Institute of Laboratory Animal Resources, Commission of Life Sciences, National Research Council (1996) Guide for care and use of laboratory animals. National Academic Press, Washington DC International Commission on Radiological Protection (1990) Recommendations of the IRCP. (Publication no 60) Pergamon Press, New York) Jung CW, Weissleder R, Josephson L, Bengele H, Brady TJ (1996) Physical properties of MION-46 and AMI-227. In: Proceedings of the International Society for Magnetic Resonance in Medicine, Fourth Scientific Meeting and Exhibition, vol 3. Berkeley, Calif., p 1681
Keshtgar MRS, Waddington WA, Lakhani SR, Ell PJ (1999) The sentinel node in surgical oncology. Springer, Berlin Heidelberg New York Limouris GS, Voliotopoulos V, Kondi-Paphiti A, Stavraka A, Vlahos L (1997) Two phase scintigraphic mapping of lymphatic drainage in cutaneous melanoma using 99mTcsulfur microcolloid/99mTc antimelanoma antibody. Anticancer Res 17:1667±1669 McIntosh SA, Purushotham AD (1998) Lymphatic mapping and sentinel node biopsy in breast cancer. Br J Surg 85:1347±1356 McMasters MK, Giuliano AE, Ross MI, Reintgen DS, Hunt KK, Byrd DR, Klimberg VS, Whitworth PW, Tafra LC, Edwards MJ (1998) Sounding board: sentinel lymph node biopsy for breast cancer ± not yet the standard of care. N Engl J Med 339:990±995 Mussurakis S, Buckley DL, Horsman A (1997) Prediction of axillary lymph node status in invasive breast cancer with dynamic contrast-enhanced MR imaging. Radiology 203:317±321 Palmacci S, Josephson L (1996) Synthesis of polysaccharide covered superparamagnetic oxide colloids. U.S. Patent #5262176 Rogers JM, Jung CHW, Lewis G, Groman EV (1998) Use of USPIO-induced magnet susceptibility artifacts to identify sentinel lymph nodes and lymphatic drainage patterns. I. Dependence of artifact size with subcutaneous Combidex dose in rats. Magn Reson Imaging 16:917±923 Vassalo P, Matei C, Heston WDW, McLachlan SJ, Koutcher JA, Castilino RA (1994) AMI-227-enhanced MR lymphography: usefulness for differentiating reactive from tumor-bearing lymph nodes. Radiology 193:501±506 Waddington WA, Keshtgar MR, Taylor I, Lakhani SR, Short MD, Ell PJ (2000) Radiation safety of the sentinel lymph node technique in breast cancer. Eur J Med 27:377±391 Weissleder R, Hahn P, Stark D. Elizondo G, Saini S, Todd LE, Wittenberg J, Ferrucci JT (1988) Superparamagnetic iron oxide: enhanced detection of focal splenic tumors with MR imaging. Radiology 169:399±403 Weissleder R, Elizondo G, Josephson L, Compton CC, Fretz CJ, Stark DD, Ferrucci JT (1989 a) Experimental lymph node metastases: enhanced detection with MR lymphography. Radiology 171:835±839 Weissleder R, Stark D, Engelstad B, Bacon BR, Compton CC, Shite DL, Jacobs P, Lewis J (1989 b) Superparamagnetic iron oxide: pharmacokinetics and toxicity. AJR Am J Roentgenol 152:175±180 Weissleder R, Elizondo G, Wittenberg J, Lee AS, Josephson L, Brady TJ (1990 a) Ultrasmall superparamagnetic iron oxide: an i.v. contrast agent for assessing lymph nodes with MR imaging. Radiology 175:494±498 Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH, Josephson L (1990 b) Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology 175:489±493 Weissleder R, Heautot JF, Schaffer BK, Nossiff N, Papisov M, Bogdanov AJ, Brady T (1994) MR lymphography study of a high efficiency lymphography agent. Radiology 191:225±230 Yutani K, Shiba E, Kusuoka H, Tatsumi M, Uehara T, Taguchi T, Nishimura T (2000) Comparison of FDG-PET with MIBISPECT in the detection of breast cancer and axillary lymph node metastasis. J Comput Assist Tomogr 24:274±280
9
Chapter 3
Different Aspects Dependent on Type and Localization of the Primary
In N-staging of malignant melanomas SLN detection using blue stain and/or 99mTc labeling methods has already reached a high standard. This is confirmed by many studies on malignant melanomas in different sites (Balch et al. 2001; Clary et al. 2001; Davison et al. 2001; Jacobs et al. 2001; McMasters et al. 2001 c; Medina-Franco et al. 2001; Mçller et al. 2001; Neubauer et al. 2001; Nieweg et al. 2001; Russell-Jones and Acland 2001; Shite and Tyler 2001). The integration of the SLN concept into treatment strategies is already more readily accepted in most countries than is SLN labeling in breast cancer, melanomas and other tumors. (For the reasons for this discrepancy see the relevant chapters in this volume.) Even in Australia, however, where melanoma incidences are very high, amazingly, SLN screening with modern labeling techniques is not routinely used in all clinics. Whereas, approximately 40 years ago confusion reigned on how to ensure diagnosis of the primaries in malignant melanoma cases (initial primary excision with histological examination versus primary irradiation followed by secondary excision with histological diagnosis), the 1980s and 1990s saw extensive discussion about prevention, early detection and subtyping (biological behavior of superficial spreading melanomas and nodular subtypes), which led to our present status of knowledge, forming the basis of our treatment strategies following the SLN concept. Even now, we can be sure that the SLN concept has greatly improved N-staging of malignant melanomas of the face, trunk and legs, and it can be said that failing to integrate the techniques of SLN detection into surgical strategies will be seen as ªmedical malpracticeº in the near future. In this context, it must again be emphasized very clearly that the survival of melanoma patients depends to a large degree on early detection and locoregional surgical cure with clearance using the optimal available diagnostic and surgical concepts.
In comparison with the SLN detection strategies applied in malignant melanoma cases, diagnostic and surgical treatment procedures are much more diversified in the case of breast cancer (Miner et al. 1998, 1999 a, b; Krag and Krag et al. 1999, 2000, 2001; Cody et al. 1999, 2001; Gambazzi et al. 2000; Noguchi et al. 2000; Teng et al. 2000; Buongmo et al. 2001; Harlow and Krag 2001; Martin et al. 2001; McCarter et al. 2001 a; Sato et al. 2001; Wong et al. 2001). Of late, in prominent centers in the United States and in Europe (e.g. at the European Cancer Centre in Milan) experience has been collected by investigating large numbers of cases ± 1000±2000 or more (Veronesi et al. 1997, 2000; Gulec et al. 1998; Krag et al. 1998; Bass et al. 1999; Linehau et al. 1999; Schreiber et al. 1999; Bedrosian et al. 2000; Teng et al. 2000; Cody et al. 2001; Harlow et al. 2001; Martin et al. 2001; McCarter et al. 2001 b; Nos et al. 2001; McMasters et al. 2001 a; Sato et al. 2001; Wong et al. 2001 a±c). Wong et al. also evaluated the accuracy in T2 and T3 cases, partly in multicenter studies (2001 a), the false-negative rate (2001 b) and, in relation to this, the predictive value of SLN dissection for the nonsentinel axillary nodes (2001 c). In some contrast, in Germany there has been an explosive development of many separate activities, which improved the experience in many clinics on one hand, but did not allow far-reaching statistically based statements. However, when the international literature is reviewed. many points can now be more clearly seen: · The SLN concept is a valuable and well practicable method, with a promising future also in breast cancer treatment (Chung and Giuliano 2001; Harlow and Krag 2001; Martin et al. 2001; McMasters et al. 2001; Paganelli et al. 1998; Sato et al. 2001). · The improved SLN detection methods allow detection of multiple SLNs in different sites and
3
12
Chapter 3 Different Aspects Dependent on Type and Localization of the Primary
·
·
·
·
·
·
with this improved tumor clearance (Uren et al. 2001). SLN-detecting methods (blue dye and isotopegamma-probe method) and their combined or alternate use are meanwhile based on advanced knowledge, and with the steadily growing wealth of experience in use of the gamma-probe it seems that acceptance of the SLN concept is increasing. Many authors (e.g. Bass et al. 1999; Cody et al. 2001) agree that the combined use of blue dye and the isotope methods helps to reduce the false-negative rate, because each method detects additional SLNs missed by the other in a total range of 8±10%. In many cases with breast cancer the dermal injection technique seems to be superior to peritumoral injection (Martin et al. 2001 a; McMasters et al. 2001 b), and according to newer knowledge, subareolar injection seems to be better than peritumoral injection, especially for medial and central localized primaries. Martin et al. (2001 b) have developed a formula for SLN detecting strategy: ± Removal of all nodes containing the isotope of the relatively magnitude of counts ± Concurrent use of blue dye to salvage those procedures in which isotope fails ± Removal of all clinically suggestive nonsentinel lymph nodes Additional immunohistochemical analysis of the SLNs using antibodies directed to cytokeratins of cancer cells improves the detection rate of micrometastases to up to 10% (Czerniecki et al. 1999; Pendas et al. 1999; Schreiber et al. 1999; Bobin et al. 2000; Liu et al. 2000; Teng et al. 2000). One consequence of the additional use of immunohistochemistry in detection of micrometastases is upstaging from stage I to stage II. So far there are no fundamental studies on the problems related to the false-negative rate following the use of the SLN concept. The answer to this very important question is the aim of NSABP protocol B32 (Harlow and Krag 2001). All the research groups currently working in the field of further evaluation of the practicability of incorporating the SLN concept into breast cancer treatment are looking forward to the final results of this project. It seems likely that if the SLN concept is inadequately handled in breast cancer treatment, when the rate of falsenegative cases is high patients will institute legal
proceedings against medical doctors. Such developments would make separate breast cancer centers in the sense of centers of excellence unavoidable. In head and neck-(oropharyngeal) cancer treatment strategies the so-called elective lymphadenectomy is still the standard in treatment strategies, but in this field too, the strategies seem to be giving way to more precise and stage-adapted protocols. Few papers have been published in recent years in which preliminary evaluation of the SLN concept is reported. At the head and neck division of the European Institute of Oncology in Milan, 11 patients with lateral T1-2N0M0 squamous cell cancer of the tongue underwent ipsilateral neck dissection 30±40 days after primary surgery. In 5 patients 99mTc labeled colloid solution was injected close to the operation scar 1 day before neck dissection, and the labeled neck nodes were revealed by lymphoscintigraphy. The other 6 patients underwent lymphoscintigraphy both before surgery and before neck dissection. Three patients had metastatic neck nodes. In all cases labeled nodes were revealed by lymphoscintigraphy. Ipsilateral sentinel nodes were removed from 8 patients and correctly predicted the state of the neck (6 negatives and 2 positives). Lymphoscintigraphy before and after surgery revealed that drainage was modified after surgery in 5 of 6 patients. The presurgery drainage pattern varied markedly among the 5 pN0 patients. In conclusion, the authors (Chiesa et al. 2000) give the following statement: The technique used allows easy and safe identification of sentinel lymph nodes and shows promise in guiding ªselective neck dissectionº ([sic] ± should be called ªneo-selective neck dissectionº [Schauer]). Surgery on the primary tumor often modifies lymphatic drainage, so that SLN biopsy may only be useful if the primary operation and the neck dissection are performed in the same session. Encouraging results have also been published by the Zçrich research group (Stoeckli et al. 2001). Localization of the SLNs was possible in 18 of 19 cases, and with a hand-held gamma probe in all 19 investigated cases. Six patients had occult metastatic disease. No skip metastases were found in the 13 neck-specimens with negative sentinel nodes.
Different Aspects Dependent on Type and Localization of the Primary
The conclusion that can be drawn on the basis of these two publications is that SLN evaluation is accurately feasible in clinically N0 cases in squamous cell carcinoma of the head and neck and seems to predict the presence of occult metastasis with a high rate of accuracy. For lung cancers, the SLN concept is clearly especially relevant to answering the question of operability in non-small-cell lung cancers. Specially adapted methods have not yet been developed. This lack of progress must be related primarily to the restricted access to the diagnostic options used (endoscopy, mediastinoscopy, fine needle aspiration cytology, minithoracotomy etc.) and to the complex topographic anatomical situation (tracheobronchial tree and lungs in close contact with the cardiovascular system with over- and undercrossing of parts of both systems). Therefore, with respect to the current status and in view of the fact that lung cancer is one of the most frequent and dangerous cancers, the development of more efficient diagnostic methods would be highly valuable. Whereas no concrete strategies have been developed for preoperative N-staging in lung cancer of various subtypes, Japanese surgeons are now discussing whether mediastinal nodal dissection must be routinely undertaken in cases of peripheral small (2 cm or less) lung cancer. In a retrospective analysis of 225 cases, Watanabe et al. (2001) came to the conclusion that mediastinal nodal dissection would be unnecessary in cases with peripheral squamous cell carcinoma measuring £ 2 cm, peripheral adenocarcinoma measuring £ 1 cm, localized bronchiolo-alveolar carcinoma measuring £ 2 cm without foci of active fibroblastic proliferation in histology (Noguchi's classification type A or B adenocarcinoma) and small cell carcinoma £ 1 cm. Candidates fulfilling these criteria were 28.4% (64/225) of small lung cancers and 10.9% of stage I A patients. These points seem to be an interesting basis for the development of a SLN concept for lung cancer cases. The discussion about the value of mediastinoscopy in N-staging that has long accompanied our strategies has lately been brought up to date by Margoritora et al. 2001 and Iwasaki et al. 2001. There are similar problems in other cancers, and especially with the pre- and intraoperative Nstaging of esophageal and gastrointestinal cancers (Kitagawa et al. 2001 a, b).
Experts report a high frequency and widespread distribution of lymph node metastasis in esophageal cancers. Based on this knowledge a ªthree-field dissectionº of the lymph nodes (paraesophageal, mediastinal, cervical) was introduced in the 1980s. In spite of reported improvements in the longterm survival of patients who underwent three-field lymph node dissection, the clinical significance of cervical lymphadenectomy remains doubtful, because the effectiveness of upper mediastinal lymphadenectomy cannot be accurately judged. Now, however, we are on the threshold of evaluation of the SLN concept, in cases with esophageal cancer, as a rule with the radioguided method (Kitagawa et al. 2001 a). Preliminary experience shows that aberrant drainage routes of lymphatics leaving the region of the primary can frequently be observed. It seems that the sentinel node navigation helps to identify lymph nodes more clearly in the first basin and to appraise the main streams of lymphatic drainage with detection of the sentinel node(s). The Japanese authors suggest that more individualized surgical strategies may be essential to improve the quality of life of patients with esophageal cancer on the one hand and to improve longterm results obtained with the gamma probe techniques on the other hand. Siewert and Sendler (2000) have lately published a review (with the title ªPotential and Futility of SLN Detection for Gastric Cancerº) of the applicability of the SLN concept to gastric cancer treatment. It emphasizes that the lymphatic flow in the stomach is not simple and points out that it is questionable whether a specific area of the stomach drains into one echelon only. In addition, it has been stated that the scientific discussion on whether D1 or extended lymphadenectomy is appropriate is not definitely closed as yet. With regard to the last statement, Miwa (2001) published data showing that extensive lymphadenectomy (D2) even in early gastric cancer (EGC) cases (n = 295) resulted in a significantly lower 10-year recurrence rate than that observed in cases with limited lymph node dissection (n = 97) (2.1% versus 211.9%; P = 0.005). Miwa (2001) showed with his results that each EGC case has its own lymphatic basins in which metastasis can develop.
13
14
Chapter 3 Different Aspects Dependent on Type and Localization of the Primary
This statement makes the search for the sentinel node(s) attractive, but the technical procedures needed to find the sentinel node or node groups seem to be much more difficult than in other tumor types. Yoshima et al. (2001) used the gamma probes NAVIGATOR GPS and 99mTc. Linearity of counting in radioactivity was fairly good, but the sensitivity of the probe was so low that the SLN would need to contain 3.7 ´ 10±3 MBq (0.1 lCi) of 99mTc or more for it to be used most effectively. In addition, the count rate of the gamma-detecting probe was variously influenced by the distance from and angle to the 99mTc source. Some recent discussions again focused on EGC, speculating that the SLN concept should fit in with the surgical strategies for these early neoplastic lesions. The following preliminary statements have been presented: · Laparoscopically assisted gastrectomy with inclusion of single node harvesting is the preferred treatment (Kitano 2001). · Node-negative cases have one way and nodepositive cases widely distributed ways of metastatic spread (Aikou et al. 2001). · In cT1N0-cases SLN mapping is possible in 98%, radioguidance works quantitatively and is reproducible (Kitagawa et al. 2001 b). · Indocyanine green is valuable in labeling procedures (Hiratsuka et al. 2001). · In cases with wall infiltration, lymph nodes with high radioisotope (RI) activity must be regarded as SLN (Yasuda et al. 2001). These points cannot simply be put together to make a ªmosaicº with a significance of its own, but they show at least some jump-off points for new approaches. The difficult conditions in esophageal and gastric cancers contrast with the situation in colorectal cancer cases, in which the handling of sentinel node labeling is much easier. In recent years some American groups have tried to standardize the SLN concept also for the colorectal group of cancers. The blue dye method is the one that has most often been preferred (Waters et al. 2000; Wiese et al. 2000; Paramo et al. 2001; Saha et al. 2001). Isosulfan blue (Lymphazurin) has been injected into the subserosa tissue (1%, 1 ml). The SLN detection rates ranged from 71% to 98%. The rate of occult micrometastases was 14%. According to these find-
ings upstaging was necessary. The rate of skip metastases was approximately 4±9%. The results were judged to be successful and the precision in upstaging, helpful in decision making on whether or not adjuvant chemotherapy is indicated. The results of the most recent publications are summarized in Table 1. In total, it seems that both the new N-staging procedures and new technical strategies are on a good track and very helpful in decreasing the locoregional recurrence rates. In neuroendocrine cancers there are severe difficulties in developing the SLN concept as a uniform concept. These difficulties are related to: · Localization of the subtypes in very different tissue categories (gastrointestinal tract and endocrine organs, lung, skin, etc.) · Extended scale of premalignancy from benign through low and moderate malignancy to highgrade types · Localization of primary and SLN very close together, especially in primaries sited in the gastrointestinal tract and lung Some of these problems are the same as we have to overcome to realize a useful concept in lung and gastrointestinal cancers, and for differentiated solutions to the problems we must therefore use the same or similar methodical or practical strategies for further progress. These difficulties stimulate attempts not only to find new methods of SLN labeling but also to develop methods of detecting tumor-involved lymph nodes using the extensive scale of imaging systems (somatostatin receptor detection, CT, MRI, Sinerem labeling, PET etc.). The neuroendocrine cancers also include Merkel cell cancers (MCC). Biologically, these tumors behave in a similar way to malignant melanomas, with early regional lymph node involvement, early distant metastases and high locoregional recurrence rates. Therefore, the SLN detection techniques (blue dye labeling, 99mTc-nanocolloid application) can be used in a similar way. The cancer cells within the nodes can also be detected in a similar way using immunohistochemistry (S100). According to the preliminary data, clearance of the regional lymph node basin is only performed when the sentinel node(s) is/are positive (Javaheri et al. 1997; Messina et al. 1997; Wasserberg et al. 1999).
14/14=100%
20/22 91% 91%
25/35 71%
98%
Subserosa
Subserosa
Subserosa around the cancer
Subserosa
Isosulfan blue dye (Lymphazurin)
Lymphazurin 1% 1±2 ml
Isosulfan blue dye 1%, 1 ml
Isosulfan Lymphazurin 1%
22
83
35
203
Waters et al. 2000
Wiese et al. 2000
Paramo et al. 2001
Saha et al. 2001
63%
0% False negative 17% SLN only site of metastasis
48 59%
Negative SLN (%)
Injection modali- SLN identification rate ty
Tracer used
No. of cases
Author/year
Table 1. Results of sentinel lymph node (SLN) biopsy in colorectal cancer
37%
15/35 = 42%
34 41%
6/6 100%
Positive SLN (%)
Occult. metastases 14% Unusual metastases 5% Skip metastases 8 (3.94%)
HE + Cam 5.2 Micrometastases 4 = 11%
HE + immunohistochemistry Cytokeratin A1
HE + immunohistochemistry
Upstaging 14%
Upstaging according to results of immunohistochemistry 11%
Skip metastasis 9%
Histopathological Remarks methods
Different Aspects Dependent on Type and Localization of the Primary 15
16
Chapter 3 Different Aspects Dependent on Type and Localization of the Primary
In comparison with worldwide activities in evaluation of the SLN concept for malignant melanoma and breast cancer, evaluation of the concept for male and female urogenital cancers started late. A short overview of SLN evaluation in male and then in female cancers is given below.
Male Cancers Cabanas' first concept defining SLNs in penile cancer was established as long ago as 1977. He recommended removal of the inguinal medially located node. His concept was fairly correct, but it was not absolutely valid, especially for deep invading cancers of the glans penis. Therefore, critical discussions have since developed. The criticisms developed slowly, because in the western world penile cancers are rare and clinical studies developed slowly and with a time-lapse. Barnes et al. recorded about 62 cases in 1989. Their retrospective analysis of the patients (44% stage I, 27% stage II, 19% stage III and 10% stage IV) demonstrated a 5-year overall survival rate of only 56%. In conclusion, on the grounds of the results obtained the group declared the SLN biopsyconcept inaccurate. Late detection because of inguinal lymph node involvement was associated with a poor prognosis. Two years later, in Ravi's (1991) concept an ªinguinal pickº was recommended. The procedure suggested seems to be similar to that of berrypicking in thyroid cancer treatment. The 5-year disease-free survival of 52 patients with inguinal ªpickº-positive and -negative disease after treatment was 82.9% and 100%, respectively. With regard to the anatomical studies of Dewire and Lepor (1992), the SLN biopsy might be useful in the management of superficial carcinomas of the prepuce or skin of the penis, as these areas drain to the superomedial zone of the superficial inguinal nodes, which include the sentinel nodes as a rule. As the lymphatics from the glans penis may bypass the superficial nodes, however, they can lead directly to the pelvic nodes. Therefore, this possibility must be included in our future approaches. In revision of his first publication (1977), in 1992 Cabanas recommended bilateral SLN biopsy and inguinofemoral dissection in node-positive cases. In negative cases he recommended monthly
controls for 1 year and examination every 2 months for the next 3 years. However, he did not consider the critical statements of Dewire and Lepor (1992). In the same year Abo Aad and de Kernion (1992) published data from which they derived some practical recommendations. In 50% of patients with node enlargement no tumor was found on histological examination; 20% of patients with clinically negative nodes had micrometastases. Because in their opinion SLN biopsy was of limited value the authors recommended: · Patients with cancer not invading the corpora and without palpable nodes should be followed up in examinations at 2- to 3-month intervals. · Patients with persistent lymphadenopathy should first undergo superficial lymph node dissection. When positive nodes are found bilateral deep node dissection should be performed. · Bilateral inguinal and pelvic lymphadenectomy is recommended for patients with lesions invading the corpora. A more highly differentiated strategy than extended SLN dissection is also recommended by Pettaway et al. (1995), because the false-negative rate amounted to 25%. Investigations recently published by Horenblas et al. (2000) were conducted in 55 exactly staged cases (T2N0 = 42, T2N1 = 4, T3N0 = 9 cases) with restricted regional lymph node dissection: the cases with positive SLNs (11 cases) gave rise to the following conclusion: The dynamic SLN procedure is a promising staging technique that can be used to detect early metastatic dissemination on the basis of individual mapping of lymphatic drainage. This short review, based on mostly limited numbers of cases, documents the statement that the primary staging problem in penile cancer is still not fully solved and that moderated or improved SLN concepts are practiced by many groups, whereas other groups prefer the ªwait-and-see strategyº supported by short-term controls. For prostate cancer treatment, up to the last few years there was no uniform, internationally accepted concept of how to stage and remove locoregional cancer spread, which could have been supported for instance by the SLN concept as this was already in existence. This delay in activity and progress can be understood when surgical strategy problems of can-
Female Cancers
cer clearance in the pelvis and the retrograde hematogenous spread of prostate cancer to the skeleton, which as is well known, sometimes takes place at the same time, are taken into consideration (Bossink and Rabe 2001). There are similar problems with bladder cancer treatment, especially in high-grade cancers. In spite of all these difficulties, new strategies are now being developed for SLN detection in prostate cancer cases. New activities focused on radioisotope-guided pelvic lymph node dissection have been started recently by a cooperative group made up of urologists (Harzmann and Wawroschek), nuclear medical doctors (Heidenreich and Vogt) and pathologists (Wagner and collaborators) at the hospital in Augsburg, Germany. The experience of this team is based on investigations of 117 prostate cancer cases, using 99mTcnanocolloid injected transrectally directly into the prostate with ultrasound guidance 1 day before pelvic lymphadenectomy (Wawroschek et al. 2001). The results obtained are summarized in Table 2. The authors emphasize a high interindividual variability of lymphatic drainage from the prostate and limited sensitivity for the detection of cancerpositive nodes when the pelvic dissection area is selected according to a stereotyped uniform principle and is limited to predetermined node groups. In addition, many clinical research groups have concerned themselves with the development of more uniform lymph node staging and clearanceprocedures for germ cell tumors, which they wished to be strongly oriented toward progress in treatment, but it proved difficult to incorporate a clear SLN strategy into a uniform concept. In seminomas, pelvic and retroperitoneal adjuvant radiation therapy has been and is still performed and late irradiation effects are accepted, even though irradiation is not necessary in a large percentage of patients. In embryonal carcinomas radiation therapy in combination with polyche-
Table 2. Advantages of SLN detection using cases with prostate cancer
motherapy is also still performed. However, with respect to high cure rates with polychemotherapy, even in cases with lung metastases, there is a trend in favor of increasingly tight restriction on locoregional adjuvant irradiation therapy. Currently, one important point in this approach is the verification or exclusion of blood vessel invasion. Therefore, when late effects of therapy and overtreatment are considered, it would be very helpful to have reliable results concerning metastatic lymph node involvement or exclusion of locoregional metastatic progress in the course of primary tumor staging. With reference to sarcomas in the leg, it must be pointed out that in the group of soft tissue malignancies only the synovial sarcomas show pronounced lymph node involvement in up to approximately 30% of cases (Schauer and Altmannsberger 1983, 1984). In such cases it would be helpful in the planning of an adjuvant therapy to have information about inguinal and femoral lymph node involvement.
Female Cancers Vulvar and vaginal or vulvovaginal malignant tumors, most of which are squamous cell cancers, while a very few are malignant melanomas, are rare entities in the group of female genital cancers. Vulvectomy and vaginalectomy combined with inguinofemoral lymphadenectomy are standard methods in more advanced cancer cases. The complication rates following these extensive surgical interventions are high. In addition, recognition of the psychosexual consequences of radical surgical protocols and better understanding of the histopathological features and lymphatic drainage of vulvar cancers have led to a more conservative surgical approach (Makar et al. 2001). More differentiated strategies should
99m
Tc nanocolloid for locoregional cancer detection and cancer clearance in 117
Authors
No. of cases
Average no. of sentinel nodes
Rate of detection by 99mTc
Cases with micrometastases
Sensitivity in detection
Sensitivity of modified pelvic lymphadenectomy
Wawroschek et al. 2001
117
4
25/27
24
96%
81.5%
17
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Chapter 3 Different Aspects Dependent on Type and Localization of the Primary
be developed, especially for patients with early stage disease. In recent years many gynecologists have tried to evaluate the SLN concept with the aim of developing more restricted surgical protocols and improving quality of life for patients with these tumor entities too (Levenbeck et al. 1995; Decessare et al. 1997; Morgan and Mikuta 1999; Rodier et al. 1999; De Cicco et al. 2000; Sideri et al. 2000; Terada et al. 2000; Ghuvani and Penalver 2001; Makar et al. 2001). The essential points of these aims are that every patient with an early stage of vulvar cancer should be individually treated and the risks of conservative therapy regimens should be balanced against the dangers and advantages of the more radical surgical treatment schemas. First results, mostly obtained in small collectives of patients, are encouraging, and it seems it may be possible to lower the morbidity of inguinofemoral lymphadenectomy in the near future. Clear-cut positive rates for application of the SLN concept in the treatment of early stages of vulvar cancer have already been given by teams at various clinics in different countries (Levenback et al. 1995; Rodier et al. 1999; De Cicco et al. 2000; Sideri et al. 2000; Terada et al. 2000; Ghurani and Penalver 2001; Makar et al. 2001). In most studies, though, the number of patients treated according to the SLN concept is low. Therefore, multicenter trials are recommended to ensure that more experience can be collected in a shorter time and used for the development of new guidelines compatible with the different subtypes and stages of vulvar cancers. N-staging for stage-related treatment of cervix cancer has long been focused on bilateral pelvic lymphadenectomy, with the possibility of developing a SLN concept disregarded. It may be that this exercise of restraint was due to the difficulties of peritumoral injection into the fiber-rich, tough cervical tissue and the impossibility of recognizing the margins of the invasive parts of the cancer. However, the first results of investigations, mostly in series with small case numbers, have now been published (Dargent et al. 2000; Medl et al. 2000; Oboyle et al. 2000; Verheijen et al. 2000; Malur et al. 2001; Lantzsch et al. 2001). Both practicable methods of SLN detection, namely the injection of isosulfan blue dye (1 ml Lymphazurin) or patent blue-violet and 99mTc albumin solution (50 MBq) were used. The injec-
tions were given into the portio of the uteri around the infiltrating cancer (Verheijen et al. 2000). In solitary or combined applications the blue dye solutions were injected paracervically into each lateral fornix immediately before surgery (Dargent et al. 2000; Medl et al. 2000; Oboyle et al. 2000). The conclusion put forward by Verheijen et al. (2000) is that the sentinel node detection is possible in a high proportion of cases and that their identification helps to avoid extensive lymph node dissection in many cases. In patients with ovarian cancer the investigation of lymph node involvement is more difficult than with other primaries. In many cases expansion into the peritoneal cavity has the most important role. Histologically, it can often be shown that the cancer cell formations grow around lymph nodes but do not invade directly or via lymphatics. In spite of this, only general, and not targeted, lymph node staging is performed in most cases. However, it will be very difficult to establish a lymph node labeling method, especially because of the overlapping soft tissue tumor infiltration around the nodes to be evaluated. Therefore, it will only be possible to evaluate the lymph nodes with the aim of diagnosis by imaging techniques in patients whose disease is in early stages, and mainly in those who have no massive spread in the peritoneal cavity. Sarcomas generally metastasize mostly by the hematogenous route, mainly into the lungs, but there are some exceptions. These are synovial sarcomas in adults and rhabdomyosarcomas of childhood. For instance, synovial sarcomas of the legs have pronounced lymph node metastases in up to 30% in the inguinal nodes and rhabdomyosarcomas have regional node involvement in approximately 8% of cases (Schauer and Altmannsberger 1983, 1984 a, b). As in other tumors, precise SLN detection could be helpful in N-staging and in decision making concerned with adequate adjuvant therapy regimens.
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Chapter 4
Basic Strategies in Sentinel Node Detection and Exclusion or Verification of Cancer Metastasis into the Regional Node(s)
Early Developments and Continuous Improvements The strategies followed in sentinel node detection and investigation depend strongly both on tumor type and on localization of the primaries. Therefore, different strategies must be developed and continuously improved on by research scientists and by clinicians practicing in the different medical disciplines. In the management of skin tumors, such as malignant melanoma or Merkel cell carcinomas, which have a frequent propensity toward regional metastases (Rodrigues et al. 2001), the sentinel node concept is well developed and already widely routinely applied. This means it is assumed that this concept is integrated in treatment protocols for malignant melanomas and Merkel cell cancers (Morton et al. 1992; Reintgen et al. 1994; Slingluff et al. 1994; Albertini et al. 1996 a; Alazraki et al. 1997; Kapteijn et al. 1997 a; Cascinelli et al. 1998; Glass et al. 1998; Joseph et al. 1998; Leong et al. 1998). In recent years the number of precisely investigated cases has increased markedly in many malignant melanoma treatment centers, so that the statistical significances are now very reliable (Cochran et al. 2000; Gesuelli et al. 2000; Mçller et al. 2000; Murray et al. 2000; Temple et al. 2000; Uren et al. 2000; Villa et al. 2000; Wagner et al. 2000 a, b; Weiss et al. 2000; Clary et al. 2001; Harlow et al. 2001; McMasters et al. 2001; Roozendaal et al. 2001; Sugranes et al. 2001; Thompson 2001). In addition, the necessity for relating the detection and removal of SLN to the Breslow stage has also been more precisely defined (Bedrosian et al. 2000; Gershenwald et al. 2000; Mçller et al. 2001; Statius et al. 2001). Many other correlations between primaries and different localizations of micrometastases (Thelmo et al. 2001) and the necessity for clearance of basins have been extensively investigated (Porter et al. 2000 a, b; Wagner et al.
2000 a; McMasters et al. 2001) with the aim of developing precise recommendations (Porter et al. 2000 b); these will be published in 2002 by EORTC (Cascinelli et al. 2000; Balch et al. 2001; Eggermont et al. 2001). In breast cancer cases the search for SLN is much more difficult, but this is another field in which experience is accumulating very fast (Krag et al. 1993; Giuliano et al. 1994; Uren et al. 1995; Albertini et al. 1996 b; Meijer et al. 1996; Nieweg et al. 1996; Gulec et al. 1997; Turner et al. 1997; Veronesi et al. 1997; Borgstein et al. 1998; Cox et al. 1998; Dixon et al. 1998; Paganelli et al. 1998; della Rovere and Bird 1998; Klimberg et al. 1999; Linehan et al. 1999; Miltenburg et al. 1999; Noguchi et al. 2000; Smith et al. 2000; Tsugawa et al. 2000; Boolbal et al. 2001; Chung and Giuliano 2001; Cody et al. 2001; McCarter et al. 2001; McMasters et al. 2001 b; Wong et al. 2001 a±c). This is easily understandable, because different localizations, T-stages, and multifocality and multicentricity of the primaries within the breast are possible, and the lymph can flow into different, partly superficial (axilla) partly intracorporeal, i.e. retro- and/or parasternal intrathoracic, lymph nodes connected in a vertical chain (mammaria interna group). In systematic investigations, Wong's group (Wong et al. 2001 a) analyzed the accuracy of sentinel node analysis in higher T-stages (T2±3) and found that the results were less accurate than in stage T1; additionally, the group found that the ability to identify multiple sentinel nodes improves diagnostic accuracy (Wong et al. 2001 b) and that the likelihood of positive nonsentinel nodes (NSNs) correlates with increasing tumor size and the presence of multiple sentinel nodes (Wong et al. 2001 c). It seems that specific guidelines ought to be developed on: · The best method of administering the contrast media (e.g., in breast cancer, subdermal versus peritumoral administration, or peritumoral administration (versus subareolar) in centrally located cancers.
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Chapter 4 Basic Strategies in Sentinel Node Detection and Exclusion or Verification of Cancer Metastasis
· Exact evaluation of quality and quantity of the labeling media to be injected (blue dye solutions, 99mTc-colloid, etc.).
Possible Prescreening Methods for SLN Detection and Evaluation In suitable cases, the following prescreening strategies for SLN detection in the regional basins and investigations of palpable and suggestive lymph nodes are generally possible: · Preoperative radiodiagnostic procedures and/or nuclear medical techniques directed at detection of the SLN and their involvement in metastatic cancer spread using ± Magnet resonance tomography/imaging (MRT/ MRI) ± Computed tomography (CT) ± FDG and methionine PET technique (see Chapter 5, section by Avril et al.) 1 · Somatostatin antibodies for nuclear medical detection of primaries and their locoregional and systemic spread ± It must be emphasized that with any of these methods positive reactions cannot be obtained unless there is a sufficient local tumor cell mass with diameters of 4±8 mm. This means that micrometastases (<2 mm) cannot be detected and that negative results thus do not exclude cancer metastasis. · Fine-needle aspiration cytology (FNAC) can be used in preoperative diagnosis, for instance to confirm breast cancer or other cancers, but it should not be used routinely in prescreening procedures for the diagnosis of disease within the axillary or other node groups, because incipient micrometastases cannot be reliably detected and a false-negative result can be fatal. Only in the relatively rare cases in which suspicion of a palpable node is very high can FNAC be used to confirm node involvement. In such cases with positive results, high-dose chemotherapy can be administered even before surgery. FNAC should
1
Massively invaded sentinel lymph nodes may be detected by PET but missed by lymph scintigraphy (Blocklet et al. 2001; Acland et al. 2001) and Sinerem labeling techniques (see Chapters 5 and 19), which are still in the experimental stage
not be used for primary melanoma diagnosis, because it can initiate hematogenous spread. An additional advantage is that FNAC yields tissue that can be subjected to immunohistochemical stainings during prescreening investigations for cancers of different origin to confirm the presence of cancer cells and to characterize them in terms of origin, differentiation product and proliferation activity. The number of immunohistochemical stainings depends on the number of smears available, but in theory all staining procedures are possible providing the smears are correctly preserved. The following principles are possible: staining of cytokeratin patterns, which are characteristic for specific organ cancers (Altmannsberger et al. 1981, 1982; Schauer et al. 1982), stainings for characteristic cellular differentiation products of neuroendocrine markers, such as chromogranin, S100protein insulin, glucagon, gastrin, vasoactive intestinal polypeptide (VIP), gastrointestinal polypeptide (GIP), pancreatic polypeptide (PP), calcitonin, adrenocorticotropin (ACTH), thyroglobulin and HMB45, which is characteristic for malignant melanomas. The specificity of HMB45 for melanoma cell detection in SLN is interesting. Baisden et al. (2000) stained 244 cervical and axillary lymph nodes from patients in whom melanoma was not suspected All nodes were immunohistochemically negative. In 12 of 66 patients with malignant melanomas (18%) microscopy revealed cancer cells. In the remaining 54 cases 4 patients (= 7%) had HMB-45-positive cells. In 4 (4%) of 96 lymph nodes investigated nevus cell aggregates were detected (S-100 positive). However, since these cells were HMB-45 negative they were obviously not melanoma cells. Recently new antibodies have been tested as melanoma markers. Sidham et al. (2001) tested Melan A (clone A103) and MART-1 (clone M2± 7C10) and compared them with S-100 protein and HMB-45. The Az-values (area under receiver-operating characteristic curve) were higher with Melan-A (0.9742) and MART-1 (0.9779) than with S-100protein (0.8034) and HMB-45 (0.8651). These results demonstrate a higher diagnostic accuracy with Melan-A- and MART-1, with superior detection of melanoma micrometastases. Recently in some publications the reverse transcriptase polymerase chain reaction (RT-PCR)
Tracers Most Frequently Used for Detection of SLN
analysis for tyrosinase mRNA has been used as a molecular marker for the presence of melanoma cells (Pellegrino et al. 2000; Blaheba et al. 2001; Shivers et al. 2001). The results of most investigations were and still are surprising: the rates of positive SLN are very much higher than expected. Shivers et al. (2001) published a positive detection rate of 16% (36/233 cases) according to histological examination, and with additional immunohistochemical evaluations the rate increased to 22% (= 52 positive cases). In RT-PCR-investigations of 181 cases, the number of lymph node-positive cases was 114 (= 70%). Many research groups have doubts, especially about the biological significance of such very high rates, which are in such sharp contrast to the histopathological and immunohistochemical evaluations. An explanation for this mystery can be seen, in my opinion, in the facts that it is vital nevus cells, or devitalized parts of them, containing the tyrosinase genetic material or RT-PCR-relevant material of apoptotic or necrotic melanoma cells that are detected by the RT-PCR-reaction and not living cell populations of the malignant melanoma. This
can easily be understood, because 70% of malignant melanomas of the skin develop in junctional nevi and substitute rests of nevus cell populations, and also because the cell loss rate is high in most infiltrating melanomas. These possibilities, which can result in genuinely positive, but also in false-positive, RT-PCR reactions in lymph node investigations of melanoma patients, are summarized in Fig. 1.
Fig. 1 a±c. Schematic illustrating possible scenarios that can yield positive RT-PCR reactions for tyrosinase gene and related products. a Yellow-shaded area contains nonneoplastic nevus cells from random areas of a melanoma; these contain the tyrosinase gene but are irrelevant as far as metastasis is concerned. b Green-shaded area contains devita-
lized apoptotic or necrotic melanoma cells or fragments of such cells; these also contain tyrosinase gene material and are also irrelevant in terms of metastatic spread. c Vital cancer cells containing the tyrosinase gene are those in the red-shaded area, and these are the only ones with potential for growth and further spread
Tracers Most Frequently Used for Detection of SLN The simplest technique that can be used to visualize draining lymph vessels and the SLN is the operative search for these tissue structures after injection of the dye ªpatent blueº or other blue dyes. Moreover, radioactive tracers such as 99m technetium sulfur nanocolloid can be used, either separately or in combination with injection of such blue dye solution. In a patient in whom breast cancer has been detected, this material is injected intradermally over the cancer or peritu-
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Chapter 4 Basic Strategies in Sentinel Node Detection and Exclusion or Verification of Cancer Metastasis
morally at the 3, 6, 9, and 12 o'clock positions into the breast parenchyma adjacent to the cancer. The first possibility is now preferred in cancers that are not deep lying (see Chapter 21). The nuclear medicine physician detects the spread to different lymph nodes with a gamma camera and marks the localization of any lymph node detected on the skin. Intraoperatively the surgeon can detect the radioactive colloid as increased radioactivity in a lymph node with a probe marking the sentinel nodes (Morton et al. 1992; Alex and Krag 1993; Krag et al. 1993, 1998 a, b; Kapteijn et al. 1997 b; Pijpers et al. 1997; Borgstein et al. 1998; Miner et al. 1999). This approach has helped make it possible to detect the exact localizations of SLN and to differentiate between a single sentinel node and of two or more sentinel nodes, possibly in different positions. The pathologist is subsequently able to detect micrometastases microscopically and can even distinguish very small cancer cell clusters with the aid of immunohistochemistry in a limited number of lymph nodes. The arguments in support of the detection and evaluation of the sentinel node(s) is also derived from rational points. It has been pointed out that it is easier for pathologists to investigate one or two nodes in serial sections by H-E staining and additional immunohistochemical stainings with antibodies directed at cytokeratin of the epithelial cancer cells than for them to investigate 12 or more lymph nodes after axillary revision at levels I and II. However, there are no rational ideas on how institutes of pathology with their limited number of technicians, could perform this work. The question has important implications, from various points of view: Extended locoregional lymph node extirpation, i.e. axillary revision, is not indicated in all cases, because in 80% of pT1NxM0 breast cancer cases, for instance, the nodes are negative and there is only a low probability of node involvement in squamous cell cancers of the nasopharynx and oral cavity with a low grade of malignancy and invasion or in superficial spreading melanomas of the skin in the early stages. Therefore, new approaches have had to be developed to distinguish between tumor-infiltrated and tumor-free sentinel nodes, with or without macro- or micrometastases. So far there are three possible ways of achieving this:
· Demonstration that the structure of the lymph nodes is intact and there is no destruction wrought by tumor infiltration. At present this cannot be reliably ensured by the labeling of sinus histiocytes using a material that is rapidly resorbed by phagocytosis, such as ultrasmall paramagnetic iron oxide particles (= USPIO = Sinerem etc.). · Demonstration of cancer-related defects in lymph nodes with a loss of phagocytosis by sinus histiocytes or direct labeling of metastatic cancer cells with labeled antibodies, directed mainly at the surface structures of epithelial metastatic cancer cells. · Detection of increased glucose metabolism in cancer cell populations, using F-18-FDG-PET. With reference to the first of these, the highest level research activities using USPIO have been reported from the Harvard Center of Molecular Imaging Research Group chaired by Weissleder and his colleagues. With regard to lymphatic spread of breast cancer, this group has recently tried to image specific cancer cell equipment (e.g. transferring receptor molecules, cathepsin D etc.). In these screening programs carried out partly in animal experiments many new approaches were started. Working with Hægemann, Weissleder and colleagues (2000) have recently demonstrated that MRI utilizing monocrystalline iron oxide nanoparticles (MIONs) targeted to an engineered transferrin receptor (Tf) enables imaging of gene expression. Iron oxide nanoparticles with a cross-linked dextran coat were conjugated to transferrin through the linker molecule N-succinimidyl 3(2'pyridyldithio)propionate (SPDP) to yield Tf-S-SCLIO. SPDP-conjugation allowed approximately a 4fold increase in the number of Tf-molecules attached per iron oxide nanoparticle and resulted in a 10-fold improvement of binding and uptake by cells. This translated into an imaging probe that was 16 times as good for imaging gene expression in a cellular MRI assay. It may be that this approach can be used for cancer cell detection in vivo, expressing transferrin receptor protein. With the problems existing in the approach explained in point (c) above in mind, local application of labeled antibodies or FAB fragments of
References
them seems to be more promising. Under these conditions it would be possible to use Fab' fragments of antibodies labeled with (for example) 99m technetium or another radioactive substance for detection by scintigraphic techniques. At the moment such investigations can be focused on cancers in which overexpression of CEA, c-erb B2 oncoprotein (breast cancer, lung cancer, gastric cancer melanoma) has already been confirmed preoperatively by measuring p105 (part of the extracellular domain of p185 protein) in the serum or an immunohistochemically positive reaction for p185 in aspiration biopsy material or needle biopsy cylinders using the antibody 9G6 (Dianova) (Marx et al. 1990; Borg et al. 1991; Schauer et al. 1990, 1992). However, this method can only be applied in approximately 20% of breast cancer cases. Further research and development is therefore necessary. In all investigations in which antibodies or fragments of them are used as cancer cell markers, it is necessary to realize that antibodies, or parts of them, are subject to phagocytosis of the sinus histiocytes. This misleading fact must be considered in nuclear medical imaging and also in histochemical investigations after in vivo application of the antibodies.
Critical Points of the SLN Detection Process SLN detection, for instance in breast cancer patients with successive axillary revision, is already practiced in almost all German centers. The same approach seems to be followed in many other European, American, and Asian centers. Many centers still adopt this approach because the sentinel node concept allows detection of atypically located sentinel nodes and because it has a low false-negative rate (only a few percent). Furthermore, so far no results of comparative prospective studies comparing identical pT stages and axillary revision in one arm and SLN dissection alone in a second arm and including the corresponding survival curves have been published. However, some hospitals assume that further studies to consolidate the place of the SLN investigation technique are not necessary and have already abandoned the use of lymphadenectomy, which was historically performed as a means of control.
As far as pathologists are concerned, it has to be pointed out that participation in these programs for SLN detection demands manpower in the technical and diagnostic phases of the investigations necessary for the evaluation of sentinel nodes in serial sections. Furthermore, immunohistochemical investigations conducted in serial sections are cost intensive. This is a problem that must be thought over and solved before extensive programs are started in clinics, as otherwise it might not be possible to perform the extensive investigations that are absolutely necessary in an uninterrupted sequence and in a technically faultless manner.
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Cox CE, Pendas S, Cox JM, Joseph E, Shons AR, Yeatman T, Ku NN, Lyman GH, Berman C, Haddad F, Reintgen DS (1998) Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 227:645±651 Dixon M (1998) Sentinel node biopsy in breast cancer. Brit Med J 317:295±296 Eggermont AM, Keilholz U, Testori A, Cook M, Lienard D, Ruiter DJ (2001) The EORTC melanoma group translational research program on prognostic factors and ultrastaging in association with the adjuvant therapy trials in stage II and stage III melanoma. European Organization for Research and Treatment of Cancer. Ann Surg Oncol 8[Suppl]:38S±40S Gershenwald JE, Mansfield PF, Lee JE, Ross MI (2000) Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (>04=4 mm) primary melanoma. Ann Surg Oncol 7(2):160±165 Gesuelli GC, Sartelli M, Berbellini A, Brianzoni E, Simonacci M, Sigona M (2000) Sentinel lymph node identification in the staging of cutaneous melanoma. Blue dye vs. radioguided localization. Minerva Chir 55(8-8):513±516 Giuliano AE, Barth AM, Spivack B, Beitsch PD, Evans SW (1996) Incidence and predictors of axillary metastasis in T1 carcinoma of the breast. J Am Coll Surg 183(3):185± 189 Glass EC, Essner R, Morton DL (1998) Kinetics of three lymphoscintigraphic agents in patients with cutaneous melanoma. J Nucl Med 39:1185±1190 Gulec et al. (1997) Gamma probe guided sentinel node biopsy in breast cancer. Q J Nucl Med 41:251±261 Harlow SP, Krag DN, Ashikaga T, Weaver DL, Meijer SJ, Loggie BW, Tanabe KK, Whitworth P Jr, Kuhn J, Kusminsky R, Carp NZ, Gadd M, Rawlings M Jr, Slingluff CL Jr (2001) Gamma probe guided biopsy of the sentinel node in malignant melanoma: a multicentre study. Melanoma Res 11(19):45±55 Hægemann D, Josephson L, Weissleder R, Basilion JP (2000) Improvement of MRI-probes to allow efficient detection of gene expression. Bioconjug Chem 11(6):941±946 Joseph E, Brobeil A, Glass F, Glass J, Messina J, DeConti R, Cruse CW, Rapaport DP, Berman C, Fenske N, Reintgen SD (1998). Results of complete lymph node dissection in 83 melanoma patients with positive SLN. Ann Surg Oncol 5:119±125 Kapteijn BAE, Nieweg OE, Mooi WJ, Balm AJ, Mçller SH, Peterse JL, Valdes-Olmos RA, Hoefnagel CA, Kroon BB (1997 a) Localizing the sentinel node in cutaneous melanoma: gamma probe detection versus blue dye. Ann Surg Oncol 4:156±160 Kapteijn BAE, Nieweg OE, Mçller SH, Liem IH, Hoefnagel CA, Rçtgers EJT, Kroon BBR (1997 b) Validation of gamma probe detection of the sentinel node in melanoma. J Nucl Med 38:362±366 Klimberg VS, Rubio IT, Henry R, Cowan C, Colvert M, Korourian S (1999) Subareolar versus peritumoral injection for location of the sentinel lymph node. Ann Surg 229(6):860±864; 864±865 Krag D, Harlow S, Weaver D, Ashikaga T (1998 a) Technique of sentinel node resection in melanoma and breast cancer: probe guided surgery and lymphatic mapping. Eur J Surg Oncol 24:89±93
References Krag DN, Ashikaga T, Harlow SP, Weaver DL (1998 b) Development of sentinel node targeting technique in breast cancer patients. Breast 4:67±74 Krag DN, Weaver DL, Alex JC, Fairband JT (1993) Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 2:335±339 Leong SPL, Steinmetz I, Habib FA, McMillan A, Gans JZ, Allen RE Jr, Morita E, El-Kadi M, Epstein HD, Kashani-Sabet M, Sagebiel RW (1998) Optimal selective sentinel lymph node dissection in primary malignant melanoma. Arch Surg 132:666±673 Linehan DC, Hill AD, Akhurst T, Yeung H, Yeh SD, Tran KN, Borgen PI, Cody HS 3rd (1999) Intradermal radiocolloid and intraparenchymal blue dye injection optimize sentinel node identification in breast cancer patients. Ann Surg Oncol 6(5):450±454 Marx D, Schauer A, Reiche C, May A, Ummenhofer L, Reles A, Rauschecker HF, Sauer R, Schumacher M (1990) cerbB2-expression in correlation to other biological parameters of breast cancer. J Cancer Res Clin Oncol 116:15± 20 McCarter MD, Yeung H, Fey J, Borgen PI, Cody HS 3rd (2001) The breast cancer patient with multiple sentinel nodes: when to stop? J Am Coll Surg 192(6):692±697 McMasters KM, Wong SL, Edwards MJ, Ross MI, Chao C, Noyes RD, Viar V, Cerrito PB, Reintgen DS (2001 a) Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery 130(2):151±156 McMasters KM, Wong SL, Martin RC 2nd, Chao C, Tuttle TM, Noyes RD, Carlson DJ, Laidley AL, McGlothin TQ, Ley PB, Brown CM, Glaser RL, Pennington RE, Turk PS, Simpson D, Cerrito PB, Edwards MJ; University of Louisville Breast Cancer Study Group (2001 b) Dermal injection of radioactive colloid is superior to peritumoral injection for breast cancer sentinel lymph node biopsy: results of a multiinstitutional study. Ann Surg 233(5):676± 687 McMasters KM, Reintgen DS, Ross MI, Wong SL, Gershenwald JE, Krag DN, Noyes RD, Viar V, Cerrito PB, Edwards MJ (2001 c) Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol 8(3):192±197 Medina-Franco H, Beenken SW, Heslin MJ, Urist MM (2001) Sentinel node biopsy for cutaneous melanoma in the head and neck. Ann Surg Oncol 8(9):716±719 Meijer S, Collet GJ, Pijpers HJ, Hattum L van, Hoekstra OS (1996) Less axillary dissection necessary due to sentinel node biopsy in patients with breast carcinoma. Ned Tijdschr Geneeskd 9; 140(45):2239±2243 Miltenburg DM, Miller C, Karamlou TB, Brunicardi FC (1999) Meta-analysis of sentinel lymph node biopsy in breast cancer. J Surg Res 15; 84(2):138±142 Miner TJ, Shriver CD, Flicek PR, Miner FC, Jaques DP, Maniscalco-Theberge ME, Krag DN (1999) Guidelines for the safe use of radioactive materials during localization and resection of the sentinel lymph node. Ann Surg Oncol 6:75±82 Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, Foshag LJ, Cochran AJ (1992) Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392±399
Mçller MG, Borgstein PJ, Pijpers R, Leeuwen PA van, Diest PJ van, Gupta A, Meijer S (2000) Reliability of the sentinel node procedure in melanoma patients: analysis of failures after long-term follow-up. Ann Surg Oncol 7(6):461±468 Mçller MG, Leeuwen PA van, Diest PJ van, Vuylsteke RJ, Pijpers R, Meijer S (2001) No indication for performing sentinel node biopsy in melanoma patients with a Breslow thickness of less than 0.9 mm. Melanoma Res 11(3):303±307 Murray DR, Carlson GW, Greenlee R, Alazraki N, Fry-Spray C, Hestley A, Poole R, Blais M, Timbert DS, Vansant J (2000) Surgical management of malignant melanoma using dynamic lymphoscintigraphy and gamma probeguided sentinel lymph node biopsy: the Emory experience. Am Surg 66(8):763±767 Nieweg OE, Kapteijn BA, Peterse JL, Rutgers EJ, Dongen JA van, Kroon BB (1996) Identification of the sentinel node in patients with breast carcinoma. Ned Tijdschr Geneeskd [9] 140(45):2235±2239 Noguchi M, Motomura K, Imoto S, Miyauchi M, Sato K, Iwata H, Ohta M, Kurosumi M, Tsugawa K (2000) A multicenter validation study of sentinel lymph node biopsy by the Japanese Breast Cancer Society. Breast Cancer Res Treat 63(1):31±40 Paganelli G, Cicco C, Cremonesi M, Prisco G, Calza P, Luini A, Zucali P, Veronesi U (1998) Optimised sentinel node scintigraphy in breast cancer. Q J Nucl Med 42:49±53 Pellegrino D, Bellina CR, Manca G, Boni G, Grosso M, Volterrani D, Desideri I, Bianchi F, Bottoni A, Ciliberti V, Salimbeni G, Dandini D, Castagna M, Zucchi V, Romanini A, Bianchi R (2000) Detection of melanoma cells in peripheral blood and sentinel lymph nodes by RT-PCR analysis: a comparative study with immunohistochemistry. Tumori 86(4):336±338 Pijpers R, Borgstein PJ, Meijer S et al. (1997) Sentinel node biopsy in melanoma patients: dynamic lymphoscintigraphy followed by intraoperative gamma probe and vital dye guidance. World J Surg 21:788±793 Porter GA, Ross MI, Berman RS, Lee JE, Mansfield PF, Gershenwald JE (2000 a) Significance of multiple nodal basin drainage in truncal melanoma patients undergoing sentinel lymph node biopsy. Ann Surg Oncol 7(4):256±261 Porter GA, Ross MI, Berman RS, Sumner WE 3rd, Lee JE, Mansfield PF, Gershenwald JE (2000 b) How many lymph nodes are enough during sentinel lymphadenectomy for primary melanoma? Surgery 128(2):306±311 Rasgon BM (2001) Use of low-dose technetium Tc99m sulfur colloid to locate sentinel lymph nodes in melanoma of the head and neck: preliminary study. Laryngoscope 111(8):1366±1372 Reintgen D, Cruse CW, Wells K, Berman C, Fenske N, Glass F, Schroer K, Heller R, Ross M, Lyman G, Cox C, Rapaport D, Seigler HF, Balch C (1994) The orderly progression of melanoma nodal metastases. Ann Surg 220:759±767 Rodrigues LK, Leong SP, Kashani-Sabet M, Wong JH (2001) Early experience with sentinel lymph node mapping for Merkel cell carcinoma. J Am Acad Dermatol 45(2):303± 308 Roozendaal GK, Vries DJD de, Poll D van, Jansen L, Schraffordt Koops H, Nieweg OE, Kroon BB (2001) Sentinel nodes outside lymph node basins in patients with melanoma. Br J Surg 88(2):305±308
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Chapter 4 Basic Strategies in Sentinel Node Detection and Exclusion or Verification of Cancer Metastasis Rovere G della, Bird PA (1998) Sentinel-lympho-node in breast cancer. Lancet 352:421±422 Schauer A, Osborn M, Altmannsberger M, Weber K (1982) Expression of intermediate filaments in different human tumors. Jahrestagung der Gesellschaft fçr Histochemie, Gargellen-Montafon, congress volume Schauer A, Marx D, Ummenhofer L, Rauschecker H, Gatzemeier W, Sauer R, Schumacher M, Sauerbrei W (1990) Die Multicenter Studie ¹Kleines Mammacarcinom. Vorlåufige Ergebnisse ± Neue Aspekteª. Dtsch Ørzteblatt 87:3628±3638 Schauer A, Marx D, Lipp I, Schumacher M, Sauerbrei W, Rauschecker H, Sauer R (1992) Diagnostic tools and prognostic factors in human breast evaluated by morphological and immunohistochemical methods. In: Gogliotti L, Sapino A, Bussolati G (eds) Breast cancer: biological and clinical progress. Kluwer, Dordrecht, p 176 Shidham VB, Qi DY, Acker S, Kampalath B, Chang CC, George V, Komorowski R (2001) Evaluation of micrometastases in sentinel lymph nodes of cutaneous melanoma: higher diagnostic accuracy with Melan-A and MART-1 compared with S-100 protein and HMB-45. Am J Surg Pathol 25(8):1039±1046 Shivers SC, Li W, Lin J, Stall A, Stafford M, Messina J, Glass LF, Reintgen DS (2001) The clinical relevance of molecular staging for melanoma. Recent Results Cancer Res 158:187±199 Slingluff CL Jr, Stidham KR, Ricci WM, Stanley WE, Seigler HF (1994) Surgical management of regional lymph nodes in patients with melanoma. Experience with 4,682 patients. Ann Surg 219:120±130 Smith LF, Cross MJ, Klimberg VS (2000) Subareolar injection is a better technique for sentinel lymph node biopsy. Ann J Surg 180(6):434±437 Statius Muller MG, Leeuwen PA van, Lange-De Klerk ES de, Diest PJ van, Pijpers R, Ferwerda CC, Vuylsteke RJ, Meijer S (2001) The sentinel lymph node status is an important factor for predicting clinical outcome in patients with State I or II cutaneous melanoma. Cancer 15; 91(12):2401±2408 Sugranes G, Vidal-Sicart S, Piulachs J, Bombuy E, Pons F, Castel T, Rull R, Herranz R, Visa J (2001) Gamma-detecting probe used intraoperatively to locate the sentinel lymph node in patients with malignant melanoma. Eur J Surg 167(8):581±586 Temple CL, Scilley CG, Engel CJ, Shum DT, Lohmann RC, Mattar AG, Zabel PL (2000) Sentinel node biopsy in melanoma using technetium-99m rhenium colloid: the London experience. Ann Plast Surg 45(5):491±499 Thelmo MC, Morita ET, Treseler PA, Ngyuen LH, Allen RE Jr, Sagebiel RW, Kashani-Sabet M, Leong SP (2001) Micrometastasis to in-transit lymph nodes from extremity and truncal malignant melanoma. Ann Surg Oncol 8(5):444±448 Thompson JF (2001) The Sydney Melanoma Unit experience of sentinel lymphadenectomy for melanoma. Ann Surg Oncol 8[Suppl]:44S±47S
Tsugawa K, Noguchi M, Miwa K, Bando E, Yokoyama K, Nakajima K, Michighishi T, Tonami N, Minato H, Nonomura A (2000) Dye- and gamma probe-guided sentinel lymph node biopsy in breast cancer patients: using patent blue dye and technetium-99m-labeled human serum albumin. Breast Cancer 7(1):87±94 Turner RR, Ollila DW, Krasne DL, Giuliano AE (1997) Histopathological validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 226:271±278 Uren RF, Howman-Giles RB, Thompson JF, Malouf D, Ramsey-Stewart G, Niesche FW, Renwick SB (1995) Mammary lymphoscintigraphy in breast cancer. J Nucl Med 36(10):1775±1780 Uren RF, Howman-Giles R, Thompson JF, McCarthy WH, Quinn MJ, Roberts JM, Shaw HM (2000) Interval nodes: the forgotten sentinel nodes in patients with melanoma. Arch Surg 135(10):1168±1172 Veronesi U, Paganelli G, Galimberti V, Viale G, Zurrida ST, Bodeni N, Costa A, Cicco C, Geraghty JG, Luine A, Sacchini V, Veronesi P (1997) Sentinel node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 349:1864±1867 Villa G, Agnese G, Bianchi P, Buffoni F, Costa R, Carli F, Peressini A, Solari N, Cafiero F, Mariani G (2000) Mapping the sentinel lymph node in malignant melanoma by blue dye, lymphoscintigraphy and intraoperative gamma probe. Tumori 86(4):343±345 Wagner JD, Corbett L, Park HM, Davidson D, Coleman JJ, Havlik RJ, Hayes JT 2nd (2000 a) Sentinel lymph node biopsy for melanoma: experience with 234 consecutive procedures. Plast Reconstr Surg 105(6):1956±1966 Wagner JD, Gordon MS, Chuang TY, Coleman JJ 3rd, Hayes JT, Jung SH, Love C (2000 b) Predicting sentinel and residual lymph node basin disease after sentinel lymph node biopsy for melanoma. Cancer 15; 89(2):453±462 Weiss M, Konz B, Schmid-Wendtner MH, Sander C, Dresel S, Tatsch K, Volkenandt M, Hahn K (2000) Metastases in malignant melanoma despite histologically negative sentinel lymph node: should the concept be changed? Nuklearmedizin 39(7):214±217 Wong SL, Chao C, Edwards MJ, Tuttle TM, Noyes RD, Carlson DJ, Laidley AL, McGlothin TQ, Ley PB, Brown CM, Glaser RL, Pennington RE, Turk PS, Simpson D, McMasters KM (2001a) Accuracy of sentinel lymph node biopsy for patients with T2 and T3 breast cancers. Am Surg 67(6):522±526 Wong SL, Edwards MJ, Chao C, Tuttle TM, Noyes RD, Carlson DJ, Cerrito PB, McMasters KM (2001 b) Sentinel lymph node biopsy for breast cancer: impact of the number of sentinel nodes removed on the false-negative rate. J Am Surg 192(6):684±649 Wong SL, Edwards MJ, Chao C, Tuttle TM, Noyes RD, Woo C, Cerrito PB, McMasters KM, University of Louisville Breast Cancer Sentinel Lymph Node Study Group (2001c) Predicting the status of the nonsentinel axillary nodes: a multicenter study. Arch Surg 136(5):563±568
Chapter 5
Positron Emission Tomography: Significance for Preoperative N-Staging N. Avril, W. Weber, M. Schwaiger
Introduction Positron emission tomography (PET) is an imaging technique that measures the concentration of positron-emitting radiopharmaceuticals in the body. It is based on external scintigraphic radiation detectors and, using appropriate mathematical algorithms, results in quantitative tomographic images. Depending on the radiolabeled probe used, PET determines physiological and biochemical processes in vivo noninvasively. Such processes include glucose and oxygen metabolism, blood flow, amino acid transport, and the presence and concentration of receptors, as well as the pharmacokinetics of pharmacological agents. Positron-emitting radioisotopes comprise common natural elements such as 11C, 15O, 13N, and 18F (Table 1). They can be used to radiolabel almost every organic molecule without significant modification of the biological behavior of the probe. The main advantage of PET over conventional scintigraphic procedures is its unique data acquisition, which allows quantitative measurements of regional tissue radioactivity. PET consists of three major components: molecular probes labeled with positronemitting radionuclides, the PET equipment enabling data acquisition, and mathematical models that describe the in vivo behavior of specific radiotracers in order to quantify physiological processes Table 1. Frequently used positron emitters (T1/2 physical half-life, Emax maximum positron energy, Rp path length in water with 50% (95%) of the positron stopped) Radionuclide
T1/2
Emax (MeV)
Rp (mm)
11
20.4 min
0.97
0.3 (1.6)
13
9.9 min
1.19
0.5 (2.1)
15
2.05 min
1.72
0.7 (3.3)
0.64
0.2 (0.9)
C N O
18
F
109.7 min
based on regional radioactivity measurements (Brown et al. 1993; Higashi et al. 1997; Avril et al. 2001).
Imaging Principles Positron emitting radionuclides are characterized by an excess of protons resulting in a nuclear imbalance. Protons are converted to neutrons by the emission of positrons. Positrons have the same mass as electrons, but are positively charged. After emission from the nucleus, positrons travel varying distances in tissue, depending on their kinetic energy. In the tissue they immediately interact with atomic electrons, resulting in annihilation of both particles (positron and electron). Their combined mass is converted into two high-energy photons that travel in opposite directions (180 8 apart) from the annihilation site. The energy of these photons is 511 keV for all positron emitters. PET scanners consist of radiation detectors arrayed in a circular fashion around the object to be scanned. The annihilation photons are detected by two opposing radiation detectors. A decay event is only recorded when both detectors simultaneously detect the annihilation photons. Therefore, unlike conventional gamma camera imaging, the PET scanner does not require additional collimation of the photons to define their direction. The result of this is that PET displays greater sensitivity and better spatial resolution than other scintigraphic imaging techniques currently available. Despite the relatively high energy (511 keV) of the annihilation photons, there is significant photon attenuation when the radioactivity distributed in the body is measured. Attenuation decreases the number of true coincidence events and is greater for coincidence lines passing through the center of the object. Therefore, it is necessary to compensate for the attenuation prior to the quantification of re-
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Chapter 5 Positron Emission Tomography: Significance for Preoperative N-Staging
gional radioactivity concentration. For defined objects the attenuation can be calculated, but measured attenuation correction is more accurate. This is achieved in most PET scanners by acquiring a transmission scan using one or more rod sources of 68 Ge/68 Ga activity that rotate around the object. The PET images are reconstructed from projection data from the emitted annihilation photons by the application of mathematical principles, referred to as filtered back-projection, or by the use of iterative reconstruction methods. PET data are presented in color or gray-scale images consisting of cross sections through the object. Modern PET scanners have a field of view of between 15 and 25 cm, which allows simultaneous acquisition of multiple transaxial slices. Depending on the imaging protocol employed, current PET instrumentation allows ªdynamic imagesº to be obtained by acquisition of multiple time frames in the same field of view. This enables analysis of the tracer concentration over time for particular organs. In contrast, combination of the data sets of consecutive ªfields of viewº enables whole-body imaging in humans. The images produced by PET are spatial maps of radioactivity distribution. The spatial resolution of current PET instrumentation is approximately 5±7 mm. However, for research purposes, PET scanners with a spatial resolution of less than 2 mm are being developed. The limited spatial resolution of PET results in considerable partial volume effects. Therefore, the true tracer concentration will be underestimated in the measurement of the radioactivity concentration of small objects. However, if the dimensions of given structures are defined correction factors can be applied to compensate for partial volume effects.
Radiopharmacy The preparation of PET radiopharmaceuticals requires a dedicated radiopharmaceutical facility. The most frequently used positron-emitting radionuclides (11C, 15O, 13N, and 18F) have short physical half-lives, ranging from 122 s for 15O to 110 min for 18F (see Table 1). They are produced in a cyclotron by accelerated particle bombardment with either protons or deuterons. A few positron-emitting radionuclides are generator products (e.g. rubidium-82, which is used to evaluate organ
blood flow). Because of the short physical halflives of the most common positron-emitting radionuclides, the cyclotron has to be in close proximity to the PET scanner. However, 18F-labeled compounds (t1/2 110 min) can be transported to more distant PET scanners (satellite concept). Fluorine, although not often found in naturally occurring molecules, can readily substitute for a hydrogen or hydroxyl group. The tremendous interest in 18F-labeling is also based on logistical considerations, as a single tracer synthesis can be used for multiple patients. Important factors concerning PET radiopharmaceuticals are the time of synthesis, the yield and purity, and the specific activity. In most circumstances the synthesis must be completed within three half-lives of the radionuclide used. The glucose analogue 18F-fluorodeoxyglucose (FDG) is the most commonly used PET radiopharmaceutical. This tracer enables visualization of regional glucose metabolism. Following intravenous injection of FDG, the tracer is distributed throughout the body in a similar manner to glucose. The presence of glucose transporter proteins (Glut-1, -2, -3, -4, -5) is essential for facilitation of glucose transport through the cellular membranes. High levels of glucose transporter type 1 (Glut-1) have been reported in various malignant tumors (Brown et al. 1993; Higashi et al. 1997; Avril et al. 2001). After transmembranous transport, FDG is intracellularly phosphorylated by the enzyme hexokinase. FDG-6-phosphate is a poor substrate for either glycolysis, glycogen synthesis, or pentose phosphate shunt pathways. The rate of dephosphorylation may vary in tumors; however, it is assumed to be low. FDG-6-phosphate is a polar molecule that cannot pass the cell membrane and is therefore trapped intracellularly. The accumulated amount of FDG-6-phosphate in the cells is proportional to the exogenous glucose utilization. Depending on the time lapse to PET scanning after tracer injection, the PET signal initially represents intravascular 18 F-FDG activity, followed by extracellular FDG equilibration during the first few minutes. Later, the majority of the 18F signal reflects intracellular FDG-6-phosphate. In the brain, the rate of glucose transport exceeds the rate of glucose utilization, and therefore, hexokinase activity is considered to be the ratelimiting step. In muscle cells, Glut-1 and Glut-4 are stored in cytoplasmatic microsomes and translocated into the cellular membrane depending on the energy demand. The rate-limiting step for glu-
Quantitative Measurements Table 2. Radiopharmaceuticals used for detection of increased metabolism and tumor growth Radiopharmaceutical
Targeted process
F-18-fluorodeoxyglucose (FDG)
Glucose metabolism
F-18-fluoride
Bone remodeling
F-18-fluorothymidine
DNA synthesis (thymidine phosphorylation)
F-18-fluoromisonidazole (FMISO)
Hypoxia
F-18-fluoromethyltyrosine
Amino acid transport
F-18-fluoroethyltyrosine
Amino acid transport
C-11-methionine (MET)
Amino acid transport and metabolism
C-11-choline
Choline metabolism
O-15-water
Perfusion
cose metabolism (FDG uptake) of tumor cells is still unknown. Various fundamental biological and physiological properties can be defined by PET imaging (Table 2).
Quantitative Measurements Several methods are employed for the analysis of PET studies in oncology. Usually, regions of interest (ROI) are placed in the images to obtain the regional radioactivity concentration in tissue. The simplest means of analysis is to calculate target-tonontarget ratios. Dose uptake ratios have also been introduced to normalize regional tracer uptake with reference to injected dose and patient's body weight. Different terms are used, including SUV (standardized uptake value), SUR (standardized uptake ratio), DUR (differential uptake ratio) and DAR (differential absorption ratio). These methods compare regional tracer uptake in patients with different background radioactivity, although several factors have to be taken into account when this approach is used. SUV values vary depending on how soon imaging is done after intravenous tracer injection. For objective comparison of the tracer uptake of tumors in different patients, it is important to use the plateau phase of tracer retention at the time of imaging. Most tumors have
reached the plateau phase by approximately 1 h after injection of FDG. When tracer uptake on different occasions in the same patient is compared, e.g., in therapy-monitoring studies, increasing FDG accumulation over time requires that PET imaging be carefully timed. Another source of inaccuracy is the distribution of FDG in different body compartments. Fat, for example, has a lower FDG uptake than other tissues. Therefore, FDG uptake in tumors will be overestimated in heavy patients. To correct for these effects the use of the lean body mass or the body surface area has been suggested (Zasadny et al. 1993; Kim et al. 1996). However, when these correction methods were applied in a study population of breast cancer patients no better results were obtained than with other SUV approaches to differentiating between benign and malignant breast tissue (Avril et al. 1997). As a result of the competition between the transport of endogenous glucose and FDG molecules into the cell, FDG uptake in tissue is sensitive to variations in blood glucose levels. In patients with lung cancer a markedly decreased FDG uptake (41.8Ô15%) was found when plasma glucose levels were about double those recorded in fasting conditions (Langen et al. 1993). The lumped constant (LC) calculates glucose metabolism based on FDG uptake. This parameter relates the steady state phosphorylation rate of FDG to that of glucose and was determined first for brain tissue by means of the 14carbon-2deoxyglucose method (Sokoloff et al. 1977). It was found to be different in other tissues, such as the myocardium, and also not uniform among different brain regions, e.g. the hippocampus and cerebellum. Furthermore, the LC is dependent on blood glucose and insulin concentrations. Therefore, even tumors or metastases in the same patients may not have the same lumped constant. Hence, FDG data cannot be extrapolated to quantitative aspects of tumor glucose metabolism. During data acquisition the most serious sources of inaccuracy are attenuation of the emitted annihilation gamma rays, partial volume effects, and patient movement during PET scanning. Attenuation correction is necessary to obtain quantitative data. Lack of attenuation correction leads to overestimation of tracer accumulation at the body surface and distortion in shape. Partial volume effects, caused by limited sampling and resolution, result in underestimation of regional tracer uptake. This effect is greater in tumors
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Chapter 5 Positron Emission Tomography: Significance for Preoperative N-Staging
smaller than twice the resolution of the imaging system; although this does not mean that PET cannot detect small lesions. If the concentration of the tracer within the lesion is high enough, image contrast will be sufficient for detection. For appropriate correction, necessary recovery coefficients need to be determined from phantom studies. In the evaluation of regional tracer uptake, the placement of regions of interest (ROI) in target and nontarget organs, the size of the ROI, and the time since tracer injection are all important factors that need to be considered. Compartmental analysis methods demonstrating underlying physiological parameters require sophisticated acquisition and processing protocols. Patlak et al. (1983) introduced a theoretical model of blood±brain exchange for the analysis of multiple-time tissue uptake data. This approach can be generalized to include tumors if a unidirectional tracer transfer process predominates during the PET data acquisition period. Dynamic data acquisition for the assessment of time±activity curves over the tumor and measurement of the tracer input function are necessary for calculation of the tracer influx constant (K). The potential advantage of determining the influx constant by Patlak analysis is that it does not require PET scanning to be performed at the time of the plateau phase of tracer accumulation in tumors. Furthermore, if the input function is obtained from the arterial blood pool in PET images, the Patlak analysis is not affected by scanner cross-calibration. For analysis of oncological PET studies, however, dynamic PET studies are often not available, and owing to time constraints, whole-body imaging is clinically more valuable than dynamic measurements over a limited field of view.
Clinical Applications Initially, PET was used for studies of the brain and the heart, but its applications in oncology are now expanding more and more. Although many PET studies have focused on organ physiology and pathophysiology, it is increasingly being used in patients for the diagnosis and staging of malignant tumors. The clinical success of PET is primarily related to the use of 18F-fluorodeoxyglucose (FDG), a glucose analogue that assesses regional glucose metabolism within the body. Various malignant tu-
mors are characterized by increased glucose metabolism, as was first described by Warburg and his group in the early 1920s (Warburg et al. 1930; Warburg 1956). Recently, the molecular basis of this finding has been found. Increased metabolism, including increased rates of glucose consumption, was noted following activation of oncogenes or loss of tumor suppressor genes (Flier et al. 1987). Cells expressing the ras or src oncogenes exhibited increased rates of aerobic glycolysis and increased levels of glucose transporter proteins only hours after malignant transformation by oncogenic viruses. In addition to the increased glucose transport into cells, a five-fold overexpression of the type II hexokinase gene was found in a hepatoma cell line compared with normal hepatocytes (Rempel et al. 1996). Recent molecular studies suggest that cellular energy metabolism is predominantly affected by the expression of transcription factors that regulate the genes that encode metabolic enzymes following the development of malignancy. Since FDG-PET is able to delineate malignant tissue, metabolic imaging can be used to differentiate between benign and malignant tumors, assess the extension of disease, detect tumor recurrence and monitor response to therapy.
Patient Preparation Patients undergoing neurological and oncological FDG-PET imaging are studied in the fasting state. Pregnant and breastfeeding women must be excluded. Diabetic or other patients presenting with hyperglycemia often have decreased FDG uptake in the target organs. Therefore, the blood glucose level of all patients should be obtained prior to FDG injection. If the blood glucose level exceeds 150 mg/dl, FDG-PET imaging is not recommended.
Diagnosis of Primary Tumors There are a number of studies reporting on the accuracy of FDG-PET for diagnosing primary tumors. Increased glucose metabolism is essential for successful visualization of malignant tissue. There are only a few tumors that are characterized by low metabolic activity. These include differen-
Limitations of PET Imaging
tiated thyroid carcinomas, neuroendocrine tumors, hepatocellular carcinomas, mature teratomas, and prostate cancer. In general, FDG-PET should not be used as a screening test for identifying cancer. Rather, patients should be referred to PET imaging for further evaluation and characterization of suggestive masses found by conventional imaging modalities. Although PET offers excellent diagnostic accuracy for many tumors, it cannot substitute for histological verification. The clinical application of FDG-PET in the diagnosis of primary tumors is therefore often restricted to high-risk patients about to undergo surgery or to guidance of invasive procedures by identifying viable tumor tissue.
Diagnosis of Lymph Node Metastases PET offers particular advantages in evaluating lymph nodes. When CT is applied the size of the lymph nodes is a determining factor, although even lymph nodes that are normal in size can be tumor involved, just as lymph nodes can be nonspecifically enlarged. In detection of breast cancer and melanoma and in the mediastinal staging of lung cancer, FDG-PET is clearly superior to conventional imaging modalities. In principle, PET permits the recognition of positive lymph nodes regardless of size, but has limited sensitivity in detecting microscopically small tumors. Spatial resolution is an important factor, as existing PET scanners do not have sufficiently high resolution to enable detection of micrometastases. The further development of PET scanners and new imaging processes should, however, improve the spatial resolution in the future.
Staging of Disease The prime advantage of PET in the staging of malignant disease is mainly based on the fact that PET imaging is not influenced and clouded by anatomical details. These make assessments by CT and MR imaging difficult, especially in patients presenting with subtle abnormalities. Increased metabolic activity of malignant tissue results in a favorable image contrast, which makes the reading of PET images relatively easy. On the other hand, the lack of anatomical landmarks often hampers the exact localization of metabolically active tissue.
These problems can be addressed by combining anatomical and functional imaging. Current PET scanners complete whole-body imaging within a time frame of about 60 min. Therefore, wholebody PET imaging enables primary tumors to be characterized, lymph nodes evaluated and distant metastases identified in a single imaging procedure.
Monitoring Effects of Therapy The quantitative assessment of tumor metabolism by FDG-PET is a unique means of monitoring the response of malignant tissue to therapy. Various studies have shown that the reduction of tumor glucose metabolism precedes a reduction in tumor volume (for a recent overview see Weber et al. 2000). In addition, a reduction in FDG uptake may be quantified more easily than reduction of tumor size, which is conventionally assessed by measuring the maximum diameter of the tumor mass. Weber at al. (1999, 2000) have shown high reproducibility of the FDG signal, indicating that tumor glucose utilization rate is stable without therapeutic interventions. Monitoring the effects of therapy consists in predicting response to therapy by repetitive measurements of tumoral glucose metabolism and assessing response to therapy by measuring the metabolic activity of any residual masses. Various studies have shown that repetitive measurements of tumoral glucose metabolism early after the onset of therapy (e.g., after the first or second course of chemotherapy) make it possible to predict response. Tumors found by histology after completion of chemotherapy to have had a good response are characterized by a significant decrease in glucose metabolism, whereas nonresponding tumors generally maintain their metabolic activity.
Limitations of PET Imaging Intracellular accumulation of FDG is not a tumorspecific process but reflects regional tissue glucose metabolism. Therefore, false-positive PET results can occur, typically when inflammatory processes are present. Acute soft tissue infections, abscesses, and also tuberculosis or sarcoidosis have been reported to result in increased glucose consumption.
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Chapter 5 Positron Emission Tomography: Significance for Preoperative N-Staging
The specificity of FDG-PET imaging depends heavily on the prevalence of inflammatory processes and ranges from 60% for ovarian masses to almost 100% for axillary lymph node staging in breast cancer.
Exclusion of Brain Metastases in Staging Programs Brain tumors are not subject to the ªsentinel node problem,º because as a rule they do not metastasize. However, in the staging procedure, peripheral cancer metastases into the brain as well as other organs must be excluded or confirmed. Some basic information is therefore of interest at this point. Normal gray matter has a considerably higher glucose metabolism than white matter. Therefore, the contrast between brain tumors and normal tissue is often low. This makes FDG-PET studies of the brain more difficult to interpret than those of other parts of the body. In most cases, the FDG uptake of high-grade tumors is within the same range as that of normal cortex, whereas low-grade tumors typically appear as areas with reduced glucose metabolism. Radiolabeled amino acids provide a much better image contrast than FDG for the detection of brain tumors. In a comparative study, the contrast between brain tumors in C-11methionine PET studies was an average of 2.5 times that for FDG-PET (Kaschten et al. 1998). Unlike that of FDG, the uptake of C-11-methionine is increased in both high- and low-grade tumors. Therefore, methionine PET has been shown to differentiate between low-grade tumors and nontumoral lesions. Concerning primaries of the brain it is important to note that accumulation of C-11methionine in low-grade oligodendrogliomas can be as high as in glioblastomas. Therefore, radiolabeled amino acids appear to be more valuable for detecting and delineating gliomas than for grading tumors (Wurker et al. 1996).
System-immanent Properties of PET to Support the Sentinel Node Concept For metastases of peripheral cancers, CT and MRI are the methods of choice. However, PET, and especially C11-methionine-PET, can be helpful as a second method to determine whether a metastasis derives from a fast- or a slow-growing cancer. Finally, it must be pointed out that PET is superior to CT and MRI at least in some circumstances. Its advantages are described in the part of the book relating to the different cancer entities [see Chapters 21±27 for value of PET in staging cancers of the breast, thyroid, aerodigestive tract, lung, esophagus and gastrointestinal tract; for evaluation specifically of breast cancer see work by Smith et al. (1998) and Crippa et al. (1998), which is cited with more detail in Chapter 21]. In addition, it must be emphasized that PET detects only cancer-infiltrated lymph nodes, which can be identical with the sentinel node(s), but in the case of breast cancer a positive PET excludes any possibility of avoiding complete axillary revision. Complete axillary revision (levels I and II) must be carried out without fail in all cases, and in some supplementary FNAC should also be performed for greater certainty.
References Avril N, Bense S, Ziegler SI, Dose J, Weber W, Laubenbacher C, Romer W, Janicke F, Schwaiger M (1997) Breast imaging with fluorine-18-FDG PET: quantitative image analysis. J Nucl Med 38:1186±1191 Avril N, Menzel M, Dose J, Schelling M, Weber W, Janicke F, Nathrath W, Schwaiger M (2001) Glucose metabolism of breast cancer assessed by 18F-FDG PET: histologic and immunohistochemical tissue analysis. J Nucl Med 42:9±16 Brown RS, Wahl RL (1993) Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer 72:2979±2985 Flier JS, Mueckler MM, Usher P, Lodish HF (1987) Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 235:1492±1495 Higashi T, Tamaki N, Honda T, Torizuka T, Kimura T, Inokuma T, Ohshio G, Hosotani R, Imamura M, Konishi J (1997) Expression of glucose transporters in human pancreatic tumors compared with increased FDG accumulation in PET study. J Nucl Med 38:1337±1344
References Kaschten B, Stevenaert A, Sadzot B, Deprez M, Degueldre C, Del Fiore G, Luxen A, Reznik M (1998) Preoperative evaluation of 54 gliomas by PET with fluorine-18-fluorodeoxyglucose and/or carbon-11-methionine. J Nucl Med 39:778±785 Kim CK, Gupta NC (1996) Dependency of standardized uptake values of fluorine-18 fluorodeoxyglucose on body size: comparison of body surface area correction and lean body mass correction. Nucl Med Commun 17:890± 894 Langen KJ, Braun U, Rota Kops E, Herzog H, Kuwert T, Nebeling B, Feinendegen LE (1993) The influence of plasma glucose levels on fluorine-18-fluorodeoxyglucose uptake in bronchial carcinomas. J Nucl Med 34:355±359 Patlak CS, Blasberg RG (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Metab 3:1±7 Rempel A, Mathupala SP, Griffin CA, Hawkins AL, Pedersen PL (1996) Glucose catabolism in cancer cells: amplification of the gene encoding type II hexokinase. Cancer Res 56:2468±2471
Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakadura O, Shinohara M (1977) The [C-14]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897±916 Warburg O (1956) On the origin of cancer cells. Science 123:309±321 Warburg O, Wind F, Neglers E (1930) The metabolism of tumors. Arnold Constable, London, pp 254±270 Weber WA, Ziegler SI, Thodtmann R, Hanauske AR, Schwaiger M (1999) Reproducibility of metabolic measurements in malignant tumors using FDG PET. J Nucl Med 40:1771±1777 Weber WA, Schwaiger M, Avril N (2000) Quantitative assessment of tumor metabolism using FDG-PET imaging. Nucl Med Biol 27:683±687 Wurker M, Herholz K, Voges J, Pietrzyk U, Treuer H, Bauer B, Sturm V, Heiss WD (1996) Glucose consumption and methionine uptake in low-grade gliomas after iodine-125 brachytherapy. Eur J Nucl Med 23:583±586 Zasadny KR, Wahl RL (1993) Standardized uptake values of normal tissues at PET with 2-[fluorine-18]-fluoro-2deoxy-d-glucose: variations with body weight and a method for correction. Radiology 189:847±850
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Chapter 6
Detection and Radiological Imaging of SLN
In many tumor diseases, locoregional recurrence after operation is a serious problem, and is always a shock to patients and doctors alike. The problem of locoregional recurrences is also especially important when the patients are treated by breast-conserving surgery, because locoregional recurrences occur even in approximately 10% of cases where primaries are small (pT 1 a±1 c) and homogeneous radiation therapy has been delivered to the remaining breast. When all operable breast cancers are considered together, the locoregional recurrence rate increases to ranges of up to 35% (Rauschecker et al. 2001). New approaches with the aim of improving or solving this problem are therefore a high priority. In this context, improvements are necessary to make it possible to attain R0 resection (controlled by surgeons in consultation with the acting pathologists) by intraoperative histopathological examination of the margins of the lumpectomy or wide excision specimens and of the margins of any further marginal excisions around the primary excisate, e.g., in cases with an extensive intraductal component (EIC) or direct cancer infiltration reaching parts of the margins of the primary excisate. In addition, continuous excision of the blue dye- and 99mTc-marked or -labeled strand(s) containing the draining lymphatics seems to be important for the attainment of maximum locoregional cancer clearance. Such new approaches in tumor treatment are often published on the Internet and also discussed on television, where new guidelines can be received by doctors and patients simultaneously. This leads to frequent questioning of doctors about the quality of such new diagnostic and treatment protocols and the success achieved with them. Therefore, it is now more important than ever before for all medical specialists involved in patients' cancer treatment to keep fully informed and up to date with new ideas and techniques. The new sentinel
node approach is one such theme, challenging medical doctors working in a broad field of cancer diagnosis and treatment; its application is currently in the course of being extended from melanoma and breast cancer to head and neck cancers, gastrointestinal cancers, and both male and female urogenital cancers and now involves nearly all surgical disciplines. When in breast-conserving therapy protocols axillary revision with postoperative complications (bleeding infections, seroma formation, lymphedema etc.) can be largely avoided and atypically located sentinel nodes and/or sentinel nodes in different basins can be detected, these facts indicate that breast cancer treatment has been highly beneficial. Apart from this, in the case of a false-negative diagnosis, e.g. on the grounds of examination of the axillary lymph nodes, it is well known that the development of local and regional recurrence makes both doctors and patients afraid that the primary tumor is progressing and the prognosis is therefore poorer. Initially there was a great deal of enthusiasm for the sentinel node concept, but doctors soon had to realize that good practice is not simple and that there are many aspects needing consideration, while good interdisciplinary cooperation and improvements are necessary before these methods, some of which are quite new, can be successful in all hospitals in which tumor treatment is carried out and which claim to provide optimal quality care (centers of excellence). The objective that the development of a simple, minimally invasive, technique for determining whether regional node metastasis has occurred, was clearly formulated by Krag et al. (1995) early in the emergence of the sentinel node concept and its application in patients with melanoma. This formula also fits in with most other cancer entities and in many clinics is already optimized by support from existing well-defined guidelines (Krag et al. 1995; Albertini et al. 1996; Veronesi et al. 1997; Borgstein
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Chapter 6 Detection and Radiological Imaging of SLN
et al. 1998; Cascinelli et al. 1998; Cox et al. 1998; Leong et al. 1998; Paganelli et al. 1998). It is still too early to intensify the spread of these new interdisciplinary approaches, including all techniques for blanket coverage, because in most countries processes for technical updating and development of local and multicenter studies are still only just being devised and set up, and experiences of at least some of the approaches are no more than preliminary. Furthermore, there are some important points that need further clarification. One of these is tumor cell clearance in continuity between the primary cancer and the sentinel node(s); another is, for instance, good practice in the investigation of sentinel node(s) in breast cancers with parasternal node(s) located along the mammaria interna blood vessel strands. Nonetheless, it seems clear that the most important preconditions for good end-results are highprecision work and close cooperation among specialists in nuclear medicine, surgeons, and pathologists. On this very point, Glass (2001) has recently stated very clearly that lymphoscintigraphy and radioguided surgery are now also valuable tools that can be used in contemporary surgical staging of malignancies, continuing with the warning that these techniques require attention to detail and a moderate level of experience for optimal clinical use. Glass encourages cooperation of teams. He emphasizes that the wide use of these procedures has demonstrated that the methodology can be learned with guidance from a few dozen cases. Accuracy in use significantly enhances the sentinel node technique. Discussion continues about the question of whether the sentinel node alone should be histopathologically evaluated and what distinguishes the cases in which it is necessary to investigate all nodes in the basin concerned. At first view this does not seem to be a difficult question, as the current literature demonstrates. However, in some specific regions, such as the axilla and the pelvis, the nodes are so closely packed together that at level I of the axilla, for instance, 3±5 nodes can all be sentinels and these nodes cannot be clearly separated by the gamma camera. In contrast, with the blue dye method it is easier to separate the nodes (Fig. 1 a). When radiolabeling methods alone are used (Fig. 1 b), however, and on the grounds of these we would accept basin clearance by extirpation of
the nodes at level I ± thinking that the sentinel node(s) are included in this group ± we incline to the opinion propagated years ago by the Rotterdam-Breast Cancer Research Group that only the level I lymph node group should be removed. Most research groups have not found only one sentinel node in the axillary basin: on average just under or over two nodes have been found. Because the use of different labeling solutions results in different speeds of passage through level I lymph nodes to nodes of level II, it is not clear to what extent published results are comparable. Furthermore, detection of multiple sentinel nodes in different levels of the same basin is critical with regard to strategies on further removal (Fig. 1 c). From these discussions it follows that the work carried out with reference to the sentinel node concept must be done very precisely. The ªcontinuityº between the primary and the sentinel node(s) is a serious problem in cases with malignant melanomas of the foot and lower leg draining to the inguinal nodes. Such long pathways of the lymphatics not uncommonly lead to a predisposition to the development of so-called transit metastasis with no possibility of precalculating the likelihood. There are a great many other incalculable problem areas in addition to this one. In particular, the drainage pathways of cancers localized in the upper respiratory tract or within the oral cavity are not always calculable, which means the draining lymph nodes and the lymphatics to them cannot be easily reached by a surgical approach. The same is true for cancers of the gastrointestinal tract and the pelvic region.
Methodical Work-up and Improvements The range of stains and radioactive substances that can be used for labeling is well developed, but there is still room for improvement. It is also not clear how probe and tracer techniques can be combined. One novel procedure in this connection is the radiological investigation of lymph nodes with iron oxide used for labeling of the sinus histiocytes to find defective areas of nodes with tumor infiltration (point 1 in Table 1). In addition, the problem of the injection route has not been entirely solved. It seems important that most hospitals have not accepted intratumoral
Methodical Work-up and Improvements Fig. 1 a±c. Visualization of lymphatics and the sentinel node(s) using blue stain (patent blue) and exact localization by the use of 99mTc-nanocolloid. a With free sight of the blue-stained lymphatics and blue-stained sentinel lymph nodes (SLN) the path of locoregional spread can be defined precisely. b Imaging and labeling (lymphoscintigraphy) allow precise localization of the SLN. Total excision can be controlled by use of a gamma probe. Note that in cases with centrally located primaries the singular SLN can be located in the axillary basin. [Figure kindly made available by Professor Paganelli, Milan, Italy: Detection of a solitary SLN in the axilla (99mTc-nanocolloid).] c In this case too-small colloid particles were used; the radiolabeled particles passed through the SLN too quickly and accumulated in subsequent nodes (high ªspilloverº)
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Chapter 6 Detection and Radiological Imaging of SLN Table 1. Favorite pharmaceuticals for routine use as tracers for sentinel node detection 1) Pharmaceuticals and tracers used for sentinel node detection a) Blue dyes and others Patent blue Indigo carmine blue dye (see Kim et al. 2001) Isosulfan blue dyes (Lymphazurin ± specifically used for colored N-staging)
b) 99mTc-labeled compounds: 99m Tc-nanocolloid 99m Tc-human serum albumin 99m Tc-tin colloids
see Waters et al. 2000 Wiese et al. 2000 Paramo et al. 2001 Saha et al. 2001
see Kim et al. 2001
c) Iodine-125 for staging of differentiated thyroid cancer (see also Chapter 22) d) Systemically administered compounds: Ultra small particles of iron oxide (USPIO) (see also Chapter 19) 2) Modalities of injection a) Intradermal (breast cancer, malignant melanoma) injection is preferred in the majority of breast cancers because also from deeper areas of the parenchyma the lymphatics drain first to superficial regions and then to the sentinel nodes b) Peritumoral injection is compatible with deeply located primaries which can drain to interpectoral nodes c) Intratumoral injection has been practiced in the very early stages of the sentinel node concept developed, but hen widely left because of warning signals that the tumor spread can be propagated by this application modality But now, in cases with non palpable breast cancers and diffuse cancer growth, showing very limited extension injection of a small portion of the labeling solution into the cancer area is carried out by some groups, in order to recover the lesion intraoperatively more precisely. This strategy has been called radioguided occult lesion localization (ROLL)
injection of labeling substances and/or solutions. This can be fully understood on two grounds: 1. An acute increase in hydrostatic pressure can open small veins, pressing tumor cells into the vascular lumina with a consequent increase of metastatic potential. 2. The lymph vessels are much more highly developed in the tumor periphery than in its central parts (point 2, of Table 1). For visualization of the connection of primaries with their sentinel nodes the best method is the use of blue stains; but detection of the sentinels is increased by labeling with 99mTc used as a tracer; therefore, a combination of both methods is preferred by many working-groups who are interested in sentinel node detection and investigation. A further point is improvement of the detection systems (point 3, Table 1) and kinds of imaging.
In addition, there are new approaches that pathologists can apply. · For confirmation of the diagnosis of the primary made with the aspiration biopsy or punch biopsy techniques. · For evaluation of the sentinel nodes. ± Exact statistically significant evaluation procedures are needed for SLNs. This demand implicates the key question of how many sections are needed and how far apart they must be to increase reliability in exclusion or confirmation of metastatic involvement. ± Evaluation of combined H&E staining and immunohistochemical reactions. ± Evaluation of RT-PCR techniques for cancer cell detection in sentinel nodes (see point 4d, Table 1).
Intraoperative Sentinel Node Detection by Use of the Gamma Probe
The ambitious new approaches to more intensive investigation of the SLN(s) than of the excised lymph node groups when lymph node staging is practiced indicate positive developments in lymph node staging. Nonetheless, when this procedure is practiced with the object of a high degree of safety in detection at least of small tumor cell areas (clusters), a large number of sections of the sentinel node must also be stained immunohistochemically with antibodies (e.g. against cytokeratins, or S-100 protein and other markers). As long as such investigations are covered by clinical research programs the results will be optimal, because these investigations are important factors in scientific success. However, when such investigations are introduced into clinical routine programs and there are no rules for adequate payment (payment for primary or secondary antibodies, technicians, etc.), these extremely sophisticated and intensive investigations cannot be performed, or if they are, because no adequate payment is made for them, we have to fear that they are not correctly done. Harmonization in the usage of tracer substances is a difficult problem both technically and also legally, in view of the differing laws among the nations throughout the world. Because the background preconditions are so inhomogeneous, international and comparative studies are difficult to perform. It seems that in the United States and also in some European countries the diversification of tracer development is much more advanced than in Germany. However, it seems that as the European integration progresses, some of the problems will be solved. Besides the radiolabeled tracers, the development of colloid particle production and re-
search on adaptation to clinical performances seem to be in progress.
Techniques in Sentinel Node Detection Tracers and Application Modality A large number of tracers and carrier solutions have been used in experimental and routine studies, but few of the pharmaceuticals have proved suitable for development for standard use. Their limited suitability depended mostly on their quality and was based at least partly on the requirements that they · Involve no toxicity or genetic injury to the patient and extremely low antigenicity, in order to avoid allergic or anaphylactic reactions as far as possible · Be largely innocuous in terms of radioactive injury to medical and nursing staff as well as patients With due consideration for all this, the following compounds can be seen as the favorites for routine usage (Table 1).
Intraoperative Sentinel Node Detection by Use of the Gamma Probe Figure 2 demonstrates roughly the different components of a gamma probe unit. The collimator takes up the signals coming from the labeled SLN. The signals are then sent to the scintillation crystal
Fig. 2 a, b. Collimator, with the honeycomb structure of its face (a) and perpendicular side view (b) is shown. The gamma rays pass through the collimator and are detected within the scintillation crystal photo-multiplier assembly
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Chapter 6 Detection and Radiological Imaging of SLN
and led through the photomultiplier tubes to the measuring instruments. Dedicated processing components determine the gamma ray energy and its location. The kind of imaging influences the diagnostic result. It can be dynamic, early, or early and late.
Efforts at Optimization in 99mNanocolloidMediated Sentinel Node Localization Van Dongen's group (Gommans et al. 2001) tried to optimize 99mTc-nanocolloid sentinel node detection in breast cancer cases by improving the count rate by use of higher specific concentrations of 99mTccolloidal albumin, with increased radiochemical labeling efficiency and stability. The particle size of colloidal albumin was tested by dynamic light scattering at angles of 30.28, 62.68, and 908. For labeling under nitrogen a maximum acceptable concentration of 10 MBq/lg was found, which complies with the specifications of the manufacturer, when the labeling was carried out in vacuum vials; 2.5-fold radiochemical labeling efficiency over the entire period was achieved, and a significant improvement (P < 0.002) was found in vivo. The investigators concluded that, although the rate of successful visualization of the SLN was high, the count rate achieved with the highest concentration of 99mTc-colloidal albumin was 9 times as high. This facilitated SLN detection by the gamma probe during surgery.
Histo- and Cytopathological Diagnosis It is beyond doubt that the sentinel node approach sometimes restricts the conventional histopathological diagnosis, which has to be made on the basis of primary tumors. The highest degree of limitation exists in the diagnosis of malignant melanomas. As a rule, in practice this tumor is often removed in toto with an adequate safety margin before the sentinel node search is started (see also Chapter 25). In breast cancer the diagnostic results obtained by radiodiagnosis (mammography, MRI) can be supplemented or complemented by the use of fineneedle aspiration cytology (FNAC) before SLN labeling takes place.
We cannot recommend a routine strategy in which lumpectomy/wide excision is first performed for removal of the primary and the sentinel nodes are then labeled by the blue dye method and/or 99m Tc-nanocolloid labeling, because by then the drainage ways may have changed as a result of operation-related local injuries. Such strategies would have been limited to subdermal injection topographically corresponding to the location of the primary. In surface cancers of the epidermis and mucosa (mostly squamous cell cancers) in the head and neck regions and oropharynx or vulva, the use of exfoliative cytology or minibiopsies can help to confirm the cancer diagnosis before the sentinel node biopsy procedure is started. In the diagnosis of lung cancer, verification of non-small-cell type (nSCLC) and exclusion of small-cell type (SCLC) is possible preoperatively in more than 90% of cases, when endoscopic biopsies and/or cytology methods are applied before N-staging followed by sentinel node search procedures, which can be further extended by intraoperative N-staging before lobectomy or pneumectomy. In the case of gastrointestinal cancers or neuroendocrine cancers, the diagnosis is most frequently confirmed by investigation of endoscopically taken biopsy specimens. In prostate cancer treatment sentinel node labeling with 99mTc-colloids is not limited by needle biopsies taken before N-staging is carried out. The histopathological and both cytopathological and immunohistochemical spectra for confirmation of cancer and biological analyses ± critically evaluated in chapter 30 is summarized in Table 2. Table 2 gives an overview of the spectrum of histo- and cytopathological possibilities for confirmation and subtyping of cancer and the evaluation of prognostic factors Sun et al. (2001) compared the efficiency of 99m Tc MIBI single photon emission computed tomography (SPECT) and computed tomography in head and neck cancer patients in whom involvement of cervical lymph nodes was suspected. In 40 of 50 patients with nasopharyngeal cancers (NPC) cervical lymph node involvement was detected. For 22 lymph node lesions there were discrepancies in the results between 99mTc MIBI-SPECT and CT 99m Tc, and in these MIBI SPECT correctly detected 5 metastatic and 7 benign lymph node lesions. 99m Tc MIBI SPECT and CT correctly detected all of the 18 metastatic lymph node lesions. In total,
H and E-staining CK . 8, 18 /. CD 68 allow discrimination of cancer cells from histiocytes. Actin labels myoepithelial cells
HE, vimentin, HMB45, S100 protein. Melan A/Mart-1
HE, CK, 5, 6 for squamous cell cancers CK 8, 18 for adenocarcinomas
HE, CK 5, 6 for squamous cell cancers
HE, CK 5, 6 for squamous cell cancers CK 8, 18, 19 for adenocarcinomas
HE, CK 8, 18
HE, cytokeratin (pan), neuromarkers
HE, capsular infiltration or perforation
Breast cancer
Malignant melanoma
Head, neck and oropharyngeal cancers
Genital cancers Female: vulva, cervix
Non-small-cell lung cancer (nSCLC)
Gastrointestinal cancers
Neuroendocrine cancers
Prostate cancer
Male: penile cancer
Verification subtyping
Cancer type(s)
Gleason grade acid prostate phosphatase, prostate-specific antigen in the case of marker loss also CK (pan), P504S
Degree of malignancy S100-protein chromogranin A synaptophysin
Degree of malignancy adenocarcinoma vs diffuse type c-erb B2
Degree of malignancy c-erb B2
Degree of malignancy c-erb B2 in cervical cancers
Degree of malignancy (G1±G3)
Low rate of c-erb B2-positive cases
Estrogen and progesterone receptor (staining intensity; % of positive cells c-erb B2 (p185) cathepsin D (bioch.)
Differentiation products/grading
MIB I, KiSI, S-phase, ploidy
MIB I, KiSI, S-phase, ploidy
MIB I, KiSI, S-Phase, Ploidy
MIB I, KiSI, S-Phase, Ploidy
MIB I, KiSI, S-phase, ploidy
MIB I, KiSI, S-phase, ploidy
MIB I, KiSI, S-phase, ploidy
MIB I (Ki 67)after microwave preparation KiS1 low proliferation medium, high proliferation photometric S-phase
Proliferation activity S-phase
Table 2. Important prognostic factors and labeling procedures for sentinel lymph nodes (SLN)
Six site puncture (biopsies), check at once in biopsy cylinders whether capsule tissue is invaded by cancer
Exfoliative cytology possible
Exfoliative cytology possible
Exfoliative cytology and FNAC besides biopsy useful
Exfoliative, cytology
Exfoliative and FNAC cytology
no puncture (contraindicated because of poss. spread)
FNAC possible smear from mammillae secretion possible
Imprint + FNAC
Serial sections HE and pan-cytokeratin
Serial sections S100, chromogranin A
Serial sections CK 8, 18
Serial sections cytokeratin ± staining (CK 5, 6 for squamous cell cancer CK 8, 18, 19 for adenocarcinoma
Serial sections CK 5, 6 for squamous cell cancers CK 8, 18 for endocervical cancers
Serial sections CK 5, 6 for squamous cell cancers; CK 8, 18 for adenocarcinomas
HE, HMB45, tyrosinase-RT-PCR
Serial sections of the whole SLN(s) HE, CK 8, 18, RT, PCR possible
Procedures used for cancer cell detect. in SLN
Tc-nanocolloid
99m
Hardly any experience available
Tc-nanocolloid
99m
Via mediastinoscopy or endoscopic or systemic (Sinerem), also by use of FDG PET
Blue dye and/or 99m Tc-nanocolloid
Blue dye and/or 99m Tc-nanocolloid alternatively: 99m TC-methoxyisobutyl isonitrile 99m ( Tc-MIBI)
blue dye and/or 99m Tc-nanocolloid
Blue dye (patent blue) and/or 99m Tc-nanocolloid
Labeling procedures
Histo- and Cytopathological Diagnosis 45
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Chapter 6 Detection and Radiological Imaging of SLN Table 3. Analysis of breast cancer cases classified as stages I±IIIa (AJCC system; Wascher et al. 2001) Number of cases investigated
Marker
No. of positive nodes, HE and/or IHC
No. of nodes in analyzed series
Histologically negative SLN but positive for MAGE-A3
Overall positive cases for MAGE-A3
SLN positive cases for MAGE-A3
77
MAGE-A3
48/121 40%
35/77 45%
28/73 38%
41/77 53%
50/121 41%
99m
Tc MIBI SPECT showed better specificity but lower sensitivity than CT in detecting cervical lymph node metastases in NPC.
MAGE-A3 Marker Function in Breast Cancer Patients Sentinel Node Evaluation There have been attempts to detect occult cancer cells by RT-PCR, with tyrosinase in malignant melanoma cases and with MAGE-A3 in breast cancer cases. Whereas many approaches to RT-PCR detection are limited by poor specificity, MAGE-A3 seems to be a highly specific tumor mRNA-marker, which is not expressed in noncancer cells. In recent investigations by Wascher et al. (2001), 77 AJCC stage I±IIIa breast cancer cases were analyzed. The results of this study are summarized in Table 3. MAGE-A3 mRNA expression in the SLN occurred more frequently with infiltrating lobular carcinomas than with infiltrating ductal carcinomas (P < 0.001). Use of MAGE-A3 mRNA in the development of antigen-specific targeted immunotherapy has been planned. Basically, it is beset by the same difficulties as tyrosinase RT-PCR evaluations in SLN material from patients with malignant melanomas. It is possible that the tumor marker MAGE-A4 is not derived exclusively from vital melanoma cells, but can also be present in apoptotic or necrotic melanoma cells.
Retrospective Evaluation of the Significance of SLN Located Mediastinally or Along the Mammaria Interna by Radioimaging Eubank et al. (2001) conducted a retrospective investigation into the question of mediastinal or internal mammary metastases in breast cancer patients, using FDG-PET and CT in 73 consecutive patients with recurrent or metastatic breast cancer. Both CT and FDG-PET were carried out within 30 days of each other. Overall, 40% of the patients had abnormal mediastinal or internal mammary (IM) FDG-uptake consistent with metastases, compared with 23% of patients in whom enlarged mediastinal or internal mammary (IM) nodes giving rise to suspicion were disclosed by CT. Both FDG-PET and CT were positive in 22% of these patients. In the subset of 33 patients with assessable followup by CT or biopsy, the sensitivity, specificity and accuracy for nodal disease were 85%, 90%, and 88%, respectively, according to FDG-PET; 54%, 85% and 73%, respectively, according to prospective interpretation of CT; and 50%, 83% and 70%, respectively, by blinded observer interpretation of CT. Among the 33 patients in whom locoregional disease recurrence only was suspected also had unsuspected mediastinal or IM disease according to FDG-PET. The inescapable conclusion to be drawn from this well-documented series is that FDG-PET can uncover nodal involvement in these nodal regions that has not been recognized by conventional staging methods. These preliminary results should be further validated by prospective histo- and cytopathological studies in the future. Suspicion of IM node involvement by locoregional cancer spread seems to be an important point in implication of this node group in the radiotherapy field of treatment and/or adjuvant chemotherapy treatment protocols.
Inclusion and Exclusion Criteria for Sentinel Node Investigation
Siddon et al. (1982) underscored the utilization of parasternal lymphoscintigraphy in radiation therapy of breast carcinoma. The decision to pursue the internal mammary nodes (IMN) has long been a source of controversy. Dupont et al. (2001) mapped 1,470 cases to correct the N-staging and determine the therapeutic consequences the mistaken staging had had for therapy. It is important to recall that mapping to the IMN basins with a finding of metastasis means stage N3-disease according to the current staging system. In Dupont's series 5 (14%) of 36 cases with sentinel nodes in the IMN basin had to be upstaged and more frequently had multiple positive IMNs. These patients then had additional radiation therapy.
Inclusion and Exclusion Criteria for Sentinel Node Investigation These criteria are very important: they have been intensively evaluated for breast cancer and also for malignant melanoma, but for many other cancers only rare certified results are available. In breast cancer cases, as a rule it makes sense to look for the SLN only when the diagnosis of the primary is secure according to mammography and/or MRI or has been confirmed at least cytologically. This can be achieved by punch or aspiration biopsy, perhaps including evaluation of socalled prognostic factors such as ER and PR status, c-erbB2 overexpression, mutated p53 expression or vimentin expression (Domagala et al. 1990). In
breast cancer series with vimentin coexpression, Domogala et al. found an association with low or missing estrogen and/or progesterone receptor expression and high proliferative activity measured with the antibody Ki-67 (1990 a), a worse prognosis even in node-negative cases (1990 b) and an association with a high degree of malignancy (1990 c). Cases with local multifocality can be included in the sentinel node detection regimen, because these foci are by definition located close together and therefore drain into the same basin in most cases, in addition to which multifocality is often found by MRI or intraoperatively when the primary is excised. However, as MRI investigation techniques become more advanced it is becoming more and more possible also to find small tumor foci around the primary and with this a higher rate of the ªstate of multifocalityº even before surgery. This is an important point and should be taken up when radiological diagnosis (MRI) has already raised the suspicion of multifocality. In cases with multicentricity involving the development of tumor nodes in different quadrants, sentinel node examination is generally pointless, because in most cases mastectomy is the method of choice and multicentric intradermal and/or peritumoral injections of 99mTc would need too high a total dosage. Only when parasternal nodes must be suspected as target nodes more often but not exclusively in medially or centrally localized primaries can labeling of these foci by peritumoral injection and looking for parasternal SLN (along the IM) be of value with respect to postoperative radiation and/or chemotherapy. The exclusion criteria for SLN investigation are summarized in Table 4. In position I the assessment criteria (triple
Table 4. Specific tumor types and axillary conditions in which looking for sentinel nodes is unreasonable and in which it should be carried out
a
a) Multicentric cancers in different quadrants
As a rule should be excluded with regard to resection.a The safest strategy is still mastectomy and axillary revision at levels I and II
b) Clinically positive axillary nodes
Enlarged, indurated and immobilized nodes. Confirmation by aspiration or punch biopsy in questionable cases
c) Clinically visible lymphangiosis carcinomatosa
Confirmed by biopsy
d) Inflammatory breast cancer Previous breast surgery with extensive scar formation
Confirmed by biopsy Accumulation of fluid in scar formations can lead to wrong or false results
For exceptions see Chapter 21
47
48
Chapter 6 Detection and Radiological Imaging of SLN Fig. 3. Criteria for clinical and histopathological sentinel node evaluation (breast cancer)
diagnosis) are summarized as preconditions for sentinel node labeling with blue dye and/or 99mTcnanocolloid. In position II the requirements for labeling multifocal cancers are summarized. In cases with multicentric cancers peritumoral labeling can only be useful for adjuvant radio- and/or chemotherapy (III) (Fig. 3).
Criteria for Clinical and Histopathological Sentinel Node Evaluation (Breast Cancer) In contrast to the clearly defined conditions in which sentinel node search and detection are helpful to avoid axillary revision in levels I and II and exceptions in which parasternal location of the sentinel node(s), for instance in cases with multicentric, partly centromedially localized cancers is helpful with regard to far-reaching decision making, there are clearly defined entities in which the search for sentinel nodes is contraindicated. These constellations are summarized in Table 4, which also gives an overview of specific tumor subtypes and axillary conditions in which sentinel node search is unreasonable or not indicated or should not be carried out. Recurrence rates in cases with breast cancers in central or retroareolar locations and treated by mastectomy or lumpectomy are still under discussion.
In their follow-up studies (99 patients) Simmons et al. (2001) found a 4.8% (2 of 42 patients) local recurrence rate 3 years after mastectomy and a 4.8% recurrence rate (1 of 21) 5 years after lumpectomy. In cases with subareolar cancers the local recurrence was 1 of 25 (4%) for patients undergoing mastectomy and 1 of 11 (9.1%) for patients undergoing lumpectomy (P > 0.99). The authors concluded that lumpectomy is a reasonable treatment option for selected patients with central or retroareolar breast cancers. On the basis of these still preliminary results ± which are based on a relatively small number of cases ± it can be concluded that in selected cases with subareolar cancers regardless of the surgical option (mastectomy or lumpectomy) sentinel node labeling is a helpful strategy for further decision making. Recently, Macmillan et al. (2001) tried to test the relative benefits of the sentinel node concept and of the four node axillary sampling technique already tested 10 years ago by the Rotterdam group and now called 4 NAS, in breast cancer. This approach has already been abandoned throughout the world in view of the possibility of skip metastases or metastases bypassing these nodes. Macmillan's group investigated 200 breast cancer cases. A sentinel node (SN) was found in 96%. The SN was contained in the 4NAS in 153 cases (80%) and identified separately in 38 cases (20%). That means that 20% of the SNs are not included in the 4NAS biopsy material. Finally, 49 of
References
the 60 node-positive patients were positive according to 4NAS and SN biopsy. The SN was not identified in 2, and in 8 the SN was falsely negative compared with 4NAS. For 1 patient the SN was positive and the 4NAS were negative. The authors conclude from these results that SNB has no advantage when nodes are assessed by standard histological investigation, but the results of Macmillan's group also demonstrate clearly that the SLN concept is really superior to 4NAS procedure. Furthermore, these results indicate that the SN concept cannot be practiced using simple routine techniques, but needs serial sectioning of the SN(s) and usage of immunohistochemistry for single cancer cell detection in the SLN.
Comparative Experimental Tracer Studies 99m
Tc is now the most used tracer and was introduced many years ago for SLN detection. But is it really the best? For further elucidation comparative animal-related studies were started (Edina et al. 2001). The investigators compared the uptake of 99mTc-labeled human serum albumin colloid (99mTc HSAC), 99m Tc-labeled antimony sulphur colloid (99mTc-SC), and a 99mTc-labeled dextran 70 solution (99mTcDX) and their selectivity in identification of the sentinel node(s) of normal mice and tumor-bearing mice. After injection into the footpad, the radiopharmaceutical uptake in the SLN (popliteal lymph node) and the lumbar lymph node (LLN) was measured at different time points after intradermal and intratumoral injection, respectively, in normal and murine mammary cancer (M2)-bearing mice. The results were: · 99mTc-HSAC uptake in the SLN was significantly higher than LLN uptake. · 99mTc-SC showed high uptake in the SLN but also high accumulation in the LLN. · Uptake of 99mTc-DX was low in both the SLN and the LLN. Intradermal administration of the radiopharmaceuticals was superior to intratumoral injection. In summary, we can conclude: · 99mTc-HSAC exhibited the highest uptake in the SLN, combined with the smallest amounts of
radiopharmaceutical passing through to the LLN. · Therefore, according to the authors (Edeira et al. 2001), 99mTc-HSAC appears to be the best radiopharmaceutical for sentinel node detection.
References Albertini, JJ, Cruse CW, Rapaport D, Wells K, Ross M, DeConti R, Berman CG, Jared K, Messina J, Lyman G, Glass F, Fenske N, Reintgen DS (1996) Intraoperative radio-lymphoscintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223:217±224 Borgstein PJ (1998) SLN biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 186:275±283 Cascinelli N, Morabito A, Santinami M, MacKie RM, Belli F (1998) Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351:793±796 Cox CE, Pendas S, Cos JM, Joseph E, Shons AR, Yeatman T, Ku NN, Lyman GH, Berman C, Haddad F, Reintgen DS (1998) Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 227:645±651 Domagala W, Lasota J, Bartkowiak J, Weber K, Osborn M (1990 a) Vimentin is preferentially expressed in human breast carcinomas with low estrogen receptor and high Ki-67 growth fraction. Am J Pathol 136(1):219±227 Domagala W, Lasota J, Dukowicz A, Markiewski M, Striker G, Weber K, Osbon M (1990 b) Vimentin expression appears to be associated with poor prognosis in node-negative ductal NOS breast carcinomas. Am J Pathol 137(6):1299±304 Domagala W, Wozniak L, Lasota J, Weber K, Osborn M (1990 c) Vimentin is preferentially expressed in highgrade ductal and medullary, but not in lobular breast carcinomas. Am J Pathol 137(5):1059±1064 Dupont EL, Salud CZ, Peltz ES, Nguyen K, Whitehead GF, Ku NN, Reintgen DS, Cox CE (2001) Clinical relevance of internal mammary node mapping as a guide to radiation therapy. Am J Surg 182(4):321±324 Edreira MM, Colombo LL, Perez JH, Sajaroff EO, Castiglia SG de (2001) In vivo evaluation of three different 99mTc-labelled radiopharmaceuticals for sentinel lymph node identification. Nucl Med Commun 22(5):499±504 Eubank WB, Mankoff DA, Takasugi J, Vesselle H, Eary JF, Shanley TJ, Gralow JR, Charlop A, Ellis GK, Lindsley KL, Austin-Seymour MM, Funkhouser CP, Livingston RB (2001) 18fluorodeoxyglucose positron emission tomography to detect mediastinal or internal mammary metastases in breast cancer. J Clin Oncol 1; 19(15):3516±3523 Glass EC (2001) Nuclear medicine in the detection of the sentinel node. Ann Surg Oncol 8 [Suppl]:5S±8S Gommans GM, Dongen A van, Schors TG van der, Gommans E, Visser JF, Clarijs WW, Ward JW de, Bos J van de, Boer RO (2001) Further optimization of 99mTc nanocoll sentinel node localization in carcinoma of the breast by improved labeling. Eur J Nucl Med 28:1450±1455
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Chapter 6 Detection and Radiological Imaging of SLN Kim R, Osaki A, Kojima J, Toge T (2001) Significance of lymphoscintigraphic mapping with Tc-99m human serum albumin and tin colloid in sentinel lymph node biopsy in breast cancer. Int J Oncol 19:991±996 Krag DN, Meijer SJ, Weaver DL, Loggie BW, Harlow SP, Tanabe KK, Laughlin EH, Alex JC (1995) Minimal access surgery for staging of malignant melanoma. Arch Surg 130(6):654±658; 659±660 Leong SPL, Steinmetz I, Habib FA, McMillan A, Gans JZ, Allen RE Jr, Morita ET, el-Kadi M, Epstein HD, Kashani-Sabet M, Sagebiel RW (1997) Optimal selective sentinel lymph node dissection in primary malignant melanoma. Arch Surg 132:666±673 Macmillan RD, Barbera D, Hadjiminas DJ, Rampaul RS Lee AH, Pinder SE, Ellis IO, Blamey RW, Geraghty JG (2001) Sentinel node biopsy for breast cancer may have little to offer four-node-samplers: results of a prospective comparison study. Eur J Cancer 37(9):1076±1080 Paganelli G, De Cicco C, Cremonesi M, Prisco G, Calza P, Luini A, Zucali P, Veronesi U (1998) Optimised sentinel node scintigraphy in breast cancer. Q J Nucl Med 42:49± 53 Paramo JC, Summerall J, Wilson C, Cabral A, Willis I, Wodnicki H, Poppiti R, Mesko TW (2001) Intraoperative sentinel lymph node mapping in patients with colon cancer. Am J Surg 182(1):40±43 Rauschecker H, Clarke M, Gatzemeier W, Recht A (2001) Systemic therapy for treating loco regional recurrence in women with breast cancer (Cochrane Review). Cochrane Database Syst Rev 4 CD 002195 Saha S, Nora D, Wong JH, Weise D (2000) Sentinel lymph node mapping in colorectal cancer ± a review. Surg Clin North Am 80(6):1811±1819
Schauer A, Marx D, Schauer M, Binder C, Kuhn W, Meden H. Breast preserving surgery decision making. Anticancer Res 18(3C):2107±2137 Siddon RL, Clin LM, Zimmermann RE, Mendel JB, Kaplan WD (1982) Utilisation of parasternal lymphoscintigraphy in radiation therapy of breast carcinoma. Int J Radiat Oncol Biol Phys 8(6):1059±1063 Simmons RM, Brennan MB, Christos P, Sckolnick M, Osborn M (2001) Recurrence rates in patients with central or retroareolar breast cancers treated with mastectomy or lumpectomy. Am J Surg 182(4):325±329 Sun SS, Tsai SC, Ho YJ, Kao CH (2001) Detection of cervical lymph node metastases in nasopharyngeal carcinomas: comparison between technetium 99mmethoxyisobutylisonitrile single photon emission computed tomography and computed tomography. Anticancer Res 21(2B):1307± 1310 Veronesi U, Paganelli G, Galimberti V, Viale G, Zurrida S, Bedoni M, Costa A de Cicco C, Geraghty JG, Luini A, Sacchini V, Veronesi P (1997) Sentinel node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 349:1864±1867 Wascher RA, Bostik PJ, Huynh KT, Turner R, Qik, Giuliano AE, Hoon DS (2001) Detection of MAGE-A3 in breast cancer patients sentinel lymph nodes. Br J Cancer 85(9):1340±1346 Waters GS, Geisinger KR, Garske DD, Loggie BW, Levine EA (2000) Sentinel lymph node mapping for carcinoma of the colon: a pilot study. Am Surg 66(10):943±945; 945±946 Wiese DA, Saha S, Badin J, Ng PS, Gauthier J, Ahsan A, Yu L (2000) Pathologic evaluation of sentinel lymph nodes in colorectal carcinoma. Arch Pathol Lab Med 124(12): 1759±1763
Chapter 7
Lymphatic Drainage to the SLN
7
For optimal sentinel node detection the fluids used must have the following qualities. · They must be easily resorbed into the lymphatic flow and well transported to the target node, with no resorption or at least with only minimal resorption into the bloodstream (veins and capillaries). · Storage of the fluid (colloid) within the target lymph node must be long enough for clinical, i.e. intraoperative, evaluations, and the period of storage must be correlated with the tracer used. These demands are at least partly supported by the anatomical structures and correlated physiological dynamics (Fig. 1). With reference to resorption, the fundamental structural differences between the lymphatic and the arteriovenous vascular systems must be seen in the fact that lymphatics are characterized as an ªopen systemº without basement membrane formation, whereas arteries, veins, and also capillaries have a well-developed basement membrane. This difference is one of the main factors in the quick resorption of small amounts of fluid in the interstitium via the lymphatics and the very small amounts resorbed via the bloodstream. In addition, with the increase in the interstitial pressure after fluid injection, the valves of the lymphatics are opened still more widely and the fluid is compressed within the lymphatic system. Because there is no circulation comparable to that of the bloodstream, lymphatic fluid cannot be ªback-wateredº and the lymphatic stream is directed exclusively into the vasa afferentia of the SLN. Figure 1 demonstrates the structural differences between lymphatics and blood vessels, which are essential for rapid fluid resorption. On the left of Fig. 1 a lymphatic vessel with a perpendicular course can be seen. On the right a vein (upper part) and a small artery (lower part) are shown. Note the gaps between the endothelia
Fig. 1. Schematic illustrating the structural differences between lymphatics and blood vessels. On the left a lymphatic vessel with a straight course can be seen, and on the right a vein and a small artery. Note the gaps between the endothelia of the lymphatic vessels, which are essential for rapid resorption of the interstitial fluid
of the lymphatic vessels, which is essential for rapid resorption of the interstitial fluid.
Time Schedule After interstitial injection of labeled fluids resorption via the lymph vessels begins immediately. Lymph vessels are kept open by anchoring filaments. Valves support drainage of the fluid towards the marginal sinuses of the regional lymph node. Early investigations on the lymphatic drainage of the mammary gland were performed by Hultborn et al. (1955). He demonstrated that in most of his patients lymphatic drainage of cancer involved the axillary nodes.
52
Chapter 7 Lymphatic Drainage to the SLN
These facts about special histological features are very important for the understanding of cancer cell drainage and basic to our aim of complete locoregional cancer clearance. Besides the histology and physiology of the lymphatics, it is very important to be informed about the lymph flow pattern in the entire breast. This can easily be understood with regard to our main intentions of · Evaluation of lymphatic drainage (to axillary and/or IM nodes) · N-Staging with the possibility of surgical, pathohistologically controlled locoregional cancer clearance · In cases with positive node status, improved possibility of judgment of cancer progression, connected with the indications for chemotherapy and, if appropriate, locoregional radiation therapy All quadrants can drain into the axilla (Fig. 2 a), but centrally and medially located primaries, especially, can also drain to the IM node chain or to the interpectoral and subclavicular nodes (not illustrated in Fig. 2). Justification for subdermal injection of the labeled nanocolloids is derived from the knowledge that the lymphatics from the deeper parts of the breast drain primarily to superficial (subdermal) lymphatics and then to the axillary nodes (Fig. 2).
Involvement of the Regional Lymph Nodes in Breast Cancer Earlier studies focused on drainage of the lymphatic fluid to regional lymph nodes fell into two types: · Experimental, performed by using colored fluids or tracer substances and evaluation of secondary storage after resorption · Systematic pathohistological examinations of nodes or node groups that must be particularly considered [axilla levels I and II, parasternal (IM chain), in special cases also supra- and infraclavicular groups, interpectoral node group etc.) The percentage axillary lymph node involvement by breast cancer (all cases) and prevalence of in-
Fig. 2 a, b. Topography of the glandular body of the breast from the aspect of lymphatic drainage to the axillary lymph nodes. a Breast parenchyma with lacteal sinuses (1), ducts (2) and lobules (3) [I, II axillary nodes levels I and II; III axillary nodes of the apex (level III)]. b Drainage of lymphatics from deeper parts of the breast first to the superficial (subdermal) and then to the axillary nodes [1 interlobular, 2 interductal lymphatics, 3 primary (red), 4 axillary lymph node (level 1)]
volved lymph node(s) (groups and chains) are summarized in Table 1. Developments in examination of the SLN concept have been extended to different primaries and intensified in recent years. As evaluated in the individual chapters in the second part of the book, approaches to various cancer types, including different subtypes, have been attempted and at least some strategies based on the results of this are now in routine use. Qualified application techniques for the tracers have already been defined, and the related lymphatic basins have also been evaluated. The results reported in the international literature are summarized in Table 2. The hypothesis that breast cancer has generally already seeded by both lymphogenic and hematogenous routes by the time it is first detected has long
Involvement of the Regional Lymph Nodes in Breast Cancer Table 1. Identification rates and rates of metastases in sentinel lymph nodes of breast cancer patients (data partly compiled by B.A.E. Kapteijn, The Netherlands Cancer Institute, 1997) Author(s) year
Injection modality
Patent blue tracer
Size of primary
22
Peritumoral
Tracer
Not evaluated
82
39
Giuliano 1994
174
Intratumoral
Blue dye (patent blue)
Tis 15 mm T1 104 mm > T2 55 mm
66
32
Giuliano 1995
162
Intratumoral
Patent blue
Median 1.5 cm
100
42
Uren 1995
34
Peritumoral
Tracer + patent blue
Not evaluated
100
67
Schneebaum 1996
15
Not given
Tracer + patent blue
Not evaluated
87
20
Kapteijn 1996
30
Intratumoral
Patent blue
Mean 2.9 cm
87
38
Meijer 1996
30
Peritumoral
Tracer
18 < 20 mm
100
32
Albertini 1996
62
Peritumoral
Tracer patent blue
Mean 22 mm
92
32
Cox et al. 1998
167
Peritumoral
Blue dye: Lymphazurin and 99m Tc sulfur colloid
Invasive breast cancer 17 DCIS cases
Krag 1993
Patient no.
240
Peritumoral subdermal
99m Tc colloid, additional blue dye in 40 cases with subdermal administration
T1=71%; T2=19%; T3=10%
Kern KA 1999
40
Subareolar
Blue dye isosulfan
Clinical stages I±II
Giuliano et al. 2000
133
Peritumoral (around edges)
Vital blue dye: lymphazurin 1%
£ 4 cm
De Cicco et al. 1998 a; for further data see De Cicco et al. 1998 b
been a constant topic of discussion and has been accepted as true in many hospitals in recent decades. This assertion is misleading and has led to the administration of systemic chemotherapy even in the early stages of tumor development and for low-grade, e.g., tubular and mucinous, cancers, on the assumption that primary generalization of tumor spread may already have taken place and with the intention of allaying patients' fears about their survival. However, this assumption does not seem to have been confirmed or supported by results documenting high 10-year cure rates in N0 cases or in early stages of lymph node involvement (N1 with micrometastases).
Identification rate
Rate of metastases (%)
31.1 5.9 234/240 = 97.5%
45% in 38% SLN only
38 99
45.6
These high cure rates would not be possible if hematogenous spread were present in practically all cases. The increasing number of publications reporting high cure rates of 85% in N0 cases after 8±10 years' follow-up has convinced a steadily increasing proportion of doctors participating in interdisciplinary breast cancer treatment that the ªprimary systemic disease concept,º which was never accepted by most pathologists, can also no longer be accepted by clinicians. In Germany it was Kreienberg who first declared, in a lecture given at the Congress of the German Senology Society, that the assumption of systemic disease had been an a priori error.
53
54
Chapter 7 Lymphatic Drainage to the SLN Table 2. Lymphatic regions demonstrated by lymphoscintigraphy. [From Ege (1996)] Injection site
Lymph node groups
Breast, gynecology/ surgery
Mammary, periareolar
Axillary, supraclavicular, upper parasternal
Dermatology
Peritumoral, intracutaneous Dorsum of the foot Dorsum of the hand Chest wall subcutaneous, subperiosteal
Superficial lymphatic at risk Femoral, inguinal, external iliac, para-aortic Epitrochlear, axillary, supraclavicular Axillary, supraclavicular, upper parasternal
Ear nose and throat
Buccal mucosa Orbit Larynx
Jugular Deep cervical Paralaryngeal, superior/inferior jugular
Gastrointestinal
Lower esophagus Gastric cardia
Mid-mediastinal, celiac, upper periaortic Celiac, upper periaortic
Gynecology Surgery Urology
Vulva Rectal
Inguinal, external iliac Superior hemorrhoid, inferior mesenteric, per rectal Internal presacral, obturator, common iliac, para-aortic Periprostatic, internal iliac
Per anal, ischiorectal fossa Intraprostatic
Abdominal Surgery
Subcostal posterior rectus sheath Hepatic capsule Splenic capsule Peritoneal cavity
Nonetheless, there are published results that could indeed support the idea. Schlimok and Riethmçller (1990) found a high rate of cytokeratin-positive cells in breast cancer cases when they investigated bone marrow smears. Discussion of these results is difficult, because the rate of metastatic involvement of the bone marrow was much lower in autopsy investigations carried out by Eder (1984) than in clinical investigations at the time of initial clinical tumor staging when the primary has been detected and operated on. Two different possible explanations for this discrepancy have been discussed in the literature: One is that there are cross-reactions to nonneoplastic cells in the bone marrow, e.g., pre-stages of plasma cells. The other assumes a balance between slow tumor cell growth in the bone marrow and effective immune defense over long periods. However, neither of these assumptions is completely plausible and no scientifically convincing confirmation is available for either. In contrast to these discussions, which have not led to any really significant conclusions, a much more convincing point for a primary ªnonsystemic concept,º namely the excellent 10-year cure rates
Diaphragmatic, parasternal, internal mammary Ô mediastinal Right parasternal, mediastinal Splenic hilar Anterior mediastinal
amounting to 85±87% without any signs of tumor recurrences in breast cancer patients with tumors in early stages at the time of treatment must be emphasized. These results, which are confirmed by a number of publications from many study groups, are the most important and convincing argument against the concept of primary systemic tumor cell spread (ªsystemic diseaseº).
Direct and Secondary Hematogenous Metastasis of Breast Cancer Besides the characteristic locoregional spread via the lymphatics, breast cancer can metastasize very quickly via the bloodstream. Initial, direct hematogenous spread via cancer cell invasion of the veins is a well known fact to take place, and its importance has been discussed from many angles. The first organ involved in these circumstances is the lung. In addition to this, however, the venous bloodstream can also be reached secondarily via cancer infiltration of the axillary sentinel node, with involvement of further nodes in the axillary pyramid
Is Intraoperative SLN Staging Possible in Breast Cancer Cases?
or primary spread to subclavian nodes. The cancer can then extend to the venous angle (confluence of left jugular and subclavian veins), with invasion of the thoracic duct and drainage into the superior vena cava. In these cases spread via the right atrium and ventricle of the heart into the lung (Fig. 3 a) and from there via the arterial bloodstream into the liver and brain (Fig. 3 b) is possible. That invasion of the primary lymphatic pathways entering the thoracic duct is a preliminary stage of hematogenous metastasis is a little-known but interesting fact. With reference to this possibility, it is clear that blood vessel invasion and transport of cancer cells cannot initially be recognized and influenced, whereas lymphatic transport, including that taking place as a precursor stage of hematogenous metastasis, can be interrupted by locoregional lymphadenectomy (axillary revision, with or without radiation therapy). Paganelli and his group, in Milan (see Albertini et al. 1996, De Cicco et al. 1998 a, b), were the first to conduct extensive investigations into: · The probability of SLN labeling in breast cancer patients · The dependence of adequate labeling on the size of nanocolloid particles · The possibility of labeling nonaxillary lymph nodes, e.g., those in the IM group (different basins) These important facts can be derived from Fig. 4 a±c, which summarizes the results of these investigation programs.
Is Intraoperative SLN Staging Possible in Breast Cancer Cases? As long ago as in the 1970s, our group developed our system of intraoperative axillary node staging in breast cancer cases by staining frozen sections of the nodes and simultaneously investigating imprint cytologies taken from the cut surface of each node (Schauer 1977, 1981). The correspondence between histology and cytology results was 98%. This method was immediately adopted by numerous national and international cooperative groups. The disadvantage of this strategy (one aim of which is to avoid two sessions of surgery) was that for each case we needed one pathologist, one cyto-
Fig. 3. a Lymphatic spread from the primary (1) to the axillary (2) or infraclavicular (3) lymph nodes and from there to the venous angle (4). Spread to the parenchyma of the lung follows (5) with a secondary liver metastasis forming via primary spread into the lung (6). b Cancer cells from a lung metastasis (1) or cancer cells that have flowed through the lung can be transported via the left heart (2) into the brain (3) or the liver (4)
pathologist, and three technicians (two to prepare the histopathological sections and one to stain the imprints).
55
56
Chapter 7 Lymphatic Drainage to the SLN
Fig. 4 a±c. The scale of the three figures demonstrates very clearly: a the classic result of lymph node labeling; b spillover when the particle size of the colloid is too small; c labeling of lymph node chains of the basis and the possibility of also labeling sentinel nodes of the mammaria interna group. a Classic case with labeling of a SLN belonging to the axillary node group on level I in a case with a primary
located in the central part of the breast above the areolar region. b The number of SLN labeled depends to a high degree on the size of the nanocolloid particles. c Note that SLN localization in the internal mammary chain is not only possible in cases with medial primaries, but also in cancers located in the lateral quadrants. (Kindly supplied by Professor Paganelli, Milan)
It is interesting to read that the Milan group (Galimberti et al. 2000) has lately tried taking 60 sections from the sentinel node(s) and staining them intraoperatively with the aim of obtaining
immediate knowledge of the sentinel status so as to be able to continue with axillary revision at once in positive cases.
References
Their sentinel node detection rate was 98.7%. Comparison with complete axillary node dissection showed that the sentinel node predicted the axillary status in 96.8% of cases. However, when the intraoperative frozen section method was used the axillary status was correctly predicted in only 86.5%. The lower rate cannot be tolerated; it can be understood as the result of the Milan group's use, so far, of H-E staining only. It could be that the introduction of ultrarapid immunohistochemistry (see chapter 17) in the Milan scheme will bring about a considerable improvement in these results. Technical developments directed at avoiding loss of tissue parts by cutting the tissue to obtain frozen sections and staining a large number of sections immunohistochemically, use of the ultrarapid staining techniques (see Nåhrig et al. in this book, Chap. 17) and the introduction of scanning methods for fast evaluation of a large number of sections could theoretically help to avoid subjecting patients to two diagnostic operations. Even now, however, it seems clear that intraoperative sentinel node staging will only become possible with considerable improvements of the techniques and the introduction of adequate pathological and cytological investigation techniques.
References Albertini JJ, Lyman GH, Cox C Yeatman T, Balducci L, Ku N, Shivers S, Berman C, Wells K, Rapaport D, Shons A, Horton J, Greenberg H, Nicosia S, Clark R, Cantor A, Reintgen DS (1996) Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276:1818±1822 Cox CE, Bass SS, Ku NN, Berman C, Shons AR, Yeatman TJ, Reintgen DS (1998) Sentinel lymphadenectomy: a safe answer to less axillary surgery? Recent Results Cancer Res 152:170±9 De Cicco C, Cremonesi M, Luini A, Bartolomei M, Grana CH, Prisco G, Galimberti V, Calza P, Viale G, Veronesi U, Paganelli G (1998 a) Lymphoscintigraphy and radioguided biopsy of the sentinel axillary node in breast cancer. J Nucl Med 39:2080±2084 De Cicco C, Chinol M, Paganelli G (1998 b) Intraoperative localization of the sentinel node in breast cancer: technical aspects of lymphoscintigraphic methods. Semin Surg Oncol 15(4):268±271
De Cicco C, Sideri M, Bartolomei M, Grana C, Cremonesi M, Fiorenza M, Maggioni A, Bocciolone L, Mangioni C, Colombo N, Paganelli G (2000) Sentinel node biopsy in early vulvar cancer. Br J Cancer 82(2):295±299 Eder M (1984) Die Metastasierung: Fakten und Probleme aus human-pathologischer Sicht (Metastasis: facts and problems in human pathology). Verh Dtsch Ges Pathol 68:1±11 Ege GN (1996) Lymphoscintigraphy in oncology: lymphatic regions demonstrated by lymphoscintigraphy. In: Henkin RE, et al (eds) Nuklearmedizin, vol II. Mosby, St. Louis, pp 1505±1523 Galimberti V, Zurrida S, Intra M, Monti S, Arnone P, Pruneri G, De Cicco C (2000) Sentinel node biopsy interpretation: the Milan experience. Breast J 6(5):306±309 Giuliano AE, Haigh PI, Brennan MB, Hansen NM, Kelley MC, Ye W, Glass EC, Turner RR (2000) Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node negative breast cancer. J Clin Oncol 18(13):2553±2559 Hultborn Larsson L-G, Ragnhult I (1995) The lymph drainage from the breast to the axillary and parasternal lymph nodes, studied with the aid of colloidal AU198. Acta Radiol 43:52±64 Kern KA (1999) Sentinel lymph node mapping in breast cancer using subareolar injection of blue dye. J Am Coll Surg 189(6):539±545 Krag DN, Weaver DL, Alex JC, Fairband JT (1993) Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 2:335±340 Kreienberg R (1997) Der aktuelle Stand der Brustkrebsbehandlung. Lecture given at the Congress of German Society of Senology, Berlin, 1997 Paganelli G, De Cicco C, Cremonesi M, Prisco G, Calza P, Luini A, Zucali P, Veronesi U (1998) Optimised sentinel node scintigraphy in breast cancer. Q J Nucl Med 42:49± 53 Paganelli G, De Cicco C, Chinol M (2000) Sentinel node localization by lymphoscintigraphy: a reliable technique with widespread applications. Recent Results Cancer Res 157:121±129 Schauer A (1981) Mammacarcinom. Pathologische Anatomie in Chirurgie der Gegenwart. Urban und Schwarzenberg, Munich Vienna Baltimore, pp 6±39 Schauer A, Droese M, Rahlf G (1977) Pathologische Anatomie des Mammacarcinoms. Langenbecks Arch Chir 345:39±44 Schlimok G, Riethmçller G (1990) Detection, characterization and tumorigenicity of disseminated tumor cells in human bone marrow. Semin Cancer Biol 1:207±215 Uren RF, Howman-Giles RB, Thompson JF, Malouf D, Ramsey-Stewart G, Niesche FW, Renwick SM (1995) Mammary lymphoscintigraphy in breast cancer. J Nucl Med 36:1775±1780
57
Chapter 8
Specific Developments in Sentinel Node Labeling Using 99mTc-Colloids
Introduction Dowlatschalhi et al. (1997) were one of the clinical research groups to investigate the significance of micrometastases with a cut-off ranging from 0.2 mm to 2 mm for survival of the patients. The detection rate was inadequate when HE routine staining only was used. Serial sectioning of the nodes with combined HE staining and immunohistochemical investigations appeared to increase the detection rate by 9±33%. Statistically, a definite survival disadvantage was noted for patients with such occult metastases. Therefore, improvements in sentinel lymph node (SLN) labeling and investigation and in corresponding therapy, which must be adequate, are very important. In this context, for the development of a highly qualified sentinel node concept the following must apply: · An exact labeling technique to detect sentinel node(s) · Serial sectioning combined with immunohistochemistry (staining for cytokeratins etc.) to detect even solitary cancer cells
8
Against this background, knowledge of the steps of development of the sentinel node concept will help toward a better understanding of the important features of the SLN concept.
Radionuclides in Conventional and Routine Nuclear Medicine Applications Garzom et al. reported as long ago as in 1965 on usage of some of the oldest tracers, namely 99mTc labeled colloids, in lymphoscintigraphy. In subsequent years a large number of tracer colloids labeled with 99mTc came up for discussion and were studied in comparative investigations; our own group was using gallium-67 for tumor localization studies at that time (Heidenreich et al. 1971). Since then a large number of experimental studies have been carried out in attempts to find the best radionuclides for use in humans, the optimal colloid particle size, and the best time points for scintigraphic evaluations. Some of the historical developments in the use of radionuclides and different gamma probe de-
Table 1. Physical properties of some radionuclides frequently used for intraoperative orientation (summarized by Keshtgar et al. 1999) Physical property
Technetium99m
Iodine-125
Iodine-123
Iodine-131
Indium-111
Half-life of radioactive decay
6.02 h
60.1 days
13.1 h
8.04 days
2.83 days
Energy of gamma ray emission
140 keV
27 keV
159 keV
364 keV
171,247 keV
Beta particle emission
None
None
None
606 keV (bmax)
None
Soft tissue thickness to reduce gamma rays to 50%
46 mm
17 mm
47 mm
63 mm
51 mm
Thickness of lead to reduce gamma rays to 50%
0.17 mm
0.05 mm
0.5 mm
2.4 mm
0.9 mm
Thickness of lead to reduce gamma rays to 10%
0.9 mm
0.06 mm
1.2 mm
7.7 mm
2.5 mm
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Chapter 8 Specific Developments in Sentinel Node Labeling Using
vices have already been extensively reviewed by Keshtgar et al. (1999). One of the best study models for evaluation of quality and usefulness in SLN detection has been the use of iodine-131 for thyroid cancer diagnosis, and especially for the detection of radiolabeled lymph node metastases in cases with papillary carcinomas, which are characterized by early and predominantly lymphogenic metastasis. In the last decade, however, various combinations of monoclonal antibodies with radioactive tracers such as 99mTc, 131I, 125I, and 111In have been used to label many cancer entities, and particularly endocrine, neuroendocrine, and colorectal cancers and regional and systemic cancer spread. The physical properties of some frequently used tracers are summarized in Table 1.
Quality of the Colloids Used and the Particle Size For use in lymphoscintigraphy and in SLN detection, the labeling of colloids has developed to the point where a labeled colloid has the status of an ideal radiopharmaceutical instrument. This is underlined by a large number of publications documenting the highly successful usage of the method. Because there are so many features, such as sterility, particle size and consistent quality of the colloids, that have important roles, only nationally and internationally registered colloid solutions can be used routinely in humans. But these obligatory restrictions do not cover the entire problem of the inconsistent quality of the colloid solutions used. Experience has shown that in certain types of colloid solutions the particle size can vary considerably from batch to batch. The London group (Keshtgar et al. 1999) found variations in the order of a factor of 4, though they were using the same preparations from the same company. It must be assumed that users now ask the companies for a guarantee of particle consistency, as such high variabilities would not be compatible with a continuous high quality of diagnosis and decision-making. Different size averages are used for lymphoscintigraphy (50±88 nm) and sentinel node labeling (100±200 nm). The most frequently used colloid solutions are: · Nanocoll (manufacturer: Sorin Biomedica Diagnostics, Italy). This preparation contains 0.5 mg
99m
Tc-Colloids
of human serum albumin with 95% of labeled particles less than 80 nm in diameter. · Sulphur Colloid (manufacturer: CIS-US). This preparation is available in the USA; depending on the labeling protocol, the labeled particles are between 40 and 1,000 nm in diameter. Radiopharmaceuticals used in experimental studies are: · 99mTc-labeled human serum albumin (Nawaz et al. 1985) · 99mTc-labeled human immunoglobulins, or parts of them, tested for lymphoscintigraphy and in lymphatic flow measurements (Svensson et al. 1999). In daily work in clinical practice it is reasonable for different surgical disciplines to decide on the use of a particular colloid preparation that can then be steadily and routinely applied. However, when a patient is to be imaged on one day and operated on the next, larger particle colloids may be more suitable than they would be for a patient in whom administration of the tracer and the operation are planned for the same day. This can be necessary in special cases when the flow within the lymphatics is more important than or just as important as the actual SLN detection. In addition, investigations with small-particlecontaining colloids can detect a higher number of regional lymph nodes, and this can be helpful for locoregional cancer clearance in special cases. The use of such colloids should be considered for patients with multifocal and multicentric disease. The results obtained thus far have shown that the smaller the colloid particles the higher has been the uptake and storage in the parasternal lymph nodes. An optimum size for parasternal node labeling was found to be in the range of tenths of nanometers. Investigations conducted by the Milan group (De Cicco et al. 1998; Paganelli et al. 1998) have demonstrated similar results in humans in the last few years. This group report finding a higher number of sentinel nodes when smaller particles were used (see Chapter 7). These new results are interesting in three different ways: · The frequently discussed problem of whether there is one sentinel node in most cases or two or more sentinel (reached by spillover or by-
Quality of the Colloids Used and the Particle Size
passing) cannot be easily solved by investigating several nodes in the same basin. Only in cases with different localizations, e.g., an axillary SLN and a parasternal node at the same time or, in the case of melanomas of the trunk, diagonal metastatic spread e.g., into an axillary and an inguinal node, can evaluation judgments be made. · These results also clearly show that the colloid particles can be quickly transported through a lymph node, entering the node via the vasa afferentia and leaving via the vas efferens. This point is also interesting with reference to the discussion, suggesting that tumor cells can enter a lymph node, pass through it in about 48 hours or even less, and infiltrate the next node without the growth of a metastasis in the first. · The third point is that the unwanted side effect of resorption into the blood circulation is possible when a very small particle size is used. On the basis of the knowledge obtained in the course of past developments, obviously it has not been easy to elaborate ideal criteria defining the required quality of the colloids to be used. Whereas the most frequently used radioactive substance, 99mTc, is also now almost unrivaled in routine investigations, earlier many investigations aimed at determining the quality characteristics of the colloids to be used were performed. To obtain consistently uniform quality in both routine investigations and clinical study programs, the following criteria must be fulfilled: · The product must be licensed and available at short notice. · Consistently adequate particle size must be guaranteed. · Stability during storage must also be guaranteed. · The colloid must be rapidly transported and stored in the lymph node for a adequate period of time. · Neutral behavior in the bloodstream, without swelling or shrinkage, must be guaranteed. · Biological degradation with resorption in an adequate time period is also a requirement for colloids to be used in humans. These demands are fully justified, because toosmall particles only a few nanometers across are resorbed via the bloodstream to a large extent, while particles hundreds of nanometers in diame-
ter are stored largely in the interstitial spaces and are not transported via the lymphatics to an adequate degree. Modern gamma cameras are sufficiently sensitive to record the passage of the tracer even in the early phases of resorption by the lymphatic stream. Investigation of the earliest phases makes it possible to ensure that the tracer migrates. Such investigations presuppose a high quality of the probes used. The renewed search for the SLN in putative lymphogenically spreading cancers has stimulated industrial companies to step up their work on improving the devices they have on offer. Sensitivity in signal detection, number of counts detected per time unit, transportability and ease of handling are the main features that have been steadily developed and improved. When the quality of probe types is assessed the following points must be taken into account: · Sensitivity of the probe type, i.e., determination of counts per time unit. · Resolution, meaning the minimum local distance between two signals, which must be statistically significantly separate. · Energy resolution, or the possibility of distinguishing between degraded and nondegraded radiation. · Collimation, or in other words, perceived signal from a circumscribed volume of tissue. Three options have been discussed for the application of labeling solutions using local nonsystemic procedures. Most of the discussions about this problem have been fixed almost exclusively on sentinel node labeling in breast cancer cases; in some ways, however, the same problems can also be discussed for patients with skin cancer, such as squamous cell cancer and melanomas. In breast cancer cases the following options are under discussion and/or in use for administration of the tracer colloids: · Subdermal injection (some working groups prefer this modality for the majority of cases) · Peritumoral injections (4 sites: 12 o'clock, 3 o'clock, 6 o'clock, and 9 o'clock positions) · Intratumoral injection: this method has now been largely abandoned because of the danger of cancer spread
61
62
Chapter 8 Specific Developments in Sentinel Node Labeling Using
In any discussion of the significance of these three options, it must be emphasized that the female breast develops from genetically prefixed cell populations in appendages of the skin. It follows from this that the lymphatics also grow from the subepidermal network, with periductal tissue formation inward, i.e., into the subcutaneous tissue, and also with the glandular breast parenchyma developing in deep tissue. Therefore, it seems perfectly reasonable to think that, in cases of cancers near the body surface and also in the middle parts of the breast, a tracer given by subdermal injection into the deeper areas of the corium (where the lymphatic network is intensively developed and communicates with the lymphatics in the glandular region of the breast) is correct from the biological point of view, because the lymphatic flow runs from deeper tissue parts toward the subepidermal regions and from there to the sentinel node(s) (method I). The second option, peritumoral injection (method II), should be used for cancers in deeper localizations (deeper middle parts of the breast and deep prefascial localizations). The critical dividing point for choosing between methods I and II is still not known, because axillary sentinel nodes are easier to label using method I and the rate of correct detection of sentinel nodes in the mammaria interna basin seems to be higher with method II. The first task to be fulfilled by comparative studies must be to obtain further information on the partly open question of whether method I or II should be preferred. In our opinion it is already clear that in cancer cases with predominantly medial or central localizations, when parasternal lymphatic spread must be assumed method II (peritumoral injection on all four sides of the tumor) should be preferred. The localization of the tumor from the aspect of depth can be determined from the side views visualized in mammographic investigations. The third option, intratumoral injection of the tracer fluid (method III) is now no longer considered acceptable by most investigators, for various reasons: · Destruction or obliteration of lymph vessels in the center of the primary · Discontinuity of the lymphatic flow · Increased pressure in the center of the primaries, and because of this · Risk of opening of veins, with consequent propagation of metastatic spread
99m
Tc-Colloids
These are all real and serious dangers, which make the practice of this method taboo in general in nearly all cases. However, it seems that a few exceptions are now crystallizing out: in very small and diffusely growing cancers some authors recommend injection of a very small volume of more strongly radioactive 99mTc-labeled colloid solution into the putative tumor area. Experience of this is obviously minimal, however. It may be that this method could be of value in the case of very tiny multicentric cancers (e.g., multicentric lobular cancer) detected on MRI. Keshtgar et al. (1999) point out in their book that there is little evidence to support the assumption that intratumoral manipulations such as those mentioned in the current discussion about the injection of labeled solutions, have an influence on tumor progression because they can foster tumor cell seeding. At first glance this statement seems likely to be correct, but no extensive statistically evaluated studies are available; such studies could not be performed for ethical reasons. Therefore, this question cannot be answered with any scientific confirmation in humans. The consequence is that we have to argue on the basis of our biological knowledge and our knowledge of general pathology. Keshtgar et al.'s opinion is supported and partly confirmed by the following facts: · There are some investigations that clearly show that manipulations on the primaries lead to an increase in the number of circulating cancer cells in the bloodstream. · There are also models (e.g., the rat tail model) which demonstrate the development of intensive lung metastases after local traumatization of transplanted tumors.
Injection Techniques Using 99mTc Nanocolloids and/or Blue Dyes in Breast Cancer Cases Most authors agree that blue dyes should not be used for subdermal labeling when the techniques discussed above are applied, because such dyes will persist within the soft tissue structures for long periods and will be visible. Blue dye labeling must be reserved much more for when the dye solution is to be injected peritumorally. In contrast to the limitations on blue dye injections, 99mTc-nanocolloid solution can be injected
Injection Techniques Using
both subdermally and peritumorally. Peritumoral injection is recommended especially for deepseated, i.e., prefascially located, cancers. Gallowitsch (2001) stated that increased lymphatic flow is initiated by rising interstitial pressure after injection of a certain volume, leading to distension of the endothelia of the lymphatics. This statement must be viewed positively in connection with the lymphatic flow, but it demands caution insofar as there is a possibility that cancer cells can flow more easily into the opened lymphatic vessels. Therefore, the bolus of each injection should be targeted very precisely, near to but beyond the cancerous areas, but also not too far away from the neoplastic lesion. Based on his experience, Gallowitsch states that for subdermal injection volumes of 0.1±0.2 ml
99m
Tc Nanocolloids and/or Blue Dyes in Breast Cancer Cases
seem to be appropriate, whereas for deeper, peritumoral injection larger volumes selected from a range of 3±8 ml are necessary. At first glance the much larger volumes for peritumoral administration are a shock, but can be understood and seem justified when we consider that peritumoral injection involves dividing the overall volume into four portions which are then distributed over the whole circumference of the primary and that the solution is injected into easily deformable parenchyma, which generally has a large fatty tissue component. The different administration modalities are demonstrated in Figs. 1±3. The arrows by the lymph vessels show the direction of lymphatic flow to the axillary nodes.
Fig. 1±3. Main localizations of ductal and lobular invasive breast cancers. Different injection modalities for the contrasting solutions are necessary. Fig. 1. Subdermal injection of labeling solution into deep corial parts, preferred in cases with superficially or nearly superficially located primaries. This subdermal injection modality is gaining wider acceptance because the labeling fluid is resorbed faster and labeling of the axillary sentinel lymph nodes (SLN) is more intensive. Nonetheless, reduction of the sentinel node labeling in other basins must be discussed in cases with more deep-seated or centrally or medially located primaries. This schematic illustrates superficially located, small and palpable breast tumors. 99mTC-nanocolloid solution is injected subdermally into the deep corium with rapid resorption of the colloid by the lymphatic vessels (arrows). The solution should be injected a few millimeters above the cancer, but not intratumorally
63
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Chapter 8 Specific Developments in Sentinel Node Labeling Using
99m
Tc-Colloids Fig. 2. Intramammary peritumoral injection of the labeling solution in cases with more deep-seated primaries; in such cancers it is possible to inject the solution subdermally with the syringe perpendicularly above the tumor for axillary sentinel node labeling, but peritumoral injection allows more precise labeling of sentinel nodes in the mammaria interna and subclavicular basins also
Canavese et al. (2000a) found in 40% falsely labeled SLN in cases after unjustified subdermal application and in 60% falsely labeled nodes following parenchymal injection some centimeters away from the primary in the same quadrant, and in 100% when the labeling solution was given by subdermal injection in the diagonally opposite quadrant of the same breast. These results document very clearly how important it is to administer the marker solution in a very precisely selected site, not into but very close to the cancer and with injection into points around the whole circumference (see Fig. 2). Because all cancers in any of the four quadrants of the breast can spread into the axillary lymph nodes, it seems it is not the search for the first sentinel node in the axillary basin alone that is important, because getting information about extraaxillary SLN (e.g., nodes in the marginal area of the glandular body), parasternal (mammaria interna group), interpectoral, or subclavicular nodes, whether alone or in addition, is also important for further treatment strategies (see Fig. 3). The simultaneous use of vital blue dye and radioguided surgery can be helpful in dealing with this problem (Canavese et al. 2000 b).
Precision in Tracer Administration In this context, and in agreement with Figs. 1±3, the reliability of subdermal and peritumoral tracer application for tumors near the surface and in the middle parts of the breast, respectively, has been well documented for the axillary nodes as initial basins, but not with the same degree of precision for parasternal (mammaria interna-related) nodes. In order to achieve exact parasternal labeling, strong peritumoral labeling near the cancer margins or intratumoral labeling would be necessary; but intratumoral injection has been abandoned. In practice, deep-seated tumors should be labeled with the assistance of ultrasound guidance. In centrally located primaries the best results of parasternal lymph node labeling were not obtained with subareolar injection, but again much more by precisely administered peritumoral injection of the labeling solutions (see Uren et al. 1995; Alex and Krag 1996; Alazraki et al. 1997; Veronesi et al. 1997; Barnwell et al. 1998; Borgstein et al. 1998; Crossin et al. 1998; Krag et al. 1998; Moresco et al. 2000).
Use of Liposomes for Radioimaging Within the Sentinel Node Concept Fig. 3. Deep peritumoral injection in prefascially located primaries: note that the lymphatic stream can lead to the interpectoral nodes. Note drainage through the pectoral muscle (perpendicular intralympathic arrows). In cases with deep lying primaries drainage to the axillary nodes, the mammaria interna nodes and to other basins is also possible, instead of or as well as the axillary nodes. Peritumoral labeling thus seems to be the method of choice for cancers in this category
The most frequent and specific (paraglandular) sentinel node localizations are summarized in Fig. 4 a±c.
Danger of Opening of Capillaries and Venules with Increasing Risk of Hematogenous Cancer Cell Transport The discussion about hematogenous spread of cancer cells or cell clusters as a consequence of iatrogenic opening of veins within the primary will never be over, because the problem of how to calculate whether spontaneous opening in areas of necrotic cancer or iatrogenic opening has had an important role in spread and the definitive outcome cannot be solved by scientific means. We therefore have to be very careful in performing our labeling procedures.
The distance between the injection site and the cancer, which in the case of the peritumoral labeling procedure should be only a few millimeters for correct sentinel node labeling, the pressure applied in hand-guided injection, and the quantity of colloid solution used all have important roles in good practice, as explained and demonstrated in Fig. 5 a±c.
Use of Liposomes for Radioimaging Within the Sentinel Node Concept New animal experimental approaches have now been set up to test the use of radiolabeled liposomes in scintigraphic imaging (Boerman et al. 2000; Cao et al. 2000; Goins and Phillips 2001; Phillips et al. 2001 a, b). Whereas 99mTc-nanocolloids are routinely used to indicate the localization of SLN with and with-
65
66
Chapter 8 Specific Developments in Sentinel Node Labeling Using
99m
Tc-Colloids Fig. 4 a±c. Localization of SLN in dependence on primary localization, organizational structure of individual lymphatic network, and tumor size. a Scenario I: Localized in lower axillary node(s). This is the scenario encountered in 90% of cases of breast cancer in which metastasis develops. b Scenario II: Localized in paraglandular lateral lymph node(s). This is a rare localization of the sentinel node, being encountered together with other atypical localisations in approximately 8% of cases. c Scenario III: Localized in the parasternal lymph node chain. This localization is encountered especially when the primary is located centrally or medially. Any of these localizations can be encountered, separately or in combination
Use of Liposomes for Radioimaging Within the Sentinel Node Concept
Fig. 5 a±c. Analyses of factors involving risk of hematogenous cancer cell spread. a Left: blood vessels are intact and it is not possible for cancer cells to enter them directly. Right: blood and lymph vessels are open, so that entry of cancer cells into the vascular system is possible. b Normally structured cross section of a small vein with subendothelial basement mem-
brane and dense wall structure. Note closed syncytial connections of the endothelia and the basal membrane. c Left: Longitudinal, right: cross section of a small vein. High pressure causes horizontal and longitudinal tension, with opening of the syncytial connections and discontinuity of basement membrane by longitudinal extension by up to 15%
out cancer cell infiltration, one aim of the investigations with liposomes, among others, is to detect cancer cell infiltrations of lymph nodes. Previously, liposomes have been used predominantly as vehicles for drugs, in order to achieve selective deposition and thereby reduce general drug toxicity. Radiolabeling of liposomes with gamma emitters such as 67Ga, 111In, and 99mTc opened up the possibility of using them in imaging approaches. But, because liposomes are rapidly taken up by the mononuclear phagocytic system (MPS), after systemic application liver and spleen, as the organs with the highest capacity in the reticuloendothelial system, were the main target organs, so that systemic application of liposomes in peripheral lymph
node evaluation was primarily not possible (Phillips et al. 2001 a). However, one characteristic of the recently developed long-circulating liposomes (LCLs) is that they resist recognition by the MPS. This favorable property of LCLs enhances the circulating half-life time and has made it possible to use them in radioscintigraphic analyses. So far, LCLs have been used for: · Cancer imaging · Imaging of infectious lesions · Blood pool imaging Boerman et al. (2000) report that rapid, easy, and efficient labeling of preformed LCLs with 111In and
67
68
Chapter 8 Specific Developments in Sentinel Node Labeling Using 99m
Tc is now possible and that, in preliminary patient-related imaging studies, the sensitivity and specificity for cancer and inflammatory lesions were good. Cao and Suresh (2000) developed a bispecific monoclonal antibody, (Bs MAb) (174H.64X antibiotin), which can bind to tumorspecific antigen and biotin. In addition, the investigators prepared biotin-coated liposomes loaded with the model drug 99mTc-DTPA (diethylenetriamine pentaacetic acid), which can bind to the biotin-binding arm of the bs MAb. This system has been tested in the mouse KLN205 squamous carcinoma model (see Fig. 6). The schedule of the experimental tests was: · Injection of the bs MAb 24 h first into tumor allograft-bearing mice · Waiting for clearance of circulating bs MAb · Then application of biotinylated 99mTc-labeled liposomes The results show that pretargeting with bs MAb enhances liposomal drug targeting by four times. In further experimental studies in San Antonio, USA (Goins et al. 2001; Phillips et al. 2001) there
99m
Tc-Colloids
have also been attempts to label liposomes coated with biotin and coencapsulated with blue dye and glutathione with 99mTc using hexamethylpropyleneamine oxime. In comparative studies on rabbits, 0.3 ml of 99m Tc-biotinylated liposomes containing blue dye were administered in both hind feet, followed by an injection of 0.3 ml of 5 mg avidin s.c. in only one hind foot. The labeling efficiency for liposomes encapsulating blue dye was 92Ô1.9%; 24 h later the popliteal nodes of the legs on the side where avidin had been injected showed intensive blue staining, as opposed to no blue coloration in the control leg, where coloration was quite absent. The tissue counts were 12.2Ô1.5% of the injected dose (% ID) in the experimental nodes, compared with 1.2Ô0.1% ID in the control nodes (p < 0.0001). The authors conclude that biotinylated liposomes encapsulating blue dye can be labeled with 99mTc, providing successful visualization and radiolocalization of 99mTc in the SLN.
Fig. 6. Principle of labeling cancer cells by using bispecific monoclonal antibodies (bs MAb) binding to tumor-specific antigen and biotin at the surface of 99mTc-DTPA-labeled liposomes
References
References Alazraki NP, Eshima D, Eshima LA, Herda SC, Murray DR, Vansant JP, Taylor AT (1997) Lymphoscintigraphy, the sentinel node concept and the intraoperative gamma probe in melanoma, breast cancer and other potential cancers. Semin Nucl Med 27:55±67 Albertini JJ, Lyman GH, Cox C, Yeatman T, Balducci L, Ku N, Shivers S, Berman C, Wells K, Rapaport D, Shons A, Horton J, Greenberg H, Nicosia S, Clark R, Cantor A, Reintgen DS (1996) Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276:1818±1822 Alex JC, Krag DN (1996) The gamma-probe-guided resection of radiolabeled primary lymph nodes. Surg Oncol Clin North Am 5:33±41 Barnwell JM, Arredondo MA, Kollmorgen D, Gibbs JF, Lamonica D, Carson W, Zang P, Winston J, Edge SB (1998) Sentinel node biopsy in breast cancer. Ann Surg Oncol 5:126±130 Boerman OC, Laverman P, Oyen WJ, Corstens FH, Storm G (2000) Radiolabeled liposomes for scintigraphic imaging. Prog Lipid Res 39:461±475 Borgstein PJ, Pijpers R, Comans EF, Diest PJ van, Boom RP, Meijer S (1998) Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 186:275± 283 Cao Y, Suresh MR (2000) Bispecific MAb aided liposomal drug delivery J Drug Target 8:257±266 Canavese G, Gipponi M, Catturich A, Di Somma C, Vecchio C, Rosato F, Percivale, P, Moresco L, Nicolo G, Spina B, Villa G, Bianchi P, Badellino F (2000 a) Sentinel lymph node mapping in early stage breast cancer: Technical issues and results with vital blue dye mapping and radioguided surgery. J Surg Oncol 74:61±68 Canavese G, Gipponi M, Catturich A, Di Somma C, Vecchio C, Rosato F, Tomei D, Nicolo G, Carli F, Villa G, Agnese G, Bianchi P, Buffoni F, Mariani G, Badellino F (2000 b) Pattern of lymphatic drainage to the sentinel lymph node in breast cancer patients. J Surg Oncol 74:69±74 Crossin JA, Johnson AC, Stewart PB, Turner WW Jr (1998) Gamma probe guided resection of the sentinel lymph node in breast cancer. Am Surg 64:666±668 De Cicco C, Chinol M, Paganelli G (1998) Intraoperative localization of the sentinel node in breast cancer: technical aspects of lymphoscintigraphy methods. Semin Surg Oncol 15(4):268±271 De Cicco C, Cremonesi M, Luini A, Bartolomei M, Grana CH, Prisco G, Galimberti V, Calza P, Viale G, Veronesi U, Paganelli G (2001) Lymphoscintigraphy and radioguided biopsy of the sentinel axillary node in breast cancer. J Nucl Med 42(5):826
Dowlatshahi K, Fan M, Snider HC, Habib FA (1997) Lymph node micrometastases from breast carcinoma reviewing the dilemma. Cancer 80(7):1188±1197 Gallowitsch HJ (2001) Lymphoscintigraphy and dosimetry. In: Munz DL (ed) The sentinel lymph node concept. (International Forum Nuclear Medicine) Zuckschwerdt, Munich, pp 57±67 Garzom OL, Palcos MC, Radicella R (1965) Technetium99m labelled colloid. Int J Appl Radiat Isotopes 16:613 Goins BA, Phillips WT (2001) The use of scintigraphic imaging as a tool in the development of liposome formulations. Prog Lipid Res 40:95±123 Heidenreich P, Remplik V, Kempken K, Hor G, Langhammer H, Bottermann G, Pabst HW, Pfisterer H, Schauer A (1971) Neoplasm localization using 67 Ga. Fortschr Geb Ræntgenstr Nuklearmed 115(1):14±27 Krag D, Weaver D, Ashikaga T, Moffat F, Klimberg VS, Shriver C, Feldman S, Kusminsky R, Gadd M, Kuhn J, Harlow S, Beitsch P (1998) The sentinel node in breast cancer ± a multicenter validation study. N Engl J Med 339:941±946 Nawaz K, Hamad M, Sadek S, Andeli M, Higazi E, Eklof B, Abdel Dayem HM (1985) Lymphoscintigraphy in peripheral lymph edema using technetium labelled human serum albumin: normal and abnormal patterns. Lymphology 18:729±735 Paganelli G (1998) Sentinel node biopsy: role of nuclear medicine in conservative surgery of breast cancer. Eur J Nucl Med 25(2):99±100 Paganelli G, De Cicco C, Cremonesi M, Prisco G, Calza P, Luini A, Zucali P, Veronesi U (1998) Optimized sentinel node scintigraphy in breast cancer. Q J Nucl Med 42(1):49±53 Phillips WT, Andrews T, Liu H, Klipper R, Landry AJ, Blumhardt R, Goins B (2001 a) Evaluation of [(99m)Tc] sulfur colloid and [(99m)Tc] human serum albumin, Nucl Med Biol 28:435±444 Phillips WT, Klipper R, Coins B (2001 b) Use of (99m)Tc-labeled liposomes encapsulating blue dye for identification of the sentinel lymph node. J Nucl Med 42:446±451 Svensson W, Glass DM, Bradley D, Peters AM (1999) Lymphoscintigraphy with Tc99m polyclonal immunoglobulin. Eur J Nucl Med 46:504±510 Uren RF, Howman-Giles RB, Thompson JF, Malouf D, Ramsey-Stewart G, Niesche FW, Renwick SB (1995) Mammary lymphoscintigraphy in breast cancer. J Nucl Med 36:1775±1780 Veronesi U, Paganelli G, Galimberti V, Viale G, Zurrida ST, Bodeni N, Costa A, Cicco C, Geraghty JG, Luine A, Sacchini V, Veronesi P (1997) Sentinel node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 349:1864±1867
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Chapter 9
Experience with and Suggestions for Cancer of Different Types and in Different Sites
Breast Cancer After a general learning period of nearly a decade, there is already an important knowledge base about the fundamental primary techniques for managing sentinel lymph node (SLN) detection in the best way. The international literature makes it clear that early experience was gained in the treatment of breast cancer and malignant melanoma, whereas experience of SLN diagnosis of other primaries is still limited. Three routes of contrast solution injection (subdermal, peritumoral, intratumoral) have been compared for SLN detection in breast cancer cases, and the intratumoral route, initially used and propagated by Giuliano et al. (1995), Kapteijn (1996), and Nieweg et al. 1997 has now been generally rul-
9
ed out by most investigators because of the very real danger of tumor spread that it entails. Nonetheless, there are still no very precise indications as to how to choose between the subdermal and peritumoral injection routes (see also Chapter 7). Roughly, it seems to be clear that in the case of more superficially located primaries subdermal injection is best, while for those in deeper locations peritumoral injection is more appropriate (see Figs. 1, 2). This still leaves some questions open, one of these being that of the best method in cancers that cannot be precisely delineated. This requires further experience (see below in this section). A further question is that of particle size and the quality of the colloid used (see also Chapter 8). It is clear that the use of very small particles can lead to ªspilloverº into the lymph nodes downstream of the SLN in the lymphatic stream,
Fig. 1. a Most frequent localization of the primary (upper lateral quadrant). The 99mTc-nanocolloid is given in a single subdermal injection. b In cases with deeper localization of the primary the labeling solution is injected in four portions (at the 3, 6, 9, and 12 o clock positions) or as shown in b with the bulk of it directed the same way as the putative lymph flow; that means, most of the tracer solution is injected toward the axilla a few millimeters away from the primary. A second portion can mark the lymphathic flow to the parasternal nodes
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Chapter 9 Experience with and Suggestions for Cancer of Different Types and in Different Sites
Fig. 2. Injection profiles differ for various cancers in different organs. For breast cancer the tracer fluid is usually given by the subcutaneous or peritumoral route injection, depending on the depth at which the tumor is located. Most of the tracer fluid should be injected in the suspected direction of flow to the sentinel node(s). This figure shows peritumoral labeling in a deeply located primary (four-spot
whereas bigger particles are held back and are first seen to be stored in the marginal sinuses (Fig. 3). However, when the particles have rather large diameters (>200 mm), the amount of colloid resorbed and transported may be too small. In such cases the sentinels cannot be detected. Because parasternal lymph node involvement has always been a critical and also an important point, the problem of the subdermal versus the peritumoral injection modality has also been tested in this connection. It has been shown that after subdermal injection much lower parasternal detection rates are obtained than after peritumoral injection. These differences make it clear that we need an individual, case-adapted approach in order to obtain the most helpful results for optimal therapy planning in every single case.
labeling). a The cancer drains exclusively into the axillary lymph nodes. b Left breast with drainage to axillary and mammaria interna (parasternal) lymph nodes. c All four peritumorally located spots of labeled solutions drain to the axillary nodes (cf. a). Arrow subdermal injection over a superficially located primary
Palpable and Nonpalpable Cancers It is clear that when the SLN concept is applied it would not be ªgood practiceº first to investigate the excised cancer histologically and not to start the SLN detection program until after the diagnosis has been confirmed. Therefore, the complicated, but meanwhile technically improved, ªtriple diagnosisº (palpable lesion, high level of suspicion on radiological examination, and cancer cells revealed by cytological investigation) is coming into its own again. With reference to safety, it must be pointed out that radiological methods have vastly improved in both sensitivity and specificity. The additional use of MRI has also improved the success rate. Analogous progress has been attained in cytoand histological examinations of smears and minibiopsies of cancers.
Breast Cancer
Fig. 3. Differences in node labeling when too-small particles are used (ªspilloverº) and normal situation, which is helpful in accurate detection of the sentinel lymph node (SLN)
Therefore, triple diagnosis is a far-reaching and reliable diagnostic instrument, which can also ethically be used to decide whether SLN detection procedures are indicated. This opinion is supported by the fact that this primarily diagnostic principle is still not seen as the basis for a serious operative process such as mastectomy, because decisions in favor of such operations are then based on further histological diagnosis of the primary, following its excision for definitive examinations of the pT value, for example. The exclusion criteria for performance of the SLN investigation based on triple diagnosis are easy to understand and apply in cases of current or recent pregnancy, mostly when · Multifocal or multicentric primaries are present. · Axillary nodes are clinically already positive and immobilized. · Operations have already been performed on the breast or in the axilla and been followed by extensive scar formation. In contrast, earlier operations that were not extensive and have been followed by only very focal scar formation or none at all in a quadrant not currently involved seem not to constitute an exclusion criterion for SLN investigations.
Injection in Nonpalpable Breast Cancers No uniform concept can be established for nonpalpable cancers, because quite different biological entities belong to this group. These cancers can be divided into the following categories: · Microcarcinomas up to 5 mm or slightly more in diameter · Intraductal carcinomas with no or with incipient early stromal invasion · Diffusely growing cancers, mostly small-cell lobular cancers with a high degree of tumor cell dissociation Figure 4 summarizes important entities classed as nonpalpable breast cancer. All three categories (Fig. 4) can be nonpalpable lesions. As is well known, palpation of such cancers is particularly difficult in the presence of fibrocystic disease, when multiple indurated fibrous nodules can be palpated in so-called shotty breasts. It must be made quite clear that type A and type B lesions (Fig. 4) are the ones that are most suitable for treatment with sentinel node biopsy, because, as a rule, these are ªearly cancers.º As progress continues to be made in the detection of breast cancer in its early stages by screening programs using mammography and in special cases
73
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Chapter 9 Experience with and Suggestions for Cancer of Different Types and in Different Sites
Fig. 4. Important entities classed as impalpable breast cancer. Type A: Microcarcinoma 5 mm or a few millimeters more in size, within fibrocystic disease, especially in a shotty breast. Type B: Retromamillary cancer intraductal
breast cancer or intraductal breast cancer in smaller peripheral ducts, with or without early stromal invasion. Type C: Diffuse invasive lobular cancer with a high degree of tumor cell dissociation (scirrhus)
also MRI the recorded incidence of such lesions is increasing steadily.
retromamillary milk sinuses. From there, these cells are secreted via the mammilla. These cells or cell aggregates can then be found in smears of the secreted material. The methods described are generally helpful in cancer diagnosis when the tumors are not palpable (types A and B), but they are perhaps not helpful in type C (Fig. 4), in which the tumor grows quite diffusely with a high degree of dissociation. In these cases, in some of which there is associated lymphangiosis carcinomatosa, sentinel node detection seems not to be an optimal or even a particularly good solution, because these tumors often develop satellite foci and their lymph drainage to lymphatic basins can involve different node chains (axillary, parasternal, interpectoral, sub- and supraclavicular). The result is that open biopsy and histopathological examination using the frozen section technique during surgery gives us an overview and allows selection of further procedures, which then consist mostly in axillary revision (levels I and II).
Problems in Confirming a Breast Cancer Diagnosis in the Primary Lesions Before SLN Evaluation The histologically/cytologically confirmed cancer diagnosis and the exact localization of the lesion must be reliably known before a patient is considered for SLN biopsy. In addition to mammographic and ultrasound investigations for exact localization of the breast cancers, MRI is also very helpful (Heywang-Kæbrunner et al. 2001). In particular, MRI is very helpful in detecting very small tumor foci, sometimes even revealing foci only 3 mm in diameter. Such small lesions can then be evaluated by ultrasound-guided puncture for cytological investigations and by Tru-Cut biopsies, which are used to obtain coherent tissue cylinders for histological diagnosis (see also Chapters 15 and 20). In this context, it must be mentioned that classic ductal cancers can be reliably recognized in smears gained by the fine-needle aspiration technique, whereas low-grade breast cancers, especially those belonging to the group of tubular cancers, cannot be definitely differentiated from benign adenosis. In such cases needle biopsies, which allow investigation of the histological pattern, are more useful for confirmation of the malignant invasive process. In addition, intraductal centrally localized cancers drain cancer cells via the ductal system to the
Reasons Why the Dermal Injection Procedure is the Most Frequently Used This is the most frequently used method; problems in cases with deep-seated or medially located primaries are discussed above. That the subdermal injection method can be used in most cases is confirmed by the fundamental investigations of Grant et al. (1959), who stud-
Breast Cancer
ied the lymphatic network of the breast, the subareolar circle and the main streams of the lymphatics to the axillary nodes, and also the development of the breast from the predestined cellular potential of the epidermis. The development of the subareolar plexus of the lymphatics is basic to our understanding that the lymphatic network grows downward as the ductal and peripheral lobular structures develop. The diffuse anastomosing branches of the network combine into two main lymphatic vessels, one collecting the lymph from the upper lateral and some of the medial parts and the other that from the caudal, lateral, and medial parts of the breast. Both these main strands drain into the axillary lymph nodes. Because of existing anastomosis in many parts, drainage to the parasternal (mammaria interna) nodes is also possible. These observations have lately been confirmed by means of lymphangiographic methods. In addition, results recorded in practice are now increasingly confirming the described important anatomical structures that have been investigated and their significance. It is an important indicator of the significance attaching to the statement that dermal injection is also appropriate for slightly more deeply localized tumor nodes that it has repeatedly been confirmed that the superficial lymphatic network communicates with the deeper lymphatics and that the lymphatic stream from deeper regions goes to the superficial central parts of the breast, because the lymph stream runs parallel to the radial sector and ends in the subareolar lymph circle and then at a conical angle. In this region many factors, including scars, can be responsible for the direction of lymphatic flow, i.e., whether it goes into the axilla and/or into the parasternal node group. The technique of labeling is as follows: An injection of 10±15 MBq of 99mTc-labeled colloid solution in 0.2 ml is given into the dermal region over the primary. The syringe is held at an angle of 10±208 to the skin. After the injection, pressing on the injection site with cotton wool is helpful to avoid reflux. In addition, any good adhesive plaster is applied over the injection site. Peritumoral injection is practiced mainly in the case of deep-seated cancers. The tracer solution is injected into four peritumoral regions: apical, caudal, medial, lateral.
The reduced resorption rate is compensated for by the large volumes of the solution. With 1±2 ml per focal application, the total amount injected amounts to 4±8 ml. In the peritumoral injection technique quantity is important. Larger volumes extend the anchoring filaments and in this way open the lymphatic vessels at the junction points of the lymphatic endothelia (see also Chapter 7). Krag et al. found that lymphatic uptake increased from 96% to 100% when the volume of solution injected was increased from 4 to 8 ml. The intratumoral injection route, viewed with some doubt even initially, has now been abandoned as a routine method.
Dermal Injection of Radioactive Colloid in Preference to Peritumoral Administration? In a multicenter breast cancer study published by McMasters et al. (2001), 229 surgeons were involved in searching for the SLNs; patients with stage T1±2 N0 were eligible. In all, 2,206 patients, 1,074 of whom received peritumoral injections of tracer, 274 subdermal and 511 dermal injections, were evaluated for detection of the SLNs. In 94% of the patients, peritumoral injections of blue dye were given in addition to the injections of radioactive colloid. The SLN identification rates were better after dermal injection than after subdermal or peritumoral injection of the radioactive colloid. Clinically, the most important end-points for comparison were the false-negative rates, which were: · 8.3% for peritumoral injection · 7.8% for subdermal injection · 6.5% for dermal injection (Table 1). For detection of the SLN(s), using the gamma probe five- to seven-fold radioactivity after dermal injection has been found and is interpreted as an advantage in node detection. When we concentrate on SLN detection in the axillary basin and disregard other possible locations (parasternal nodes in central or medial located primaries, or interpectoral nodes in deep-seated cancers), dermal injection gives a significantly better axillary detection rate than peritumoral or subdermal injection.
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Chapter 9 Experience with and Suggestions for Cancer of Different Types and in Different Sites Table 1. Results of sentinel lymph node biopsy based on injection technique. From McMasters et al. (2001) (SLN ID sentinel lymph node identification) Injection technique
SLN ID
SLN ID rate a
True positives
False negatives
Radioactive colloid Peritumoral Subdermal Dermal
965/1,074 283/297 501/511
89.9% 95.3% c 98.0% d,e
311 94 157
28 8 11
8.3% 7.8% 6.5%
Blue dye alone
208/239
87.0% b
63
8
11.3%
Overall
2,041/2,206
92.5%
641
55
7.9%
False-negative rate f
a
P < 0.0001, significant difference among peritumoral, subdermal, dermal and blue dye alone groups, Chi-square; bP = 0.20 vs peritumoral injection, Chi-square; cP = 0.0037 vs peritumoral injection, Chi-square; d P < 0.0001 vs peritumoral injection, Chi-square; e P = 0.026 vs subdermal injection, Chi-square; f No significant differences among peritumoral, subdermal, dermal and blue dye alone groups, Chi-square
Table 2. Summary of radioactive colloid injection techniques from all published literature. From McMasters et al. (2001) Injection technique
SLN ID rate
False-negative rate
Blue dye alone
79.3%
9.3%
Peritumoral radioactive colloid (with or without blue dye)
88.2%
8.0%
Subdermal radioactive colloid (with or without blue dye)
96.3%
6.4%
Dermal radioactive colloid (present study, 94% with peritumoral blue dye)
98.0%
6.5%
These results are ideal in one way, but on the other hand the reduced frequency or loss of parasternal SLN detection also means there is no further evaluation of these nodes and, depending on the result, leads to the loss of the facultative indication for regional radiotherapy. In view of the much higher radioactivity in the SLNs after dermal injection, McMasters et al. (2001) calculate that the learning process can be shortened when the dermal injection modality is given preference. McMasters et al. (2001) summarized their results in a table with their focus on false-negative rates, which helps their readers by providing a quick overview. It is therefore reproduced below. The differences among peritumoral, subdermal, dermal and blue dye alone groups are obvious, but are not significant in Chi-square tests. In addition, the authors summarized the results of solitary and combined injection modalities using blue dye and/or radioactive colloid published so far in the world literature. This table is reproduced here so that readers can use it as an aide to develop their own optimal strategies for SLN detection in breast cancer patients (Table 2)
The authors' main conclusion, on the basis of their own study results and those recorded in the world literature, is that additive dermal radioactive colloid injection and peritumoral blue dye administration have lower false-negative rates than peritumoral administration of labeling solutions alone.
Malignant Melanomas Elective Versus Uncontrolled Lymphadenectomy in Malignant Melanoma Patients Discussion about the significance of elective lymph node dissection intensified when the concept of removing SLNs was introduced. Elective lymphadenectomy was decided on in cases with clinically unremarkable lymph nodes and cancers with a thickness of 0.76±4 mm according to the Breslow scheme, which meant an overtreatment rate of more than 80% because the nodes removed were frequently tumor free. Another negative point of this surgical policy is the increased morbidity (lymphedema with reported
Malignant Melanomas Table 3. Set-up for the SLN detection in malignant melanomas Investigator
Dosage of the radio nuclide
Administration Time of measure- No. of modality ment treated cases
No. of nodes in No. of drainage scintigraphy basins
Kapteijn et al. (1997)
60 MBq 99mTc nanocolloid
Intradermal
122
Before during and after excision
60
73
Table 4. Values measured in 23 sonographically detected lymph nodes Value in vivo
Value ex vivo
Dose injected per SLN
Median
Range
Median
Range
Median
Range
36
2±722
274
6±2,985
0.69
0.0013±6.2
Background
0.0004±2.59
Table 5. Comparison of activities measurable over the SLN, soft tissue (skin) and subcutaneous fatty tissue parts Uptake per gram in SLN
Uptake in soft tissue of skin
Uptake in subcutaneous fatty tissue
Median
Range
Median
Range
Median
Range
2.1
0.003±17.4
0.01
0.00±0.22
0.0035
0.00±0.081
incidence rates of up to 40%, disturbances of wound healing, and peripheral disturbances of neuromuscular functions). In addition, the possibility of impaired immune defense after lymphadenectomy has been debated. In follow-up studies, the survival rates in cases with and without elective lymphadenectomy were quite different. However, in selected groups of patients under 60 years of age and with tumors 1± 2 mm thick the prognosis was significantly better. As in breast cancer, in the case of malignant melanoma positive locoregional lymph node(s) is/ are highly predictive of facultative tumor infiltration of the entire basin. In 1997 Kapteijn's group published a classic series of patients in whom they had used 99mTc-nanocolloid and a gamma ray detection probe to trace SLNs. They injected 60 MBq 99mTc-nanocolloid intradermally at the site of the primary tumor. Because their investigations were conducted in a classic set of cases, the results are summarized to give an overview and an impression of the practical aspects of the trial. The basic data relating to the investigation are summarized in Table 3. The scintigraphy detection program included: · Early dynamic images and a body scan, 2 hours after the tracer injection.
· A gamma detection probe (Neoprobe 1000) used intraoperatively to trace the (still radioactive) SLN (s) on the following day. The sentinel node-to-background ratios were high. The values measured in 23 sonographically detected lymph nodes area summarized in Table 4. Comparative evaluation studies have shown that uptake is similar in the SLNs and the surrounding tissue components or compartments. Skin and fatty tissue were of interest for the assessment of the values measured over the sentinel nodes. The results are briefly summarized in Table 5. Because the gamma probe evaluation technique is now accepted as a helpful instrument for precise guidance during surgery, especially in the treatment of malignant melanomas, but is nonetheless not handled with the highest accuracy in all clinics, at this point we should like to cite Kapteijn et al.'s statement (1997) that according to the high SLN-to-background ratios the intraoperative detection of SLNs is much facilitated and patient safety is much improved in terms of avoidance of regional lymph node recurrences. In addition, survival has been reported to be improved by 20% in male patients with pT3 and pT4 tumors without ulceration. However, the discussion is still controversial even in the more recent literature.
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Chapter 9 Experience with and Suggestions for Cancer of Different Types and in Different Sites
The RT-PCR now offers new possibilities for additional investigations of the node(s) (see also Chapter 4, Fig. 1), but the question of specificity in finding a metastatic node process remains unanswered. As already mentioned, this discussion is not focused on the problem of whether the melanoma cells are inside, in the lymphatic sinuses, or outside as much as on the question of whether nonneoplastic dermatogenous nevus cells containing tyrosinase are transported to a node. It is clear that in the circumstances RT-PCR must be improved and carried out with different, hitherto undefined, markers. The question of the biological significance of tumor cells that remain within the marginal sinuses of a node without breaking out into the lymph node parenchyma cannot be answered. · Serial sectioning cannot exclude the possibility that there is invasion. · There is no way to determine whether the immune defense system is still intact or whether or not single tumor cells or small tumor cell clusters can still be destroyed.
For these reasons, the German Society of Pathology came to the conclusion that whenever cancer cells are found in a node, whether within or outside the sinuses, a metastatic process must be assumed (German Society of Pathology Berlin, 1984).
Fig. 5. Steps in subdermal injection of the 99mTc-containing colloid solution. Prepare the syringe, filling it with 0.2 ml 99mTc-containing colloidal fluid bubble behind the fluid. All 0.2 ml of fluid must be injected, with the air bubble
used for control when the syringe is left in the course of the injection. It is essential to prevent backflow out of the branch canal, which can cause contamination. The canal must be covered with a robust adhesive plaster
Injection Technique in Malignant Melanomas Now that elective lymphadenectomy has been largely replaced by SLN, optimal labeling for detection and investigation procedures are required. In most departments of dermatology and also in surgical departments, sentinel node biopsy has been developed as the standard procedure for use in N-staging and in melanoma treatment management. The injection technique is analogous to that used for breast cancer diagnosis. One day before or on the day of surgical treatment, 15 MBq colloid is injected subdermally in a volume of 0.2 ml (see Fig. 3).
Malignant Melanomas
When the primary has not yet been operated on, the injection is given around the primary. In cases of previous surgery with scar formation the injection is given in four equal portions of 0.2 ml each at four sites around the wound or around the scar, each 5 mm from the edge of the scar or wound. When the primary excision had a very large tumor-free margin area it may be that the lymph flow has changed (Rees et al. 1980). Figure 5 shows how to hold the needle (at an angle of 15±208 to the surface of the skin) and exactly how to use the syringe. In the case of melanomas on the lower legs the inguinal lymph nodes are regarded as the sentinels and the search for the sentinel node(s) is sometimes not easy. For malignant melanomas the same injection techniques can be applied as in other locations, using the same amount of injection fluid. The injection sites are basically in the same positions relative to
the tumors as for primaries with other localizations. When the SLN labeling concept is applied in the case of melanomas of the lower leg, differentiation between a popliteal and an inguinal localization of the sentinel node seems to be a point on which more systematic investigations could be carried out, since long-time hyperthermic isolated cytostatic perfusion (HILP) of the lower extremity is administered in many centers. In this connection it must be stated that animal experiments in mini-pigs have shown that after such perfusions the regional lymph nodes are nearly empty of lymphatic tissue, because the cytostatics are lymphogenically reabsorbed and exert their full effect on the inguinal lymph node tissue. It is easy to understand that the lymphatic flow of labeling solutions (e.g., 99mTc-nanocolloid) is substantially altered under the influence of these fundamental structural changes.
Fig. 6. Assumptions and facts influencing the search for and the localization and excision of SLNs and prenodal lymphatics
79
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Chapter 9 Experience with and Suggestions for Cancer of Different Types and in Different Sites
For this reason, no regional cytostatic perfusion therapy should be performed before SLNs are labeled. Besides malignant melanomas, skin tumors include squamous cell cancers and Merkel cell tumors. The rules to be followed in looking for the SLN localizations for all the tumor types mentioned are quite similar: · Patients must be investigated in the early stages of tumor development when there is no obvious clinical locoregional spread. · Initially systemic basin involvement is less frequent. · If operations for tumor excision are performed first, regular tumor drainage must not be inhibited. · Tumor cells mostly disseminate without ªskipº (no regional highly developed network of lymphatics). Especially for malignant melanomas, rough indications for SLN localizations can be given. These are summarized in the overview in Fig. 6. In many cases locoregional surgery can be performed with no major difficulties.
Significance of Distance Between Margins of Malignant Melanomas or Scarring After Tumor Excision and Injection of 99mTc-Nanocolloid Rettenbacher et al. (2001) investigated 100 cases of malignant melanoma or local scarring after tumor excision. The first group of patients each received 37 MBq 99mTc-nanocolloid injected intracutaneously 2±5 mm away from the primary or the scar. On another day another group of patients also received injections of the 99mTc nanocolloid, but 10 mm away from the tumor or scar. The SLN detection rate was 94% after injection of the tracer close to the tumor or scar, and 100% after injections 10 mm away. In 84% of the 100 cases the same number and the same location of the SLNs were recorded after both near and distant tracer injections. In 16% an additional node was detected after distant injection. From this it follows that after distant injection one more lymph node had to be excised and investigated.
Fig. 7. Tongue cancer: submental and parapharyngeal lymph nodes can be the sentinel nodes. For tumors of the upper digestive tract there are so far few methods of detecting SLNs using labeled 99mTc-nanocolloids. For superficial tumors of the face see Chapter 23
Cancers of the Head and Neck and of the Upper Aerodigestive Tract Experience of searching for SLNs using 99mTc-nanocolloids in head and neck cancers and in cancers of the upper aerodigestive tract is small. In comparison with the more frequently performed so-called selective node dissection, few groups are experienced in the use of radiodiagnostic sentinel node search methods. It might be that in operations for oral cancers N-staging with early detection of the sentinel node can be significantly improved by PET and by 99m Tc-labeling (see Fig. 7). In the treatment of laryngeal cancer it might also be possible to improve the results of searching for retrothyroidal sentinel nodes by the implementation of new search programs (see Fig. 8).
Lung Cancer
Fig. 8 a±c. Laryngeal cancer: search for sentinel node(s) in early stages. a Early invasion; early stage. b ªWallpaperº cancer: superficial, with field-like extension. c Ventral com-
Lung Cancer Routine and specialized radiological examinations (including CT and MRT) of the thoracic situs and mediastinoscopy, with histopathological investigations of excised lymph node or soft tissue specimens, are the most important preoperative methods of staging for lung cancer and are helpful in further decision-making; however, there is no practicable and clinically proven strategy for preoperative determination of the exact pattern of local lymphogenic tumor spread in the sense of the SLN concept and detection of early metastases in the N2 and N3 stages. A peritumoral labeling concept has also not been developed. The basic knowledge that might be useful in efforts to develop such concepts is: · In 70% of cases, bronchogenic cancers develop in the central parts of the tracheobronchial tree, mainly in the large bronchi of the upper lobes; at least for these cancers, a sophisticated peritumoral injection technique could be developed. For peripheral cancers that are not accessible by bronchoscopy a new transthoracic injection technique could be developed. · A second strategy, which might be useful in combination with the first or separately, is systemic administration of ultrasmall paramagnetic iron oxide particles (USPIO) to detect lymph nodes, and parts of them in the presence of node destruction, radiologically.
missure just reached. a An early stage; b, c stages in which labeling could be helpful in detection of SLNs in cases with ªcross-metastasisº
Such investigations are in the experimental stages, and we are looking forward in the hope of new approaches and of success with these methods. In Fig. 9 the possibility of peritumoral 99mTcnanocolloid injection is documented (Fig. 9 a). Such strategies can be discussed at least in the early stages of non-small-cell lung cancers. Experimental studies using USPIO which were initiated by Weissleder et al. (1990) are still in progress (Fig. 9 b). Unfortunately, the specificity of results (exclusion of scars in lymph nodes) is too low for the results to be acceptable. Some studies ± carried out in Japan ± on the treatment of early carcinoid cases could be the basis for such developments. New studies on the lymphatic drainage of the different lobes of the lungs and/or their subsegments are in progress (Narçke et al. 1999). Intraoperative mapping using the blue dye method (Little et al. 1999) and 99mTc-nanocolloid labeling (Liptay et al. 2000) is now already used by some groups in diagnosis and operative management, but so far there are no internationally familiar and widely accepted concepts. The problems of the differential diagnosis of different subtypes and the possibilities of primary and node staging and, especially, of using the sentinel node concept are more intensively analyzed and discussed in the specific section of this book (see Chapter 24).
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Chapter 9 Experience with and Suggestions for Cancer of Different Types and in Different Sites Fig. 9. Lung cancer. Locoregional spread detected by local submucous injection of tracer around the tumor (a). Systemic administration, e.g. of ultrasmall paramagnetic particles of iron oxide (USPIO), can help in finding filling defects of lymph nodes (b). Carcinoids of the lung are discussed in detail separately in the specific section of the book (see Chapter 27).
Gastric and Neuroendocrine Cancers Stage-adapted surgery in gastric cancer has always been a critical point. Since the 1970s it has been well known that even in early gastric cancer cases (as defined by the Japanese Society of Gastroenterology in 1967) the rate of regional lymph node metastasis is approximately 15%. A second problem is the differentiation of gastric cancer from carcinoid tumors of the so-called mixed types (gastric cancer with carcinoid components) (see Fig. 10). The third problem is preoperative clinical staging with the aid of ultrasound. This can only give an approximative, not a definitive, answer to the question of whether the cancer has already infiltrated the wall. With these restrictions two options seem to be open. · Intraoperative regional lymph node mapping and investigation in frozen sections, possibly with the use of ultrarapid immunohistochemistry (staining for cytokeratins 8, 18, etc.).
· Intraoperative peritumoral blue dye injection or preoperative injection of 99mTc-nanocolloid into peritumoral submucosa. · Regarding point no. 1: Intraoperative lymph node mapping has long been practiced in many clinics, but this method with intraoperative investigations in frozen sections is always connected with loss of tissue parts and the results are therefore reliable only to a limited degree. ± Without using immunohistochemistry, anaplastic gastric cancer cells cannot be definitely distinguished from activated lymphatic cells. · Regarding point no. 2: Sentinel node navigation surgery (SNNS) using blue dye staining of regional lymph nodes with subsequent intraoperative mapping has been practiced by Miwa (2001) with only moderate success, and the 99m Tc labeling technique has been tried by Yoshimura et al. (2001) and Yashuda et al. (2001). The main problems arising when the radioactive labeling system is used must be seen in the fact that higher dosages of 99mTc are needed and that
Colorectal Cancers Fig. 10. Differential diagnosis during Nstaging has important implications for adjuvant tumor treatment. Submucous 99m Tc-nanocolloid injection (1) helps to detect the sentinel nodes (2) by means of a gamma ray probe in cancer cases. Systemic administration of somatostatin analogue substances or yttrium-90marked somatostatin can help to detect neuroendocrine tumors and their metastases in sentinel nodes
detection of SLNs located close to the primary is technically very difficult. These problems are encountered both with cancer cases and with carcinoid tumors. The same is true for mixed types (Fig. 10). Subserosal injections of blue dye solution or 99m Tc-nanocolloids were obviously not used, because the subserous lymphatic network can drain in different directions and lead to incorrect lymph node labeling and misinterpretations. Marker investigations for specific subtypes of stomach cancers have not been evaluated. They seem to be possible, especially for cancers with overexpression of c-erbB2, with labeled antibodies directed to the extracellular domain of p185 protein. By analogy with CEA labeling, such investigations could be beneficial for labeling procedures in 20±30% of cases. In contrast to these deficits in diagnosis, in the case of carcinoids and neuroendocrine cancers diagnosis is progressing more quickly: with the somatostatin receptor used as a marker nuclear medical investigations are quite helpful in locoregional tumor staging and also in investigations for the detection of hematogenous spread, especially to the liver. Such investigations, as well as PET, CT and MR techniques, are also helpful to exclude not only carcinoid tumors but also second primaries, e.g., additionally developing stomach cancer or colon cancer with hematogenous spread to the liver. This can be an important point, because the neuroen-
docrine tumors often develop very slowly over some years. Especially in these conditions, it can be important to exclude a second primary when fast-growing metastases are present. Figure 10 shows gastric cancer localized distally in the antrum (1), with surrounding submucous 99m Tc-nanocolloid labeling and lymphatic flow to two SLNs at the small and large curvatures (2). Blue dye has also been used intraoperatively (Miwa 2001). Further aims of investigations in gastrointestinal cancers are related to cancer typing: mixed (cancer and carcinoid) type or carcinoid only. For instance, in the case of mixed-type tumors it would be interesting to know not only whether the SLN(s) is/are tumor free, but when metastasis has developed, also whether cancer cell populations or carcinoid cell tumor components make up the cell populations of the metastatic process. These questions and their answers are important for the follow-up and for the treatment of tumor recurrences.
Colorectal Cancers Both for surgical treatment and for scientific investigations from a didactic point of view, it seems to be reasonable to consider cancers of the rectum and of the colon separately. As already pointed out, improved operation techniques aimed at monobloc resection (colon
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plus regional lymph nodes in continuity) have resulted in significantly improved 5-year survival rates. In the older literature it is reported that the recurrence rate after R0 resection combined with negative sentinel nodes is approximately 30%. Because the recurrences of surgically treated rectal cancers often developed in the presacral region, the operation techniques have been changed. Since the practice of excising the presacral tissue, including the perirectal presacral lymph nodes, en bloc with the rectum, was introduced into clinical routine, the presacral recurrence rate has declined. The monobloc resection technique with lymphadenectomy of the nodes accompanying the course of the blood vessel supply up to the root and the presacral tissue, including the retrorectal lymph nodes, has improved survival rates by approximately 20%. Therefore, we might ask what additional improvement can be reached by using the sentinel node concept. The following answers, based on recently acquired knowledge, seem to be relevant. · The chain of nodes, which is partly localized in a network and not in a simple cord, can be more accurately controlled using the gamma probe. · The retrorectal region, including small lymph nodes, at least some of which might be sentinel nodes, can also be more accurately controlled after rectum extirpation, with or without sphincter-preserving surgery. · The control investigations of sentinel nodes have been improved by combined node investigations (HE, immunohistochemistry using anticytokeratin antibodies) and by additional investigation with RT-PCR directed at carcinoembryonic antigen (CEA). · Exact histopathological evaluation of the SLN (s) allows: ± More exact exclusion or confirmation of SLN metastasis. ± Up-staging in N+ when the sentinel node is involved, with implementation of adjuvant chemotherapy. So far, only a few publications offer any answers about successful results using this new approach. In approximately 13±15% of cases the sentinel node is the only site of metastatic involvement. Because of the early stage of metastasis, sophisticated investiga-
tions using HE staining and immunohistochemistry for accurate staging should be improved. These results agree with those of restaging investigations published by Schauer V. M. et al. (1998). (See also Broll et al. 1997; Liefkers et al. 1998). The extensively tested systems of sentinel node detection have already been much improved in detail and much more intensively used in the staging of malignant melanoma and breast cancer staging than in colorectal neoplasms. The patent blue staining procedure and also 99mTc-colloid injection for one-step SLN staging of colon cancer cases have been used with no complications. Therefore, it is to be hoped that therapy revisions leading to further improvements can be started. The injection technique used in colorectal diagnosis has so far been based mostly on intra- or preoperative patent blue injection. The solution is injected subserosally in a volume of 2 ml; within 5 minutes the regional lymph node(s), i.e., the sentinel node(s) is/are reached. After injection of the dye en bloc preparation can be continued and the blue-dyed sentinel should be marked with a thread.
Fig. 11. Rectal cancer revealed by submucous injection of 99m Tc-nanocolloid in the area surrounding the cancer. Note that transport to perirectal nodes in the N1 and N2 positions is possible, but that even small retrorectal nodes can be sentinel nodes
Urogenital Cancers
Submucosal injection would be more adequate to the biological situation, however; it would be better adapted to the lymph flow from regions immediately around the cancer region to the sentinel node(s) (Fig. 11). Nonetheless, the time lapse from preoperative labeling to intraoperative marking of the SLN is too long. In this long period the fluid has already passed the sentinel and stained the subsequent nodes. It might be, however, that in the first trials colloids with too-small particles were used, with a consequent high degree of spillover. New approaches seem to be more successful (see Chapter 26: ªResults of Tsioulias et al., John Wayne Cancer Center, Calif. USAº). Figure 11 illustrates a case of rectal cancer with submucous injection of 99mTc-nanocolloid into the areas surrounding the cancer. Note that transport to perirectal nodes in the N1 and N2 positions is possible, but also that even small retrorectal nodes can be sentinel nodes.
Urogenital Cancers Penile Cancer Cabanas (1977) was the first to develop a sentinel node concept for use in the treatment of penile cancers; while this concept is frequently applied in India it is seldom used in the western world. He presented his early results as the very first re-
searcher to have developed a concept of how to find the first node in lymphatic spread of a cancer, the so-called SLN. Unfortunately, in the period immediately after Cabanas' (1977) initial publication few clinics published data on the sentinel node concept in penile cancer, deviating from the first series. Cabanas (2000) and groups working in some other clinics (Akduman et al. 2001) later confirmed most of the earlier results, or at least the principles of sentinel node dissection. Others valued the significance (Ravi et al. 1991) of positive sentinel nodes, while at the same time pointing out that negative SLNs do not guarantee the absence of regional metastases. From the aspects of the missing rates of the sentinel nodes, the average number of sentinel nodes, and the rate of bilateral sentinel nodes, the data of the Amsterdam-group (Horenblas et al. 2000) are of interest. They are summarized in Table 6. In some contrast to the briefly sketched positive rates for the use of the SLN concept, Pettaway et al. (1995) state that even more extensive biopsy (ªextensive sentinel lymph node dissectionº) has a false-negative rate of 25%. Abi-Aad and deKernion (1992) developed a concept with strategies adapted to the individual clinical findings. The strategies are summarized in Table 7. As in other cancer types (breast cancer, malignant melanoma), 15 MBq of 99mTc-nanocolloid in a
Table 6. Sentinel node evaluation in penile cancer cases, as published by Horenblas et al. (2000) No. of cases
Inguinal sentinel nodes
No sentinel nodes
One or more unilateral SLN
Bilateral drain- No. of SLNs age surgically removed
Regional lymphadenectomy in SLN+ cases
125
107
2
10
43
11
108
Table 7. Strategies linked to the clinical and histopathological case-related results, as published by Abi-Aad and deKernion (1992) Significance of enlargement of nodes Cancer +
±
50%
50%
Clinically negative, but micrometastases found by histopathology
Primaries with no invasion of corpora and no palpable nodes
Primaries with invasion of corpora, whether nodes palpable or not
Persistent lymphadenopathy
20%
2- to 3-month controls
Bilateral inguinal and pelvic lymphadenectomy
Superficial lymphadenectomy, if positive bilateral pelvic lymphadenectomy
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volume of 0.2 ml is injected around the cancer. Because of the high sensitivity in the genital region, local anesthesia administered with a needle-free syringe is indicated before the tracer injection. When the tumor has already been excised the labeled solution can be administered into the dorsum penis in the coronal region.
Prostate Cancer Labeling of SLNs in prostate cancer is currently in an experimental stage. The main problem is the route of administration for the labeling fluid. Therefore, all the experience published in recent years, most of which has been collected by the Augsburg group (Wawroschek et al. 2001), is reported and discussed in the part of the book containing sections on specific organs (see Chapter 30).
Vulvar Cancer In surgical treatment of vulvar cancers in more advanced stages lymph node revision of both groins is usually necessary. It can be assumed that at least in lower cancer stages (T1±T2) extensive lymphadenectomy can be avoided, because a high percentage of cases will still be node negative. Therefore, early detection of the cancer by gynecologists is important. Few groups have published experience based on large numbers of patients in whom blue dye and/or 99m Tc-nanocolloid sentinel node detection techniques have been used (Levenback et al. 2000, 2001; Sideri et al. 2000; Ghurani and Penalver 2001; Makar et al. 2001; Molpus et al. 2001).
Cervical Cancer The numbers of patients evaluated in sentinel node studies in cervical cancer in recent years have also been small. Therefore, there is still no large bank of experience to draw on. Both methods (blue dye and 99m Tc-nanocolloid administration) have been used (O'Boyle et al. 2000; Medl et al. 2000; Verheijen et al. 2000; Lantzsch et al. 2001). In the early stages the results seem to be good (Verheijen 2000; Lantzsch et al. 2001), but in ad-
vanced stages of local disease the sentinel search method seems not to be of value (O'Boyle et al. 2000). We know that pelvic lymphadenectomy has always been problematic, especially in early stages of cervical cancer, and discussion about adjuvant radiation therapy has been controversial in view of the need to balance survival benefits against the risk of radiation-induced injuries (radiation colitis, etc.). Criteria for use in deciding in which cases extensive bilateral pelvic lymphadenectomy can be avoided and in which cases postoperative radiotherapy is not indicated would therefore be extremely valuable. For further analyses the reader is referred to the specific section in this book (Chapter 28).
References Abi-Aad AS, DeKernion JB (1992) Controversies in ilioinguinal lymphadenectomy for cancer of the pelvis. Urol Clin North Am 19(2):319±324 Adler CP, Eder M, Schauer A, Thomas C (1984) Rundtischgespråch çber diagnostische Probleme der Metastasierung [Diagnostic problems of metastasis ± a round table]. Verh Dtsch Ges Pathol 68:164±185 Aikou T, Highashi H, Natsugoe S, Hokita S, Baba M, Tako S (2001) Can sentinel node navigation surgery reduce the extent of lymph node dissection in gastric cancer? Ann Surg Oncol 8 [Suppl]:90S±93S Broll R, Schauer V, Schimmelpenning H, Strik M, Woltmann A, Best R, Bruch HP, Duchrow M (1997) Prognostic relevance of occult tumor cells in lymph nodes of colorectal carcinomas: an immunohistochemical study. Dis Colon Rectum 40(12):1465±1471 Cabanas RM (1977) An approach for the treatment of penile carcinoma. Cancer 39:456±466 Cabanas RM (2000) Application of the sentinel node concept in urogenital cancer. Recent Results Cancer Res 157:141±149 Ghurani GB, Penalver MA (2001) An update on vulvar cancer. Am J Obstet Gynecol 185(2):294±299 Giuliano AE, Dale PS, Turner RR, Morton DL, Evans SW, Krasne DL (1995) Improved axillary staging of breast cancer with sentinel lymphadenectomy. Ann Surg 222(3):394±399; 399±401 Grant RN, Tabah EJ, Adair FE (1959) The surgical significance of the subareolar plexus in cancer of the breast. Surgery 33:71±78 Heywang-Kæbrunner SH, Bick U, Bradley WG Jr, Bon B, Casselman J, Coulthard A, Fischer U, Mçller-Schimpfle M, Oellinger H, Patt R, Teubner J, Friedrich M, Newstead G, Holland R, Schauer A, Sickles EA, Tabar L, Waisman J, Wernecke KD (2001) International investigation of breast MRI: results of a multicentre study (11 sites) concerning diagnostic parameters for contrast-enhanced MRI based on 519 histopathologically correlated lesions. Eur Radiol 11:531±546
References Horenblas S, Jansen L, Meinhardt W, Hoefnagel CA, Jong D de, Nieweg OE (2000) Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 163(1):100±104 Kapteijn BA, Nieweg OE, Petersen JL, Rutgers EJ, Hart AA, Dongen JA van, Kroon BB (1998) Identification and biopsy of the sentinel lymph node in breast cancer. Eur J Surg Oncol 24(5):427±430 Lantzsch T, Wolters M, Grimm J, Mende T, Buchmann J, Sliutz G, Koelbl H (2001) Sentinel node procedure in Ib cervical cancer: a preliminary series. Br J Cancer 14; 85(6):791±794 Levenback C, Coleman RL, Ansink A, Zee AG van der (2000) Sentinel node dissection and ultrastaging in squamous cell cancer of the vulva. Gynecol Oncol 77(3):484± 485 Levenback C, Coleman RL, Burke TW, Bodurka-Bevers D, Wolf JK, Gershenson DM (2001) Intraoperative lymphatic mapping and sentinel node identification with blue dye in patients with vulvar cancer. Gynecol Oncol 83(2):276±81 Liefkers GJ, Cleton-Jansen AM, Velde CJ van de, Hermans J, Krieken JH van, Cornelisse CH, Tollenaar RA (1998) Micrometastases and survival in stage II colorectal cancer. N Engl J Med 339(4):223±228 Liptay MJ, Masters GA, Winchester DJ, Edelman BL, Garrido BJ, Hirschtritt TR, Perlman RM, Fry WA (2000) Intraoperative radioisotope sentinel lymph node mapping in non-small cell lung cancer. Ann Thorac Surg 70(2):384±389 Little AG, DeHoyos A, Kirgan DM, Arcomano TR, Murray KD (1999) Intraoperative lymphatic mapping for nonsmall cell lung cancer: the sentinel node technique. J Thorac Cardiovasc Surg 117(2):220±234 Makar AP, Scheistroen M, Weyngaert D van den, Trope CG (2001) Surgical management of stage I and II vulvar cancer. The role of the sentinel node biopsy. Review of literature. Int J Gynecol Cancer 11(4):255±262 McMasters KM, Wong SL, Martin RC 2nd, Chao C, Tuttle TM, Noyes RD, Carlson DJ, Laidley AL, McGlothin TQ, Ley PB, Brown CM, Glaser RL, Pennington RE, Turk PS, Simpson D, Cerrito PB, Edwards MJ, University of Louisville Breast Cancer Study Group (2001) Dermal injection of radioactive colloid is superior to peritumoral injection for breast cancer sentinel lymph node biopsy: results of a multiinstitutional study. Ann Surg 233(5):676±687 Medl M, Peters-Engl C, Schutz P, Vesely M, Sevelda P (2000) First report of lymphatic mapping with isosulfan blue dye and sentinel node biopsy in cervical cancer. Anticancer Res 20(2B):1133±1134 Miwa K (2001) Optimal nodal dissection for early gastric cancer. Nippon Geka Gakkai Zasshi 102(6):484±489 Molpus KL, Kelley MC, Johnson JE, Martin WH, Jones HW 3rd (2001) Sentinel lymph node detection and microstaging in vulvar carcinoma. J Reprod Med 46(10):863± 869
Narunke T, Tsuchiya R, Kondo H, Nakayama H, Asamura H (1999) Lymph node sampling in lung cancer: how should it be done? Eur J Cardiothorac Surg 16 [Suppl 1]:217± 224 Nieweg OE, Kapteijn BA, Peterse JL, Rutgers EJ, Dongen JA van, Kroon BB (1996) Identification of the sentinel node in patients with breast carcinoma. Ned Tijdschr Geneskd 9; 140(45):2235±2239 O'Boyle JD, Coleman RL, Bernstein SG, Lifshitz S, Muller CY, Miller DS (2000) Intraoperative lymphatic mapping in cervix cancer patients undergoing radical hysterectomy: a pilot study. Gynecol Oncol 79(2):238±243 Pettaway CA, Pisters LL, Dinney CP, Jularbal F, Swanson DA, Eschenbach AC von, Ayala A (1995) Sentinel lymph node dissection for penile carcinoma: the M.D. Anderson Cancer Center experience. J Urol 154(6):1999±2003 Ravi R, Shrivastava BR, Mallikarjuna VS (1991) Inguinal pick in invasive penile carcinoma: can it stage node negative patients? Arch Esp Urol 44(9):1123±1126 Rees WV, Robinson DS, Holmes EC, Morton DL (1980) Altered lymphatic drainage following lymphadenectomy. Cancer 45(12):3045±3049 Rettenbacher L, Koller J, Kassmann H, Holzmannhofer J, Rettenbacher T, Galvan G (2001) Reproducibility of lymphoscintigraphy in cutaneous melanoma: can we accurately detect the sentinel lymph node by expanding the tracer injection distance from the tumor site. J Nucl Med 42:424±429 Sideri M, De Cicco C, Maggioni A, Colombo N, Bocciolone L, Trifiro G, De Nuzzo M, Mangioni C, Paganelli G (2000) Detection of sentinel nodes by lymphoscintigraphy and gamma probe guided surgery in vulvar neoplasia. Tumori 86(4):359±363 Verheijen RH, Pijpers R, Diest PJ van, Burger CW, Buist MR, Kenemans P (2000) Sentinel node detection in cervical cancer. Obstet Gynecol 96(1):135±138 Wawroschek F, Vogt H, Weckermann D, Wagner T, Hamm M, Harzmann R (2001) Radioisotope-guided pelvic lymph node dissection for prostate cancer. J Urol 166(5):1715±1719 Weissleder R, Elizondo G, Wittenberg J, Lee AS, Josephson L, Brady TJ (1990) Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging. Radiology 175(2):494±498 Yasuda S, Shimada H, Ogoshi K, Tanaka H, Kise Y, Kenmochi T, Soeda J, Nakamura K, Kato Y, Kijima H, Suzuki Y, Fujii H, Tajima T, Makuuchi H (2001) Preliminary study for sentinel lymph node identification with Tc-99m tin colloid in patients with esophageal or gastric cancer. Tokai J Exp Clin Med 26(1):15±18 Yoshimura M, Shiroiwa H, Umeda J, Jinbu A, Koizumi K, Takagi Y, Koyanagi Y, Abe K (2001) Experience of gamma-detecting probe for the survey of sentinel node in gastroesophageal malignancies. Kaku Igaku 38(4):351± 354
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Initial Remarks on the Histopathology of the Lymphatic System For any clinical diagnosis or treatment to be performed it is necessary to have sufficient morphological knowledge about the organization and structures of the lymphatic system. This includes knowing how the network of lymphatic vessels is organized and how this network is connected to regional lymph nodes and recognizing the nature of the synergistic structures and cellular activities of the different cell populations of the nodes, the connections between the nodes, and the significance of junctional node stations. As already explained in Chapter 7, the lymphatic capillaries begin in the periphery in the interstitium of soft tissue parts. This means that they are closed at the end and that there is no stream with peripheral loops, with inflow and outflow, as there is in the peripheral bloodstream. The lymph vessels drain the lymphatic fluid into the marginal sinuses of the lymph node via the vasa afferentia (Fig. 1). The biological processes within the nodes cannot be understood without some basic knowledge. In the cortex of the nodes we find the B-cell follicles ± these are easily detected by histological procedures ± with their germinal centers, showing high proliferative activity. The periphery of the follicular system is where the dendritic reticulum cells are localized; these are the conductors directing the orchestra made up of the different cell populations. The paracortical T-zone is sited subcortically, i.e. inside the follicular B-zone. Here we find the different categories of T-cell populations. The lymphatic sinus network is located between the follicular structures, beginning with the subcapsular marginal sinuses which drain the lymphatic fluid to the central parts (medullary sinuses) and from there through the channel system and then to the vasa efferentia, where the fluid leaves the node.
The lymphatic sinuses are outlined by and partly filled with so-called sinus histiocytes. These cells show high phagocytic activity and therefore have the functions of macrophages. This makes them the most important cell populations responsible for the clearance of the lymphatic stream, which they achieve by ªparenteral digestionº of toxins and proteins and also by digestion of living and necrotic tumor cell material.
Significance of Labeling of the Different Cellular Compartments of the Lymph Nodes for Radiological Diagnosis At least two features related to components of the lymphatic system must be mentioned in this context: · The B-cell population of the lymph nodes (cortical zone) can be labeled by using the antibody CD20. This method is used for radiological staging diagnosis of B-cell lymphomas, but when high sensitivity has developed it may also be possible to use this antibody to demonstrate neoplastic infiltration within the nodes, leading to destruction of parts of the node-specific structures. · A second approach, which is newer and still experimental, is systemic application of ultrasmall particles of iron oxide (USPIO) colloids (see also Chapters 1, 2, 9). These particles are taken up by phagocytosis, generally in the reticuloendothelial system of the organs (spleen, liver), and especially also in the peripheral lymphatic tissue (lymph nodes), where the material is strongly phagocytosed and stored by sinus histiocytes. Both labeling systems have been used by several expert groups in efforts to find areas of cancer infiltration-related defects in lymph nodes that could
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Chapter 10 General Techniques in Surgical Investigations
Fig. 1. Normal lymph node structure, showing the vasa afferentia (1) in which the lymphatic fluid is transported into the node and the vas efferens (2) in which the fluid leaves the node. Arborization of the arterial stream (3) passes through the node and small vessels end in the re-
gional fatty tissue (4). After collection of the venous blood the veins concentrate in the apposite direction and the main stream leaves the node (5) [6 marginal sinuses, 7 medullary sinuses, 8 secondary follicles (B-zone), 9 mark strands (Tzone)]
be sentinel nodes. However, the preliminary results have not been sufficiently convincing to justify introducing such methods into routine clinical investigations.
· In many other settings, including N-staging of other primaries, it is not so easy to use the usual blue dye methods, because the flow of the dye cannot be followed. · Depending on the local vascularization, the blue dye can be quickly resorbed into the bloodstream locally and excreted with the urine, which is discolored by it and becomes blue to green; in addition, long-term or even permanent blue staining of the skin can develop. · Allergic cutaneous reactions and anaphylactic shock are also possible.
Critical Points in Blue Dye (Patent Blue) Mapping In use of the blue dye method, whether alone or in combination with tracer methods, various points seem to be important. · This method is limited to particular tumor types, such as breast cancer, malignant melanoma, and now also colorectal cancer. The topographic overview it allows is optimal in some circumstances, and the lymphatic basin is generally well defined.
Therefore, with due consideration for the side-effects mentioned (points 3 and 4), these possibilities must be discussed with the patients and when informed consent is given special measures must be implemented.
Practical Use and Servicing of the Gamma Probe
Timing in Blue Staining Methods When isotonic aqueous dye solutions are used it is clear that resorption via the lymphatics is very much quicker than with the methods using labeled colloidal particles. Exact timing, accurately based on clinical experience, is therefore very important for successful operation procedures. The following points must be kept in mind: · When the preoperative injection of the tracer solution is given too early, not only the sentinel lymph node(s) (SLN/s) will be stained, but as a rule all lymph nodes within the basin. · When the preoperative injection is given too late the bulk of the solution injected will be found around the injection site and too little of the stain will reach the SLN(s). Because preoperative labeling of SLNs, for instance in colorectal cancers, with 99mTc-nanocolloids is not yet sufficiently well developed, intraoperative subserous administration of blue dye is used to look for the SLN(s). This preliminary strategy has the advantage that no such precautions as are needed with radioactive material are necessary.
Probe Guidance in Surgical Treatment In recent years it has become increasingly clear that use of a gamma probe increases the rate of SLN detection. Albertini et al. (1996) demonstrated an increase from 73% to 92%. This successful outcome paved the way for further developments of the devices used in daily routine, to improve handling and sensitivity. The great advantage of ªprobe-guided surgeryº is that the localization of the SLN/s can be evaluated even preoperatively and the surgical procedure can be guided intraoperatively. In order to determine the exact course of the lymphatics from the primary to the sentinel node, in many clinics a combination of the blue dye method and gammaguided detection is preferred. In the circumstances. at the moment it seems we can hope that optimal solutions will be developed. A second important advantage of using the gamma probe is that it is possible to check for complete excision of the SLN intraoperatively by keeping the gamma probe in the wound region
after excision of the sentinel node. If residual activity is found near the site of the sentinel node, re-excision of this region can be performed and the material can be subjected to histological investigation. Many authors have now come to the conclusion that sentinel node detection is optimal when the blue dye staining method and the gamma probe technique are used in combination, because the two methods work in synergy. The stained lymphatic cord connecting the primary with the sentinel node can be seen with the naked eye, and the gamma probe can detect macroscopically invisible, very small nodes or be used to control for completeness and to guide re-excisions if residual activity is found. The use of both methods in combination can be seen as a dual-control system aimed at complete locoregional tumor clearance. Clinical studies must demonstrate how much lower the frequency of locoregional recurrences is than after blind excision on the basis of surgical experience alone. There is no doubt that these new developments are valuable in terms of modern improved quality control.
Practical Use and Servicing of the Gamma Probe (see also Chapter 12) For controlled usage of the gamma probe several points are important to prevent accidental malfunctions with highly unfavorable consequences. · Battery-supported devices must be checked before use. Directly operating non-battery-supported devices must also be tested preoperatively for electric functionality. · Regular sensitivity testing of the gamma probe is necessary to guarantee constant sensitivity and to exclude undetected loss of sensitivity. Standard sources (iodine-129 or cobalt-57) can be used for reproducible standard measuring. · When it is the surgeons, and not specialists in nuclear medicine, who are performing the investigations in the patients, the surgeons must be familiar with the handling of the probe. · When anesthesia has started and the patient is fully prepared for the start of the operation, the gamma probe must be brought into the operating position.
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Chapter 10 General Techniques in Surgical Investigations Fig. 2. Schematic demonstrating how to protect a probe with a sterile glove, which can be drawn off after use. This makes subsequent cleaning and sterilization after the operation easier
Fig. 3. The gamma probe should be put down on a table or box with a rim at the edge so that it can never roll or fall off or be pulled down by a tug on or tension on the cable
The following points must be observed: ± Probe and cable must be covered with sterile tubing ± The probe must be covered with a glove (Fig. 2) ± The probe must be secured during the operation procedure, and accidents must be prevented by secure provision of a safe place for the operator to lay down the probe (Fig. 3).
Good Practice in Combined Use of Dye and 99mTc-labeling Procedures Depending on the localization of the primary, for instance in breast cancer cases (subcutaneous, centrally in the gland, prefascial), patent blue solution is injected subdermally or peritumorally in a volume of 0.2 ml in subdermal or 4 aliquots of 1,5± 2 ml in deep pertumoral injections (quantities vary in the published literature, and different reasons are given for larger and smaller quantities). The syringe used must be locked against accidental separation from the needle during injection under pressure, because in such an event the dye will flow over the epidermis and label more or less extensive areas of the skin. In addition, careful handling is necessary at the site of injection (empty syringe at time of withdraw-
al, pressure balance within the injection system). Gentle massage at the injection site helps to lessen or avoid reflux of the dye or labeling solution within the superficial parts of the injection channel. Because it is necessary to be prepared for anaphylactic reactions after blue dye injection, cortisone and catecholamine solutions should be immediately available and ready to hand. The injection of 99mTc labeled colloid solution must have been performed 24 hours before the operation.
Determination of the SLN's Location and Procedure for Its Excision The point on the skin that is as exactly as possible over the SLN located in the deep tissue is marked with the aid of the gamma camera. Because the hot spot(s) is/are located in deep tissue, a three-dimensional judgment is not possible at this time. These evaluations can be adequately performed with the Neoprobe 1500 or other new probes (see also Chapter 12). One of the devices frequently used in our Department of Nuclear Medicine, the Tec-Probe 2000, is shown in Fig. 4. When the device reaches the hot spot region, this is indicated by acoustic signals and a high radiation count readable on the device. These counts
Determination of the SLN's Location and Procedure for Its Excision
Fig. 4. The Tec-Probe 2000 device connected with the gamma probe
have to be compared with those of the background analysis, which should have been measured earlier in the sternal notch area with the gamma camera held perpendicular at the measuring point. To find the shortest way to the SLN the ªline of sightº described by Krag et al. (1993, 1998) is routinely used. The surgeon can find the shortest route quite precisely by changing the angle of the tip of the probe, but it is quite important that the probe is not pointing at the injection site, as this would cause the count to increase and the values indicated would be false. Blunt preparation with avoidance of bleeding is necessary. When the SLN is reached it must be excised with at least a thin layer of perinodal soft tissue, the purpose of this being to include the vasa afferentia of the nodes or any nodal metastasis in the early phases of a breakthrough of through the lymph node capsule. When the blue-stained lymphatic draining to the sentinel node becomes visible during the operation it should not be dissected early in the procedure, because there is a danger that the blue dye solution would flow out into the soft tissue in the area surrounding the node, bringing with it lymphatic fluid and also cancer cells. · It is good practice to compare the counts obtained in situ before extirpation of the sentinel node with the counts of the isolated node after extirpation to avoid misinterpretation when the radioactivity measured in situ actually came from the background. · The second control is to place the probe in the wound bed to make sure that no radioactive nodes have been left.
From the location point of the extirpated SLN the gamma camera has to be angled in all directions in a circle to make sure that no second sentinel node has been left in the vicinity of the excision point. This secondary evaluating procedure is again highly sensitive; it detects even slightly elevated activities, which must be regarded as activities in radioactive fluids within lymphatics, which can lead the operator to a SLN that has been left in place. If there are no areas leading to the suspicion of second or further SLNs, some surgeons conclude the operative lymph node clearance at this point, taking the view that skip metastases, while possible, are very unlikely. At present, however, many authors still argue that the function of the SLN concept as an intraoperative ªsignal boxº for limited lymphadenectomy is still under investigation. The goal of obtaining scientifically based and proven calculations of its value and evaluating the lymph node status in the whole axillary basin is now being approached intensively and it will still be some years before we know more about the real value of sentinel node evaluation. The most important point in this connection is that we have no statistically evaluated comparative life-tables for the tumor entities discussed, showing that the more limited surgical programs based on the SLN concept ± e.g. avoidance of complete axillary revision ± have long-term survival rates equivalent to or better than those following the more aggressive strategies for locoregional cancer clearance. Therefore, based on current documented knowledge, after SLN excision full axillary lymphadenectomy including all lymph nodes in levels I and II is practiced in many clinics during learning, control and early follow up period to be on the safe side. Experience has shown that there are difficulties when the primaries are located in the lateral quadrants near the outline of the lateral pectoralis muscles. In such cases the ªshine-through phenomenonº has an important role and can disturb the search for the sentinel node quite badly. Most of the false-negative cases in earlier sentinel node investigations were due to this. In Krag's investigations (Krag et al. 1998), in all false-negative cases the primaries were in the lateral part of the breast. For cases in which the shine-through phenomenon must be assumed, some possible ways of solving this problem can be defined:
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Chapter 10 General Techniques in Surgical Investigations
· The probe can be angled away from the injection site. · Additional collimation can be implemented to reduce radiation scatter and background activity. · Radioactivities can be separated by blocking plates (steel, tungsten). · The more highly loaded primary can be excised before the search for the sentinel node(s) is started. These possibilities should be adapted to the individual case, but they must be kept in mind, and such equipment as shields, etc. must be available in the acute situation for when its use seems appropriate or necessary.
Pitfalls of SLN Labeling and Detection The most important pitfalls in SLN detection are based on the following points. · In totally or almost totally tumor-infiltrated nodes perfusion is generally severely reduced, and sometimes the vasa afferentia are already occluded by cancer cells filling up the lumens. In such cases the lymphatic flow bypasses the tumor-infiltrated node and labels a tumor cellnegative node; the ªrealº sentinel node ± which is not detected by the probe ± would be positive, but the ªpseudosentinelº or ªsubstituteº sentinel node is seen as cancer cell negative. · A further possibility when the sentinel node is unable to take up the labeled fluid is so-called fatty degeneration of the node in elderly persons. This means that 80±90% of the node, especially the central parts, has become substituted by fat cell tissue. This degenerative change corresponds to fat cell proliferation ªe vacuoº from central parts to periphery, filling the space that has resulted from the shrinkage of lymphatic tissue. In this process the lymphatic channels have also disappeared, as they are also involved in the shrinkage process. This means that lymphatic flow is much reduced or no longer present at all. In practice, such nodes ± primarily sentinel nodes ± cannot be labeled by the methods described. · A multicentric or multifocal cancer of the breast can simulate a paraglandular SLN when one fo-
cus is localized in an extremely far lateral site in the glandular body. · Primaries that are located not in the main parts of the glandular structures, but in the axillary tail can: ± Be misinterpreted as metastases of an undetected primary. ± Be accepted as the primary (mostly after surgical excision), but labeling of the sentinel node is then impossible. · Dystopically located primaries ± in rare cases in the axilla ± can initially be misinterpreted as metastases, with a consequent search for a nonexistent primary in the glandular body of the breast.
SLN Investigation by Pathologists in Cooperation with Cytopathologists In recent years the ªworking formulaº has been: When pathologists investigate the SLN intensively and do not find any metastatic settlement investigation of the other approximately 12 lymph nodes (average in German breast cancer studies) or even more (usually after revision of the axilla) can be omitted. This is only partly correct, and mostly emanates from nonpathologists. It must be stated that investigation of the sentinel node means work-up of a large number of serial sections stained alternately with HE and immunohistochemically, using antibodies directed at cytokeratin (Fig. 5). In view of the heavy responsibility resting on anyone stating that the SLN is really negative, a large number of sections must also be stained immunohistochemically and evaluated microscopically by qualified pathologists. In addition, in the case of positive results of the sentinel node investigation, 12 or even more lymph nodes must be paraffin embedded and also evaluated histologically in addition to appraising the status and classifying it according to the TNMsystem in view of the exact N-status. The thesis that serial sectioning of one or two SLNs with HE and cytokeratin stainings takes less time than sectioning of a dozen or some more nodes after axillary revision is not fully correct, because
Handling of Histopathological Procedures Fig. 5. Segment of a lymph node near to the subcapsular region, showing disseminated single cancer cells stained (red) for cytokeratin. The typical epithelial cell layering is missing. The epithelial cancer cells cannot be detected with certainty in normal HE stainings and cannot be differentiated from reticulohistiocytic cells
· Pathologists bear a much heavier responsibility, especially in breast cancer cases, because falsenegative results caused by insufficient investigation of the node(s) can lead to axillary recurrence with a fatal outcome. · Before introduction of the sentinel node concept pathology laboratories brought three or more lymph nodes in a single paraffin block for serial sectioning. Preparation of such a large number of serial sections as dictated by the sentinel node concept was not recommended or even considered. This state of affairs was acceptable insofar as if single tumor cells were not detected in the first node reached by the flow of lymphatic drainage all secondary nodes at levels I and II were already prophylactically removed according to the principles of extended axillary revision. Altogether, the responsibility for the assurance that sentinel nodes are genuinely tumor-free has become considerably heavier, but the investment required for the investigations is no lower in terms of time or cost. In total, the new procedure followed since adoption of the sentinel node concept demands more manpower than the conventional staging investigations. Therefore, following the introduction of these new and certainly helpful investigative principles, new ground rules on financing the manpower needed and the cost-intensive immunohistochemical staining must be established in every country. Otherwise, these intensive diagnostic efforts cannot correctly be carried out. This is a ser-
ious warning and should be heeded in order to avoid later litigation against clinics and the medical staff working in them.
Handling of Histopathological Procedures When the SLN(s) is/are taken out, it/they should be immediately transported to the pathology laboratory to be opened by cutting with a fresh unused one-way scalpel into two halves, neither of which should be more than 2±3 mm thick. In the case of a large node a middle, third, slice can be taken. If it is possible, imprint cytology can be performed on material taken from the fresh-cut surfaces for cytological investigations during the operation. (This method of combined investigation was practiced for a long period in the Department of Pathology at the University Clinic in Gættingen in the 1970s and 1980s, with the aim of obtaining at least a preliminary result by cytology.) In the case of a positive result axillary revision can be performed immediately. This seems to be a very important point, since it can make it possible to avoid a second operation. Proposals for the use of ultrarapid immunohistochemistry, as proposed by Nåhrig et al. (see Chap. 17), are very helpful in other conditions, but should be avoided in sentinel node investigations. But, imprint cytology, if correctly performed, is not connected with loss of tissue parts. However, when frozen sections of sentinel nodes are taken, a thickness of at least 1 mm of native tissue is lost, and after paraffin embedding and the first sections
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Chapter 10 General Techniques in Surgical Investigations
are discarded unused, which means a second loss of tissue must be calculated in. With this double procedure, it can be that so much tissue is lost that micrometastases are missed.
Benefits of Sentinel Node Evaluation Over Primary Axillary Revision At the current state of the art there is no doubt that improvements of axillary lymph node staging overall, especially since the fundamental investigations of Krag et al. (1993), have brought advantages with them. This is true insofar as more conservative surgical treatment is possible and also in that higher degrees of diagnostic safety can now be attained. The pros and cons of the sentinel node concept are listed in Table 1. Table 1. Important advantages, each countered by a disadvantage with possibly far-reaching ramifications, of using the sentinel lymph node (SLN) concept without axillary revision Pros (advantages of the SLN concept)
Cons (danger of postoperative cancer spread within the axillary basin in falsenegative cases)
Avoidance of intra- and postoperative bleeding
In false-negative cases [SLN(s) not immunohistochemically detected or incomplete investigated, or primary ªskipº metastasis], cancer cells can be left behind, leading to infiltration of secondary nodes
Avoidance of injury to the long thoracic, thoracodorsal, and intercostobrachial nerves
Avoidance of postoperative axillary infections with development of abscesses Avoidance of lymphedema formation in the arm Excision or radiation of SLNs that would otherwise not be detected in the ªpreaxillaryº (paraglandular) or parasternal regions
Consequences: A number of the lymph nodes in the axillary basin can be infiltrated by the cancer after a short time, leading to incurability! Conclusion: The status after sentinel node control only is not to 100% calculable
In recent years we have learned from the current literature that the rate of false-negative cases can be reduced to 1±2% when surgical discipline and pathological procedures are optimally dovetailed. We have also learned that false-negative results and skip metastases cannot be fully ruled out, however. Therefore, optimal monitoring of the axillary node status (palpation, PET, etc.) is necessary in the follow-up period, especially when axillary revision has been omitted in cases with negative sentinel nodes.
Use of Radiodiagnostic Techniques Basic conditions of usage of a radiopharmaceutical substance are: · The substance is used as a ªtracer,º which means in very low dosages without pharmacological effects. · The tracer must have the property of accumulating in target organs (lymph nodes) and being stored there for a sufficiently long period to be recorded intraoperatively by a gamma probe or an imaging device (e.g., gamma camera). so that it can yield sufficient information about its regional distribution (e.g. sentinel node detection).
Choice of the Labeled Contrast Solution The most frequently used radionuclide in nuclear medicine has long been 99mTc. Clinical work with this radionuclide is largely unproblematic, because it is constantly available throughout the world at an acceptable price. Technically there are two options for its production: · Neutron irradiation of molybdenum-98 · Preparation of a fission product of uranium-235 An important step was the finding of a concept for Tc binding to other compounds. As described by Keshtgar et al. (1999), reduction to the more positively charged technetium species III and VI by stannous chloride enhances the binding capacity to other compounds. Another possibility is to use insoluble 99mTc-sulfur chloride with a TcVIII 99m
Choice of the Labeled Contrast Solution
oxidation state. Stabilizing agents such as gelatin or albumin can be used for stabilization. In consequence of the insolubility and the stabilizing effects mentioned above, labeled colloids were introduced for detection of regional lymph nodes and lymphoscintigraphic analysis. In practical procedures, there are some difficulties in the choice of special colloids for specific purposes: · National limits on availability · Difficulties in registration of new radiopharmaceuticals Therefore, globalization of different companies can help to lower the international transfer problems. For routine diagnosis and for continuous investigations in clinical studies it is important · That the preparation of labeled colloids is reproducible with reference to special qualities. · That stable labeling is maintained. · That each radiopharmaceutical has a constant well-defined particle size. The consistency of particle sizes within each batch and continuously throughout different batches used for the same purpose is a very important factor. It is well known that small particles migrate quickly from the injection site to the regional node(s) and then pass through the node within a short period, while larger particles migrate slowly and need late imaging records. Experience has made it clear that the same particle size cannot be used for lymphoscintigraphy of the nodes of the whole lymphatic basin and for isolated detection of the SLN(s). Particle sizes are qualified and measured by different modern techniques, such as electron microscopy, X-ray fluorescence and gel chromatography. Besides particle size, which is important for the speed of transport and the rate of phagocytosis by so-called sinus histiocytes of the lymph nodes, there are other factors that have roles in detection of node labeling. These are: · Number of particles with defined size. · Charge to the particles with the tracer substance. · Rate of degradation by enzymatic activity of proteases (higher degradation rates in sulfur than in albumin colloids). Specialists in nuclear medicine and physicians are familiar with the difficulties encountered in standardizing the charges.
A brief period of heating (in the range of 3 minutes) followed by cooling for a short period makes for greater radiochemical purity and reduces the quantity of particles that are smaller than 400 lm. When we select a longer heating time the proportion of small particles decreases. As Keshtgar et al. (1999) emphasize, there is a decisive gap between the experimental studies on injection techniques, maintenance of constant particle size, and visualization of the lymph node chains and experience in clinical practice according to systematic research, and there has so far been no consistent improvement. It also seems clear that comparative interdisciplinary studies on national and international bases must be subject to firm controls and that these must also apply to the radiopharmaceuticals used. Early investigations on evaluation of radiocolloid sizing techniques were performed by Warbick et al. as long ago as 1977. Some experts are of the opinion that particles in the size range of 50±80 nm should be favored for the detection of the SLN(s). However, evaluations conducted by clinically experienced research groups have demonstrated that imaging depends heavily both on the volume applied and on particle size of the colloids used. Paganelli et al. published the data compiled in Table 2 as long ago as in 1998, and these have proved valuable for orientation. Figure 6 illustrates the imaging of a case with a breast cancer located centrally in the upper quadrants, and while it is true that drainage to the axillary nodes only is indicated, at least three nodes of the axillary basin are labeled and must be removed and investigated histologically and immunohistochemically as ªsentinel nodesº in serial sections. Table 2. Sizing of radiocolloid particles for use in detection of SLN(s): published data for guidance. (Paganelli et al. 1998) Size of tracer molecules (nm)
Patients positive/ total
No. of nodes imaged
< 50
29/30
1±5
< 80
26/30
1±4
155/155
1±2
< 200< 1000
The publications available suggest that preparations with particle sizes between 100 and 200 nm should be aimed for
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98
Chapter 10 General Techniques in Surgical Investigations Fig. 6. Imaging in a case of breast cancer located centrally in the upper quadrants, showing drainage exclusively to the axillary nodes. At least three nodes in the axillary basin are labeled and must be removed. They must be regarded as sentinel nodes and sectioned for histological and immunohistochemical investigation. (Illustration kindly donated by Prof. Paganelli and his group (IEO Milan)
Because of existing problems in transporting radioactive materials within the European Union and also in rapid transoceanic exchange, specifically with reference to quality requirements, preference should always be given to national products. Such products, based on national production, are:
Product
Manufacturer and comments
Nanocoll
Manufacturer: Nycomed Amersham Sorin S.r.l., 13040 Saluggia, Vercelli Italy, labeled particles 95% < 80 nm Manufacturer: CIS bio International, France This preparation contains colloidal rhenium sulfide (0.48 mg) with average particle size ranging from 3 to 15 nm Manufacturer: Du Pont USA This preparation contains 1 mg of human serum albumin with an average particle size of 10 nm Manufacturer CIS ± USA In keeping with the labeling protocol, the labeled particles are between 40 and 1,000 nm This preparation is mostly used in Australia It has a very small particle size of 5±15 nm This has been withdrawn because of the excessive radiation dose acting on the target tissues
Nanocis
Microlite
Sulfur colloid
Antimony sulfide colloid Gold-198
References
Svensson et al. (1999) relatively recently tested a 99m Tc-labeled polyclonal human immunoglobulin, but such approaches are still in the early stages. It could be that, once labeled, FAB fragments of antibodies can be used for particular kinds of labeling, and it is possible that in the future radiopharmaceuticals will be developed that will bypass the lungs and bind to the reticuloendothelial system and, accordingly, also to the analogous cell systems within the lymph nodes. Some other radiopharmaceuticals, such as 99m Tc-dextran (molecular weight 100,000), which has some allergic potential and exhibits capillary transport (Henze et al. 1982), and 99mTc-human serum albumin (Nawaz et al. 1985), were used earlier but only for a time.
Plans for Improvements to the Quality of the Contrast Media Comparative studies on the colloidal solutions used that include liposomes are in progress. According to the investigations of Philips et al. (1998), in a rabbit model 99mTc-labeled liposomes with an average size greater than 100 nm migrate more slowly than liposomes with an average size less than 100 nm.#
References Albertini JJ, Cruse CW, Rapaport D, Wells K, Ross M, DeConti R, Berman CG, Jared K, Messina J, Lyman G, Glass F, Fenske N, Reintgen DS (1996) Intraoperative radiolymphoscintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223:217± 224 Henze E, Schelbert HR, Collins JD, Barrio JRE, Bennett LR (1982) Lymphoscintigraphy with 99mTc dextran. J Nucl Med 23:923±929 Keshtgar MRS, Waddington WA, Lakhani SR, Ell PJ (1999) The sentinel node in surgical oncology, chap 2: Radiopharmaceuticals. Springer, Berlin Heidelberg New York, p 15 Krag DN, Weaver DL, Alex JC, Fairband JT (1993) Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 2:335±340 Krag D, Weaver D, Ashikaga T, Moffat F, Klimberg VS, Shriver C, Feldman S, Kuisminsky R, Gadd M, Kuhn J, Harlow S, Beitsch P (1998) The sentinel node in breast cancer ± a multicenter validation study. N Engl J Med 339:941±946 Nawaz K, Hamad M, Sadek S, Audeli M, Higazi E, Eklof B, Abdel-Dayem HM (1985) Lymphoscintigraphy in peripheral lymphedema using technetium-labeled human serum albumin: normal and abnormal patterns. Lymphology 18:729±735 Paganelli G, Cicco C, Cremonesi M, Prisco G, Calza P, Luini A, Zucali P, Veronesi U (1998) Optimised sentinel node scintigraphy in breast cancer. Q J Nucl Med 42:49±53 Phillips WT, Andrews T, Liw HL, Klipper R, Laundry A, Goins B (1989) Evaluation of 99mTc labeled liposomes versus 99mTc sulfur colloids and 99mTc human serum albumin for lymphoscintigraphy in a rabbit model. J Nucl Med 39:314P±315P Svensson W, Glass DM, Bradley D, Peters AM (1999) Measurement of lymphatic function with technicium-99m-labelled polyclonal immunoglobulin. Eur J Nucl Med 26:504±510 Warbick A, Ege GN, Henkelman RM, Maier G, Lyster DM (1977) An evaluation of radiocolloid sizing techniques. J Nucl Med 18:827±834
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Chapter 11
Radiation-Detecting Systems
Introduction and Steps in Development Since the first intraoperative use of Geiger-Mçller needle probes for the detection of sodium phosphate bearing the b-emitting radionuclide P43 in brain tumor operations (Selverstone et al. 1949), development of radionuclear techniques has never stopped. The next step was the introduction of the use of iodine-131 or iodine-125 for the detection of metastatic spread of functionally active thyroid cancer (Harris et al. 1956; Morris et al. 1971). The use of this technique opened up the iodine-131 or iodine125 for locoregional tumor clearance (Lennquist et al. 1988), the uptake of radioactive iodine has also been exploited in postoperative adjuvant radionuclide therapy for suspected metastatic processes. Then followed the development and introduction of qualified probe techniques, first using labeled technetium phosphate for intraoperative biopsy techniques (Harvey and Lancaster 1981) and in parallel the development of 99mTc labeling of microcolloids (Aspergen et al. 1978; Meyer et al. 1979; Strand and Person 1979; Henze 1982) and lately also of liposome-labeling techniques (Phillips et al. 1992 a, b; Oku et al. 1993; Goins et al. 1994). Whereas labeled microcolloids can essentially be used for storage in sinus histiocytes after phagocytosis in lymph nodes, these 99mTc-labeled microcolloids are not suitable for direct labeling of cancer cells. In brand new approaches liposomes are used as carriers of the radionuclide 99mTc, but these techniques are still in an experimental stage. Radiolabeling of polyclonal antibodies started as long ago as the mid-1980s. At that time, Martin and his colleagues (see Aitken 1984) became the first research group to label monoclonal antibodies (MAB) directed to carcinoembryonal antigen (CEA) with iodine-131 with the aim of detecting occult metastases.
11
Initially this technique was less successful. However, it developed with the production of highly specific monoclonal antibodies (MAB) and use of iodine-125 as the radioactive label (Curtet et al. 1990; Davidson et al. 1991; Kçhne et al. 1991; Arnold et al. 1992 a, b, 1996; Reuter et al. 1992; Abdel Nabi et al. 1993; Burak et al. 1995). In addition to CEA-detecting radioimmunological labeling, in recent years many other detecting systems based on monoclonal antibodies directed
Table 1. (Neuro-)endocrine tumors detected by labeled substances Reference
Labeled substance
Tumor detected
Wångberg et al. (1996)
In-DTPA-D-Phe1 octreotide
Abdominal cancers, different types
Úhrvall et al. (1997), Waddington et al. (1994)
In-DTPA-D-Phe1 octreotide
Occult recurrences of medullary thyroid cancer
Schirmer et al. (1993)
125
I-Tyr3 octreotide
Gastroenteropancreatic tumors
Martinez et al. (1995)
125 I-Tyr3 octreotide
Occult neuroblastomas
Adams et al. (1998)
In111DTPA D Phe-octreotide + 99mTc (V) dimercaptosuccinic acid (DMSA)
Medullary thyroid cancer; gastroenteropancreatic tumors
Hoefnagel (1994)
125
I and 123IMeta-iodobenzylguanidine (mIBG)
Neural crest tumors
Martelli et al. (1998)
125
Neuroblastoma
I and 123IMeta-iodobenzylguanidine (mIBG)
102
Chapter 11 Radiation-Detecting Systems Table 2. Intraoperatively detectable radionuclides and their physical properties: Data partly published by Ell's group (see Keshtgar et al. 1999) Physical property
Tc-99m
Iodine-125
Iodine-123
Iodine-131
Indium-111
Fluorine-18
Half-life of radioactive decay
6.02 h
60.1 days
13.1 h
8.04 days
2.83 days
110 min
Energy of gamma ray emission
140 keV
27 keV
159 keV
364 keV
171,247 keV
2@ 511 keV
Beta particle emission
None
None
None
606 keV (bmax)
None
633 keV (b+max)
Soft tissue thickness to reduce gamma rays to 50%
46 mm
17 mm
47 mm
63 mm
51 mm
71 mm (c)
Thickness of lead to reduce gamma rays to 50%
0.17 mm
0.05 mm
0.5 mm
2.4 mm
0.9 mm
4.6 mm (c)
Thickness of lead to reduce gamma rays to 10%
0.9 mm
0.06 mm
1.2 mm
7.7 mm
2.5 mm
13.5 mm (c)
to cancer cell-specific antigens have been developed or are in development. One of them is the use of antibodies staining the somatostatin receptor of neuroendocrine tumors (adenomas and cancers) (Krenning et al. 1993; Wångberg et al. 1996; Úhrvall et al. 1997); another example is CD20 detecting lymphatic neoplasias. These examples show that it is worthwhile working scientifically in this field with the aim of extending, confirming, and formulating the diagnostic fundamentals of early cancer detection and spread of the primaries more precisely. The compounds used and their targets are listed in Table 1. These positive developments are based on the observation that most neuroendocrine tumors and their metastases express the somatostatin receptor and that somatostatin analogues such as octreotide bind to this receptor. This knowledge has already been incorporated into the principles of routine clinical diagnosis (see special part Chapter 27). Similar developments can be reported for specific uses of the various tracer substances available. With iodine used as the marker, the change from iodine-131 to iodine-125, which has a halflife of 60 days, in combination with monoclonal antibodies allows intraoperative detection many days after its administration, when the tumor-tobackground ratio of the activity has shifted to a positive one. In Table 2 the physical properties of the mostly used intraoperatively detectable radionuclides are listed.
In nuclear medical diagnostic research the detection of neuroendocrine primaries and their lymphatic and/or hematogenous spread has been successively developed and improved.
Preconditions for Detector Quality Preconditions for the use of a detector in the field of SLN detection are: · The device must be designed or adapted for preoperative and intraoperative use. That means that the node(s) must be detectable by transcutaneous measurement and also intraoperatively by measurement of the radioactivity in the ªoperation field.º · Long-term stability of the device used must be guaranteed. · Physical performance and good handling must be guaranteed. · Electromedical safety as per the legal requirements and sterilization techniques must be guaranteed both by the manufacturer and by the doctor in the department. The devices most frequently used are the Neoprobe 1500 (Fig. 1 a) and Neoprobe 2000 (Fig. 1 b) systems, which were specifically developed and designed for intraoperative SLN detection. The Neoprobe 2000 detector system (Fig. 1 b) is the model produced by the same company to succeed the device shown in Fig. 1 a.
Development of the Modern Gamma Camera Systems Fig. 1. a Neoprobe 1500. b Neoprobe 2000. Both devices were prepared for intraoperative use with the specific aim of sentinel lymph node (SLN) detection
The basic requirements for regular use of such detector systems in surgical disciplines are: · The function of the detector used for the purposes discussed must be stable in all stages of the surgical operations performed. · The sentinel lymph nodes (SLNs) must be detectable by transcutaneous measurements and in the surgical open operative field. · In addition, the detector system must be adequately constructed to allow its use in all stages of the operation. · From the legal standpoint, it is important that the device is electromedically safe and can be sterilized under normal conditions.
Development of the Modern Gamma Camera Systems In the early 1980s the manufacturers of modern medical imaging systems began to provide computer support for these systems so that the image data could be saved in digital form for processing and display. At the same time the imaging detectors were substantially improved. These two strategies allowed development of the cross-sectional imaging technique single-photon emission tomography (SPET). After establishment of these fundamental principles, it was possible to develop highly refined strategies designed to obtain and review image data. After the introduction of rectangular detector heads, which allow an overview of a 4 ´ 5-cm field, new improvements of the gamma camera system with incorporation of a second and third detector head became possible.
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These developments allow high efficiency in planar whole-body studies and SPET imaging by simultaneous use of two or three detector heads. The use of these highly effective sophisticated multi-detector-headed systems can help to exclude hematogenous metastatic spread, especially in investigations of patients bearing cancers with high metastatic potential. In sentinel node imaging concerning the tumor types discussed in this book a computer-supported single-headed planar gamma camera is adequate for all current requirements.
Set-up and Function of the Gamma Camera A thin scintillation crystal is positioned at the front of the gamma camera. After the impact of an incoming gamma ray, minimal quantities of visible
Fig. 2. Operating digital gamma camera system. Dual detector with large-field gamma camera. The detector geometry is variable to allow differing detector orientation for SPET.
light energy are generated within the crystal structures. This process is called ªscintillation,º and the image obtained, by analogy, ªscintigraphy.º In the gamma camera system a set of photomultiplier tubes are fixed at the back of the crystal. When the outputs are summed, the pattern of light generated is recorded. The response to the detected gamma ray is processed by special hardware and software for precise location of the gamma ray impact in an x- and y-coordinate system. The coordinate data are then digitized and saved in the computer to form a scintigraphic image: Only a few percent of the thousands of incident gamma rays per second are recorded. The images demonstrate the overall distribution pattern in a two-dimensional manner. An overview over the frequently used device constructed by General Electrics USA is given in Fig. 2.
(Picture dedicated by General Electric Medical Systems; with ref. to Keshtgar et al. 1999)
Quality Requirements for Optimal Function of Commercially Available Gamma Probes
Scattered radiation must be rejected: in order to obtain feedback, the X-ray energy absorbed in the crystal is measured. The camera must be especially equipped for development of a two-dimensional image of the relative distribution of the tracer within the human body.
Operation of a Digital Gamma Camera System · Perpendicular to surface of the gamma camera, gamma rays pass the honeycomb structures of the collimator. · The rays are detected within the scintillation crystal±photomultiplier tube assembly. · Determination of the gamma ray energy and its location is handled by dedicated processing components. · Then follows digitizing and saving as a matrix of pixel counts in the computer system by techniques designed to restrict the angle of gamma rays coming from different directions. If radiation from all locations (e.g., the primary and surrounding labeled tissue) reached the entire ªfaceº of the camera such exclusion strategies would not be considered. Protection against this unfavorable event is provided technically by installing special collimator equipment. The collimator function can be moderated by lead plates with a ªhoneycomb structureº mounted on the front of the detector. Such plates are a barrier against gamma rays arriving nonperpendicular to the detector surface. As a consequence of these attributes, the lead collimator has a low detector sensitivity at the gamma camera, which affects the quality of spatial resolution. The collimator's design must be adapted to the detector used with the option of change. The gamma camera and the computer system form a functional unit, possessing an interface through which the image data can be controlled by the operator. The data are saved in the form of a two-dimensional pixel matrix of gamma events. They can be collected as a single-frame static projection or as a dynamic sequence of short-time projections. To obtain whole-body scans, it is necessary to move the patient lengthwise relative to the detector at a constant speed. This makes it possible to scan
the tracer distribution within the whole body. This allows important scintigraphic evaluations of the different possible locations of lymph nodes with sentinel character or metastatic involvement (in skin tumors, e.g. malignant melanoma of the trunk: axillary and/or inguinal nodes, or in breast cancer: axillary and/or parasternal nodes). When we control the sequences of the dynamic frames in film form, this allows determination of the time dependency of tracer uptake at the injection point and augmentation at the structures to be imaged, namely the sentinel node position(s). The sentinel node images are very clear-cut, when the nodes are superficially located and the soft tissue between the node(s) and the camera face is only a thin layer. According to Keshtgar et al. (1999) and other authors, the detection of lymphatic transport, and especially the SLN location can be optimized by: · Use of a high-resolution collimator · A fine digitization matrix (optimally 256 ´ 256) · Careful patient positioning with smallest possible distance between radiation source (sentinel node) and detector face.
Quality Requirements for Optimal Function of Commercially Available Gamma Probes Tiourina et al. (1998) evaluated and compared four commercially available surgical gamma probes in laboratory tests to find to what extent they fulfilled important criteria: · Absolute sensitivity · Spectral resolution · Angular sensitivity · Response ratio to the radioactive source at depth By using a surgical gamma probe after peritumoral injection of a radioactive tracer, the surgeon can identify the SLN, or the first nodal site or regional metastasis in clinically node-negative patients. The authors emphasize that in the near future, the pathological status of this node will have an important impact on the treatment strategy in breast cancer and malignant melanoma patients. The authors review the requirements listed above and stress that in addition, ergonomic characteristics are important. The surgeon must consider the above characteristics, as they influence operational
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handling. Four commercially available surgical gamma probes were subjected to laboratory tests. The results for each gamma probe are summarized and discussed. They may help in decision-making when it is necessary to select the most useful device for one's own range of diagnostic activities.
· The absorption information derived from radio transmission is used as the basis for exact correction of absorption by different tissue types.
New Developments in Gamma Camera Devices
For optimal SLN detection and to protect the whole body of the patient from storage of the radioactive material administered, it is necessary for venous resorption of the colloidal solution to be extremely low. In the case of normal lymphatic stream without lymph-congestion, the tracer-bearing colloidal contrast solution is quickly transported into the nodes. No tracer activity is forced into the interstitial tissue outside the lymph node and measured there. Therefore, the contrast between the tracercontaining colloid within the node(s) and the surrounding areas where radioactivity is lacking is extremely favorable. Studies of the balance between tracer quantities taken up by the target lymph node(s), storage within them, and spillover have been performed by different research groups. Kapteijn and his group found a mean value for tracer uptake in the range of approximately 2% per gram of lymph node tissue in the sentinel nodes investigated.
The most modern and most efficient gamma camera with two detectors is now the Millennium VG device supplied by General Electric (see Fig. 3), which has the following main features: · It has variable detector geometry. · It is the only gamma camera that has a ªSchleifring-Stativº/slide ring like that in CT devices · It is available with 1-inch-thick special NaI crystals, which are also optimal for PET. · It is available with HAWKEYE radiotomographic measurement equipment. · It combines gamma camera and CT technology in a single device. · The radiotomographic sectional pictures are produced without changes to the layering of the patient. · It allows exact fusion of the radiotomographic with the emission-tomographic sections. · The anatomical and the function-scintigraphic imaging are superimposed for exact nuclear medical localization of the findings.
Operation-oriented Requirements for the Detection of the SLNs
Fig. 3. Entire HRjp Millennium VG system, with the special qualities and accessories discussed in the text
Operation-oriented Requirements for the Detection of the SLNs Fig. 4. a ªSpilloverº, i.e., a high degree of transit through a sentinel node to the next lymph node when particles of the colloid solution used are too small (< 100 nm). The concentration in the sentinel node is then too low for measurement b In ªbig nodesº fat cell proliferation e vacuo developing from the hilus of the node and extending increasingly to the periphery through the node. Finally, only a thin sickle-like ªcoatº of lymphatic tissue remains at the periphery of the node. Passage of colloid solution through the node is minimized or impossible c Unfavorable situation in nonspecific (abacterial) lymphadenitis with drastic hyperplasia making node up to ten times normal size and high dilution of the radioactive colloid particles taken up d1 The sentinel node(s) located in the paraglandular fatty tissue lies/lie so near to the primary that isolated measurement is hardly possible (ªsevere overlapº) d2 If subcutaneous fat tissue layer is extremely thick, lymph node(s) in level I can also not be detected by percutaneous measurement using the gamma probe e Breast cancer, located in the upper outer quadrant, already near to the axillary tail or in the axillary tail has a very short distance to the lymph nodes of the axilla (level I). In consequence separate measurement of radioactivity using the gammaprobe can hardly have been possible
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It is easy to understand that the absolute amount of tracer taken up must vary, depending at least partly on the degree of atrophy of the lymphatic tissue with fatty tissue proliferation ªex vacuoº in the central node parts or the presence of scars, e.g. after earlier infections of the breast (post partum, etc.). However, an adequate degree of tracer storage 24 h after administration results from the very high percentages (90±98%) of detected labeled nodes that can be found, as reported in the current international literature. As demonstrated by Keshtgar et al. (1999), the levels of tracer uptake in SLNs are highly variable. In their series of cases, node activity was in the range of 0.5±500 kBq. The proportions of the injected doses of radioactivity taken up ranged from 0.003% to 3.3%. From these data it follows that when the radioactivity in lymph nodes was very low, in the majority of the cases the nodes could be detected and resected. Besides these basic very important points elaborated by specialists in interdisciplinary teams, there are some essential points that are relevant for practical work. As already mentioned, ªspilloverº plays a part when the colloids used are made up of too-small particles (Fig. 4 a), but this can be ruled out by experimental procedures. A second point is that some large nodes do not store the colloid because massive fat cell proliferation in central parts of the node suppresses the medullary sinuses and makes them atrophic (Fig. 4 b); in these circumstances no contrast solution can pass through the node. In inflammatorily enlarged lymph nodes (Fig. 4 c) the dilution of the fluid passing through the node is very high and the storage of colloid particles is low. Detection of radiation coming from a node is difficult or impossible when the primary is located a very short distance away (Fig. 4 d1 and 4 e). When the distance from the body surface to the node is very large, as the result of a very thick subcutaneous layer of fatty tissue, this can also make measurement of radioactivity difficult or impossible (Fig. 4 e). Besides the above factors that can be responsible for attenuation, there are some other physical determinants that play an important part. The measurable counts depend significantly on the attenuation factor of soft tissue components located between the SLN and the position of the probe. The second, still more significant, factor is the energy of the gamma radiation.
When these important factors are integrated into the calculation the local radiation can be defined by a ªfractional constantº called the ªlinear attenuation coefficient,º l, which is defined as fractions of a centimeter (see Keshtgar et al. 1999). The exponential relationship between the intensity of incident Io and transmitted Ix gamma rays through a thickness (x) of absorbing tissue can be defined by the following equation: Io=Ixe±lx. The fraction of gamma rays expected to be transmitted through regional tissue can be determined with the aid of this equation. The count reduction rate using 99mTc with 140KeV gamma energy predominates over the soft tissue attenuation. For many of the radionuclides used (125I, 131I, 99m Tc, 111In) the attenuation rates are known and graphically presented.
Optimizing Gamma Ray Measurement The gamma rays ejected from the labeled SLN have to pass through the soft tissue parts containing different tissue components, such as fibrous tissue, fat cell tissue, blood vessels, and nerves. On the way to the face of the detector, while passing through these tissues, the gamma rays can be scattered by collision with outer electrons of atoms (Compton effect; Fig. 5). As a result of this collision the gamma ray loses energy and, as mentioned above, is turned aside from the primary path. When such ªfalse paths,º following a deviating route from the SLN and not a direct one, arriving at the detector face in large numbers they can seem to originate from a false location. As already emphasized, selection of a diagnostic injection site in the area of laterally located primaries in the upper quadrant too close to the points of interest for a search for SLNs can be an important source of this Compton effect and makes the measured results invalid. This falsifying factor cannot be fully eliminated, but only weakened, by the use of ªenergy windowsº and ªcollimation.º In addition, it is the task of the radiologist taking external measurements to reduce the falsifying contribution of such tissue components as parts of the breast by drawing them aside as far as possible in order to reduce the thickness of the soft tissues between the lymph
Important Factors in Performance of the Detector Fig. 5. The Compton effect can falsify gamma ray measurements
nodes being looked for and the face of the gamma probe.
Important Factors in Performance of the Detector The design characteristics of the detector are now highly developed in terms of quality and variability. The detector's sensitivity (S.S.) (definition: count rate per unit source activity (cps/MBq) has an important role, and if it is not fully integrated into the diagnostic process only suboptimal results, and perhaps even wrong results, will be obtained. Important factors in the performance of the detector are: · Arrangement of source and detector · Source dimension · Gamma ray energy · ªAcceptance windowº · Intervening media (tissues of different quality air, etc.) A further important factor influencing the diagnostic quality is the spatial resolution (discrimination of lateral activities). This can be achieved by means of a detachable collimator. The highest response of the detector is at the point of central axis (ªcentral axis lineº); the collimator has the task of limiting the acceptance of gamma rays and eliminating external sources. In the context of this selection process, ªgood spatial resolutionº discriminates between target radioactive structures and activities outside the focus, whereas ªpoor spatial resolutionº increases the sensitive area surrounding the probe.
The measurable profile should correspond to a ªGaussian distribution curve.º The spatial resolution varies with respect to · the radionuclide used · the detector · the source (labeling substance) in dependence on the degree of collimation, depth of scatter of medium between source and detector, and the chosen window. The ªenergy resolutionº results from the basic physical properties of the detector substance used and the precision of performance. In the case of scattered radiation lower response patterns (second peaks) may be detected. According to Keshtgar et al. (1999), the ªenergy resolutionº is characterized as the percentage spread relative to the full width of the profile at half its maximum height (FWHM) of the photo peak analogous to the quantification of spatial resolution. Keshtgar et al. (1999) further emphasize that the energy resolution for any radiation detector depends on the energy of the gamma ray and varies for different radionuclides. The response field of a detector is quite important when it is to be used in clinical practice. Lateral response appreciates at depth and can be expressed as an isoresponse plot. Exploration of a limiting response field helps in the examination of wide areas. In the ªline-of-sightº technique (Krag et al. 1998) these lateral response techniques are also helpful in the search for SLNs in later stages after administration of the radionuclide. For specific individual applications, improved ªspatial resolutionº is an important factor. To
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achieve the aims of the examination a removable collimator using tungsten for attenuation in a ªforward directing collarº can be applied, but the use of a collimator can have both advantages and disadvantages simultaneously. · Its main advantage is that it reduces the exposed surface area of the probe. · Its disadvantages are: ± Reduction of detector sensitivity ± Increase of the distance between the probe face and the tissue However, these disadvantages must be accepted in order to detect SLNs when these are located near to a application area with hot spots over such places. The actual management for exclusion of these unwanted side effects can be supported by shielding the area of interest with a removable steel or tungsten plate. An increase in spatial resolution can be obtained, albeit at the cost of a decline in the detector's sensitivity. Computer-supported model programs and phantom-studies can help to optimize conditions in special investigatory programs.
Quality Criteria for Gamma Probes and Dosimetric Consequences Quality criteria have been defined and published (see Institute of Physical Sciences in Medicine 1991; Eshima et al. 2000; Keshtgar et al. 1999; Waddington et al. 2000) in a desire to protect · Patients · Surgical and histopathology staff.
Management of Electromedical Safety Radiation detectors are provided with electromedical equipment. In action the detector (gamma probe) is sometimes placed into the patient's body cavities and is then directly in contact with tissues and body fluids. Therefore, specific electromedical requirements are obligatory. The most important risk ± as with other electromedical devices ± is that of leakage of the device with consecutive induction of ventricular fibrillation of the heart. The electric current can
reach the patient directly or be earthed via another device. A safety standard protocol elaborated by the International Electrotechnical Commission (IEC 60101) is intended to prevent accidents (General IEC 1988). This protocol is internationally recognized. The different national standards are adapted to the requirements of this certificate. The detector systems must comply with the requirements of CF devices, which have the potential for direct flow of electricity to the heart. As already pointed out by Keshtgar et al. (1999), the IEC document ªFundamental Aspects of Safety Standards for Medical Electrical Equipmentº IECTR 60513 (International Electrotechnical Commission 1994) and a similar British document published by British Standards Institute (1994) can be consulted for further information on safety developments that can be applied in readers' own clinics.
References Abdel Nabi H, Doerr RJ, Balu D, Rogan L, Farrell EL, Evans NH (1993) Gamma probe assisted ex vivo detection of small lymph node metastases following the administration of indium-111-labelled monoclonal antibodies to colorectal cancers. J Nucl Med 34:1818±1822 Adams S, Baum RP, Hertel A, Wenish HJ, Staib-Sebler E, Herrmann G, Enke A, Hor G (1998) Intraoperative gamma probe detection of neuroendocrine tumors. J Nucl Med 39:1155±1160 Aitken DR, Hinkle GH, Thursten MO, Tuttle SE, Martin DT, Olsen J, Haagensen DE, Houchens D, Martin EW (1984) A gamma detecting probe for radioimmune detection of CEA producing tumors: successful experimental use and clinical case report. Dis Colon Rectum 27:279±282 Arnold MW, Schneebaum S, Berens A, Mojzisik C, Hinkle G, Martin EW (199 2a) Radioimmunoguided surgery challenges traditional decision making in patients with primary colorectal cancer. Surgery 112:624±630 Arnold MW, Schneebaum S, Berens A, Petty L, Mojzisik C, Hinkle G, Martin EW (1992 b) Intraoperative detection of colorectal cancer with radioimmunoguided surgery and CC49, a second generation monoclonal antibody. Ann Surg 216:627±632 Arnold MW, Hitchcock CL, Young DC, Burak WE, Bertsch DJ, Martin EW (1996) Intraabdominal patterns of disease dissemination in colorectal cancer identified using radioimmunoguided surgery. Dis Colon Rectum 39:509±513 Aspergen K, Styrand SE, Person BRR (1978) Quantitative lymphoscintigraphy for detection of metastases to the internal mammary lymph nodes. Biokinetics of Tc99m sulfur colloid uptake and correlation with microscopy. Acta Radiol Oncol 17:17±26
References British Standards Institute (1994) Fundamental aspects of safety standards for medical electrical equipment. BS PD 6573. BSI, London Burak WE, Schneebaum S (1995) Radioimmunoguided surgery: recurrent clinical trials and applications. Semin Col Rectal Surg 6:225±233 Burak WE, Schneebaum S, Kim JA, Arnold MW, Hinkle G, Berens A, Mojzisik C, Martin EW (1995) Pilot study evaluating the intraoperative localization of radiolabelled monoclonal antibody CC83 in patients with metastastic colorectal carcinoma. Surgery 118:103±108 Curtet C, Vuillez JP, Daniel G, Aillet G, Chetanneau, Visset J, Kremer M, Thedrez P, Chatal JF (1990) Feasibility study of radioimmunoguided surgery of colorectal carcinomas using indium-111-CEA-specific monoclonal antibody. Eur J Nucl Med 17:299±304 Davidson BR, Waddington WA, Short MD, Boulos PB (1991) Intraoperative localization of colorectal cancers using radiolabelled monoclonal antibodies. Br J Surg 78:664±670 Eshima D, Fauconnior T, Eshima L, Thornback JR (2000) Radiopharmaceuticals for lymphoscintigraphy: including dosimetry and radiation considerations. Semin Nucl Med 30:25±32 Giubbini R, Bettini R, Casucci R, Garancini S, Magistretti G, Roncari G (1981) The association of lymph nodes scintigraphy with 99mTc-sulfur-microcolloid and ultrasound scan in stage diagnosis of lymphomas (author's translation). Radiol Med (Torino) 67:823±827 Goins B, Klipper R, Rudolph AS, Phillips WT (1994) Use of technetium-99m-liposomes in tumor imaging. J Nucl Med 35:1491±1498 Goldstone KE, Jackson PC, Myers MJ, Simpson AE (eds) (1991) Radiation protection in nuclear medicine and pathology. (Report no 63) Institute of Physical Sciences in Medicine, York Harris CC, Bigelow RR, Francis JE, Kelly GG, Bell P (1956) A CSI (TI) crystal surgical scintillation probe. Nucleonics 14:102±108 Harvey WC, Lancaster JL (1981) Technical and clinical characteristics of a surgical biopsy probe. J Nucl Med 22:184±186 Henze E, Schelbert HR, Collins JC, Collins JD, Najafi A, Barrio JR, Bennett LR (1982) Lymphoscintigraphy with T-99m labelled dextran. J Nucl Med 23:923 Hoefnagel CA (1994) Metaiodobenzylguanidine and somatostatin in oncology: role in the management of neural crest tumours. Eur J Nucl Med 21:561±581 International Electrotechnical Commission (1988) Medical electrical equipment. 1. General requirements for safety. [IEC 60101-1 (1988-12)] IEC, Geneva International Electrotechnical Commission (1994) Fundamental aspects of safety standards for medical electrical equipment. [IEC TR 60513 (1994-01)] IEC, Geneva Kapteijn BAE, Horenblas S, Nieweg OE, Meinhardt W, Hoefnagel CA, De Jong D, Kroon BBR (1997) Dynamic sentinel node procedure in penile cancer: a report on 19 cases. In: Kapteijn BAE (ed) Biopsy of the sentinel node in melanoma, penile carcinoma and breast carcinoma ± the case for lymphatic mapping. Thesis, University of Amsterdam Keshtgar MRS, Waddington WA, Lakhani SR, Ell PJ (eds) (1999) The sentinel node in surgical oncology. Springer, Berlin Heidelberg New York
Krenning EP, Wekkeboom DJ, Bakker WH, Breeman WAP, Kooij PPM, Oei HY, Hagen M van, Postema PTE, Jong M de, Reubi JC, Visser TJ, Reijs AEM, Hofland LJ, Koper JW, Lamberts SWJ (1993) Somatostatin receptor scintigraphy with (111In-DTPA-d-Phe1) and 123I-Tyr3)-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 20:716±731 Kuhn JA, Corbisiero RM, Buras RR, Carroll RG, Wagman LD, Wilson LA, Yamauchi D, Smith MM, Kondo R, Beatty JD (1991) Intraoperative gamma detection probe with presurgical antibody imaging in colon cancer. Arch Surg 126:1398±1403 Lennquist S, Pershiden J, Smeds S (1988) The value of intraoperative scintigraphy as a routine procedure in thyroid carcinoma. World Surg 12:586±592 Martelli H, Ricard M, Larroquet M, Violand M, Paraf F, Fabre M, Josset P, Helardot PG, Gauthier F, Terrier-Lacombe M-J, Michon J, Hartmann O, Tabone MD, Patte C, Lumbroso J, Grçner M (1998) Intraoperative localization of neuroblastoma in children with 123-I or 125-I radiolabeled metaiodobenzylguanidine. Surgery 123:51±57 Martinez DA, O'Dorisio MS, O'Dorisio TM, Qualman SJ, Caniano DA, Teich S, Besner GE, King DR (1995) Intraoperative detection and resection of occult neuroblastoma: a technique exploiting somatostatin-receptor expression. J Pediatr Surg 30:1580±1589 Medical Devices Directive 93/42/EEC (1993) Official Journal of the European Communities, no L189/90, 14 June 1993 (ISBN 0-119-1221-38) Meyer CM, Leckitner ML, Logic JR, Balch CE, Bessey PQ, Tauxe WN (1979) Technetium-99m sulfur colloid cutaneous lymphoscintigraphy in the management of truncal melanoma. Radiology 131:205±209 Morris AC, Barclay TR, Tanida R, Nemcek JV (1971) A miniaturised probe for detecting radioactivity at thyroid surgery. Phys Med Biol 16:397±404 Úhrvall U, Westlin JE, Nilsson S, Juhlin C, Rastad J, Lundqvist H, âkerstræm G (1997) Intraoperative gamma detection reveals abdominal endocrine tumors more efficiently than somatostatin receptor scintigraphy. Cancer 80:2490±2494 Oku N, Namba Y, Takeda A, Okada S (1993) Tumor imaging with technetium-99m-DTPA encapsulated in RES-avoiding liposomes. Nucl Med Biol 20:407±412 Phillips WT, Rudolph AS, Goins B, Klipper R (1992 a) Biodistribution studies of liposome encapsulated hemoglobin (LEH) studied with a newly developed 99m-technetium liposome label. Biomater Artif Cells Immobil Biotechnol 20:757±760 Phillips WT, Rudolph AS, Goins B, Klipper R, Blumhardt R (1992 b) A simple method for producing a technetium99m-labeled liposome which is stable in vivo. Int J Radiat Appl Instrum [B] 19:539±547 Reuter M, Montz R, de Heer K, Schåfer H, Klapdor R, Desler K, Schreiber HW (1992) Detection of colorectal carcinomas by intraoperative RIS in addition to preoperative RIS: surgical and immunohistochemical findings. Eur J Nucl Med 19:102±109 Schirmer WJ, O'Dorisio TM, Schirmer TP, Mojzisik CM, Hinkle GH, Martin EW (1993) Intraoperative localization of neuroendocrine tumors with 125-I-TYR(3)-octreotide and a hand-held gamma detecting probe. Surgery 114:745±752
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Waddington WA, Keshtgar MR, Taylor I, Lakhani SR, Short MD, Ell PJ (2000) Radiation safety of the sentinel lymph node technique in breast cancer. Eur J Nucl Med 27:377± 391 Wångberg B, Forssell-Aronsson E, Tisell LE, Nilsson O, Fjålling M, Ahlman H (1996) Intraoperative detection of somatostatin-receptor-positive neuroendocrine tumours using 111indium-labelled DTPA-d-Phe1-octreotide. Br J Cancer 73:770±775
Chapter 12
Quality Criteria of Gamma Probes: Requirements and Future Developments H. Wengenmair, J. Kopp, J. Sciuk
Introduction Sentinel lymph node-ectomy (SLNE) or sentinel lymphadenectomy allows reliable staging of the locoregional lymph system with only a few sentinel lymph nodes (SLN) investigated (Krag et al. 1993; Alex et al. 1993, 2000; Albertini et al. 1996; Bachter et al. 1996; 1999; Bçchels et al. 1977, 1999; Perkins et al. 1998; Vogt et al. 1999 a, b; Wawroschek et al. 1999 a, b, 2000; De Cicco et al. 2000). Vogt et al. (1999 a), in a first series of malignant melanomas, investigated 214 cases, with detection of 247 lymphatic basins; in a further investigation (Vogt et al. 1999 b), the same group demonstrated high rates of sentinel node detection (99%) in malignant melanoma treatment and increasing improvements in the learning phases in breast cancer treatment. They also documented accumulating experience of SLN labeling in prostate cancer cases. Because in 30% of cases of prostate cancer micrometastases develop from routinely dissected lymphatic basins, Wawroschek et al. (1999 a) tried to improve lymphadenectomy by 99mTc labeling techniques. Wawroschek developed an initial sonographically controlled technique for transrectal administration of 99mTc-colloid by injection directly into the glandular body of the prostate 1 day before the performance of probe-guided and -controlled pelvic lymphadenectomy (Wawroschek et al. 1999 b). Writing about gamma probe-guided SLN surgery for penile cancers, Wawroschek et al. (2000) stated that cancers of both the glans and the shaft of the penis metastasized first into inguinal lymph nodes, and into pelvic nodes only secondarily. Since these early experiences the Augsburg group has steadily improved its techniques. Therefore, the morbidity for the patient can be lower than that of standard lymphadenectomy treatment. In addition, with more precise, gamma probe-guided histological N-staging supported by
immunohistochemical cancer cell identification, more appropriate adjuvant therapeutic treatment is possible. SLNE is therefore often a better alternative than ªwatch and wait.º Besides the sophisticated clinical performance, the success of SLNE depends heavily on the quality of the gamma probe used. In recent years some research groups have defined quality criteria for gamma probes to be used for various purposes (Tiourina et al. 1998; Britten et al. 1999; Wengenmair et al. 1999 a, b). Wengenmair et al. compared different gamma probes and optimized the criteria for adequate choice (1999 a), but also improved their adaptation to the needs of clinical practice (1999 b). Comparison of the results is not possible without reproducible control methods. Some approaches to quality and performance guidelines have already been published (Heidenreich et al. 2001), but the following requirements have not yet been completely met: · Standard regulations for evaluation of quality parameters · Formulation of minimal requirements for the quality of the probe devices · Adjustment of quality parameters to the requirements of clinical applications
Quality Criteria To describe the quality of various probes the following parameters were evaluated (Fig. 1): · Spatial selectivity (radial sensitivity distribution) at 30 cm · Spatial resolution · Sensitivity · Shielding (sensitivity at the probe housing) · Energy discrimination · Display and acoustics · Shape of probe
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Fig. 1. Quality control measurements
Radial Sensitivity Distribution
Spatial Resolution
The sensitivity distribution is determined 30 cm away from the measurement area in dependence on the polar angle. The radial sensitivity distribution describes the width of the measurement cone, which can be quantified by the full width at half maximum (FWHM) of the distribution function. The radial sensitivity distribution has a strong influence on the detectability of lymph nodes in the presence of nontarget radiation (injection depot, background). With a broad measurement cone the background signal can exceed the target signal of the lymph node, which then might not be detected. A small cone improves the ratio of SLN signal to background so that the SLN can be found (Fig. 2). With strong background in the SLN area (e.g., in breast carcinoma, prostate carcinoma) a narrow measurement field (small FWHM of radial sensitivity distribution) is recommended.
The spatial resolution or ªlateral sensitivity distributionº can be determined by scanning with a probe laterally above a 99mTc point source (diameter 3 mm). The FWHM determines the minimal distance needed between two lymph nodes for them to be detected separately (Fig. 3). The spatial resolution depends predominantly on the distance between source and probe crystal. In comparative studies using test parameters similar to the real measurement situation in the patient, we determined the spatial resolution at a distance of 1 cm. To separate neighboring lymph nodes and achieve an adequately accurate localization the FWHM of the lateral sensitivity distribution should be better than the typical distance between neighboring lymph nodes or a typical node diameter in the preparation region. In the axillary, inguinal, and iliacal regions we recommend spatial resolution better than 25 mm (FWHM) for lymph nodes. In the head, neck and supraclavicular regions even better spatial resolution of less than 15 mm is necessary to achieve separate measurement of lymph nodes here, which are close together.
Shielding
Fig. 2. Influence of radial sensitivity distribution on detectability of a lymph node near to background activity
Sensitivity
Shielding
The appropriate probe sensitivity depends on radionuclide uptake in the SLN, measurement geometry and time lapse between injection and SLNE. The maximum radionuclide uptake of SLNE typically varies between 0.01% and 1%. The SLNE is usually performed on the day after 99mTc-nanocolloid injection (20 h after the injection). At this time, about 0.001±0.1% of the activity administered can be found in the lymph node intraoperatively. Assuming a typical administration of activity 200 MBq (for breast carcinoma) a spot of activity of between 2 and 200 kBq has to be localized in the SLN. The sensitivity of the measurement system should therefore be better than 5 cps/kBq to reach count rates between 10 and 1000 cps.
The way probes are constructed means that their shielding mostly has a weak spot. A high background source (e.g., injection site in breast or prostate carcinoma) in the direction of such a leakage leads to false orientation or high background signal (Fig. 4). The signal of the SLN must be higher than the background signal for the lymph node to be found. Assuming an uptake of 0.1% for a lymph node the leak sensitivity should not exceed 0.1% of the system sensitivity.
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Fig. 3. Influence of spatial resolution in separate detection of neighboring lymph nodes
Fig. 4. Distorting signal caused by a leak in shielding conceals the sentinel lymph node (SLN) in the measurement cone
Shielding Fig. 5. Commercially available gamma probe systems: 1 C-Trak, CareWise, USA; 2 ScintiProbe, pol.hi.tech, Italy; 3 Europrobe, Eurorad, France; 4 Tecprobe, Stratec, Germany; 5 Crystal Probe 2000, Crystal, Germany; 6 Neoprobe 2000, Neoprobe, USA; 7 Navigator, Auto Suture, USA; 8 Gamma Finder, Silicon Instruments, Germany
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Energy Resolution
Results
Compton scattered photons of background activity near the SLN produce additional blurring of the spatial information and enhancement in background signal. This can be avoided when the scattered photons are eliminated from the measurement signal by good energy discrimination.
On the basis of the already published and widely accepted minimal requirements of gamma probe systems (Table 1) (Wengenmair et al. 1999), we tested the systems listed below with their manufacturers: · C-Trak, CareWise, Morgan Hill, California, USA, www.carewise.com · ScintiProbe, pol.hi.tech, Carsoli, Italy, www.vilage.flashnet.it/users/polhitec · Europrobe, Eurorad, Strasbourg, France, www.eurio.fr/eurorad · Tecprobe, Stratec, Birkenfeld, Germany, www.stratec-biomedical.de · Crystal Probe 2000, Crystal, Berlin, Germany, www.crystal-gmbh.com · Neoprobe 2000, Neoprobe, Dulin, Ohio, USA, www.neoprobe.com · Navigator, Auto Suture, Norwalk, CT, USA, www.autosuture.com · Gamma Finder, Silicon Instruments, Berlin, Germany, www.silicon-instruments.de
Display and Acoustics Display and acoustics have to be adapted to the special situation in an operation cabinet. A clear correlation between the tone and the measurement signal enables the user to concentrate visually on the operation field during measurement. If the count rate varies in different SLNs, the measurement range of the acoustics should be adjustable. For quantitative measurements a digital or analogue display is recommended. The display should be clearly readable from at least 2 m away. It is of advantage if the measurement time interval and the time constant can be adapted to the statistical variation of the measurement signal.
Probe Shape A slender probe is desirable. It makes it possible to use a small incision and offers good visibility of the situs during measurement. Nowadays gamma probes with a diameter of only 15 mm can have good measurement characteristics if shielding and detector are optimized. For laparoscopic applications very thin and long probes are necessary, and are already in clinical testing. The user has to be aware that a very thin probe cannot yield the image quality obtained with normal-diameter gamma probes. Especially in new fields of application, the characteristics of the gamma probe are essential for clinical success. A kinked gamma probe allows measurement of the SLN from different angles. In addition to the direction, the depth of the lymph node can also be depicted if the probe is skillfully used. A kinked probe allows measurements pointing away from a hot spot (e.g. injection site) that might otherwise influence the results.
Test results of some commercially available probes are shown in Tables 2 and 3. More results, obTable 1. Minimal requirements of intraoperative gamma probe systems Criterion
Minimal requirement
Spatial selectivity Radial sensitivity distribution (distant field)
FWHM & 40 8
Resolution
High demands for lymph nodes in head, neck, supraclavicular region: FWHM £ 15 mm Normal requirements at extremities, axilla, groin: FWHM £ 25 mm
Sensitivity
³ 5000 cps/MBq
Shielding
£ 0.1% of maximum system sensitivity
Energy selection
Compton/photopeak discrimination; check of energy selection possible
Acoustic
Good correlation between measurement signal and tone
Digital or analogue display
Analogue: suitable measurement interval with adjustable time constant Digital: continuous display with adjustable measurement time interval
Results Table 2. Summary of control unit characteristics System
Energy selection
Display
Digital measurement
Analogue measurement
Acoustic measurement signal
Power supply
C-TRAK
Compton/ photopeak discrimination; energy window adjustable; automatic calibration possible
Analogue meter; LED+LCD
Continuous measurement; measurement time adjustable; clearly visible by additional movable LED
Easy to read; measurement range adjustable
Clear correlation between count rate and sound; measurement range and volume adjustable, measurement time constant not adjustable
Battery powered; switchable to reserve batteries; charging condition is displayed
Navigator
Compton/ photopeak discrimination; energy threshold adjustable
LCD
Continuous measurement; measurement time adjustable; difficult visibility of readings from lateral angles of view
Bar display; measurement range adjustable
Clear correlation between count rate and sound; measurement range and volume adjustable measurement time constant not adjustable
Accumulator; only 15 min before emptiness a LED indicates a weak accumulator; no reserve accumulator
Stratec
Predefined nuclide settings; manual calibration possible
LED
Continuous measurement; measurement time adjustable; clearly visible
Bar display; measurement range adjustable
Moderate correlation between count rate and sound; measurement range, measurement time constant and volume adjustable
Changeable accumulator (with reserve); LED indicates weak charging condition
Crystal
Compton/ photopeak discrimination; predefined nuclide settings
LCD
Continuous measurement; measurement time adjustable
Bar display; measurement range adjustable
Moderate correlation between count rate and sound; volume adjustable
Accumulator or mains electricity; weak charging condition is displayed
Neoprobe 2000
Compton/ photopeak discrimination; predefined nuclide settings
LED
Continuous measurement; measurement time adjustable; clearly visible
Bar display; measurement range adjustable
Clear correlation between count rate and sound; measurement range and volume adjustable, measurement time constant not adjustable
Mains electricity
119
120
Chapter 12 Quality Criteria of Gamma Probes: Requirements and Future Developments Table 2 (cont.) System
Energy selection
Display
Digital measurement
Analogue measurement
Acoustic measurement signal
Power supply
Europrobe
Compton/ photopeak discrimination; predefined nuclide settings and adjustable energy window
LED
Continuous measurement; measurement time adjustable; clearly visible
Bar display; measurement range adjustable
Clear correlation between count rate and sound; measurement range, measurement time constant and volume adjustable
Mains electricity
Pol.hi.tech
Compton/ photopeak discrimination; predefined nuclide settings and two adjustable energy windows; graphical display of energy spectrum
LED; monitor screen
Continuous measurement; measurement time not adjustable; clearly visible
Bar display; measurement range adjustable
Clear correlation between count rate and sound; measurement range and volume adjustable measurement time constant not variable
Accumulator or main electricity; weak charging condition is indicated
Silicon Instruments
Compton/ photopeak discrimination not provable; energy window not adjustable
LCD; integrated in the probe
Continous measurement; measurement time not adjustable; difficult visibility
Twinkle LED; integrated in the probe
Moderate correlation between count-rate and sound; faint noise; volume adjustable
Battery powered; empty battery cannot be changed by the user; integrated in the probe
tained with older systems, and the latest developments can be reviewed at http://www.nuklearmedizin-augsburg.de. Table 2 summarizes the assessments of the display systems, and Table 3 shows the results for the probes and collimators. The results indicate marked differences in performance. These characteristics of the measurement system have to be considered and taken into account for an SLN to be detected. The user has to be trained in the optimal strategy of measurement for the particular system that is to be applied. The results also show the improvements that have been achieved by the efforts of various companies.
Future Developments The ªSLN conceptº has already been successfully applied throughout the world: · To increase the precision of detection of the ªreal SLNs,º some of which are localized outside the sites assumed on the basis of clinical examination. · To come closer to complete surgical locoregional tumor removal. · To adapt adjuvant therapy regimens to the actual N-stage found by the use of the SLN concept. · To extend the SLN concept to other cancer entities (head and neck cancers, gastrointestinal cancers, etc.).
9 mm
33 8 31 8 70 8
Lechner collimator
Lechner 0.66 collimator
135 (at probe kink)
20.5
24 mm
Neoprobe 2000 12 mm collimated probe
Neoprobe 2000 12 mm uncollimated probe
421 (1 cm behind probe tip) 174 (at probe kink)
7.9 3.5
16 mm 11 mm
46 8 26 8
With collimator
33 8
With collimator
Without collimator
93 8
Without collimator
135 (at probe kink)
7 (at probe bend) 7 (at probe bend) 7 (at probe bend) 21.5 21.5 11.3
22 mm 18 mm 12 mm
Crystal Flex-Probe CXS-SG 03 OPSZF
8.8
0.03% 0.03% 0.06%
3.5 (8 cm behind probe tip)
10.5
17 mm
40 8
Crystal Probe 2000CXS±SG03
14 mm
0.03%
10 (at probe kink)
13.3
19 mm
40 8
Stratec kinked probe
608 518 408
0.5%
60 (12 cm behind probe tip)
11
14 mm
36 8
Stratec straight probe
608-collimator 408-collimator 208-collimator
0.9%
45 (1 cm behind probe tip)
5
20 mm
58 8
Navigator 14 mm
4.4%
5.3%
1.5%
0.7%
0.08%
0.7%
47 (1 cm behind probe tip)
6.7
18 mm
Blue-Tip
Navigator 11 mm
0.02%
0.02%
2 (at probe kink)
4 (at probe kink)
9
9.5
23 0.04%
9 mm
15 mm
50 8
Standard collimator
1.3%
350 (1 cm behind probe tip)
28
18 mm
58 8
Ratio of leak sensitivity to max. sensitivity
Max. sensitivity outside measurement-field (leak sensitivity) (cps/MBq)
Max. sensitivity of a pointsource (cps/kBq)
FWHM spatial resolution, 1 cm distance
Without collimator
FWHM, radial sensitivity distribution 30 cm distance
4 (at probe kink)
C-Trak Omni probe
Standard probes
Gamma probe system
Table 3. Summary of probe characteristics
18 mm
14 mm
18 mm
Yes
Yes
Yes
Yes
variable variable variable
15 mm 15 mm 15 mm 14 mm
No
Yes
No
Yes/no
Yes/no
Yes
Yes
Yes
Yes
Kinked
15 mm
17 mm
20 mm
14 mm
11 mm
17 mm
15 mm
15 mm
11 mm
Diameter
Probe shape
Future Developments 121
65 8 80 8
Collimator step 3
Collimator step 4
588
49 8
Collimator step 2
Silicon Instruments
42 8
Collimator step 1
ScintiProbe 18LVR
45 8
71 8
ScintiProbe 18LV-3
ScintiProbe 15-B
26 8
35 8
Standard collimator
ScintiProbe 22LV
85 8
Without collimator
Europrobe CsJ high sensitivity
36 8
With collimator 35 8
118 8
41 8
With collimator
Without collimator
123 8
Without collimator
FWHM, radial sensitivity distribution 30 cm distance
With collimator
Blue-Tip
Europrobe CdTe
Neoprobe 2000 14 mm straight probe
Neoprobe 2000 19 mm
Gamma probe system
Table 3 (cont.)
15 mm
20 mm
25 mm
23 mm
22 mm
20 mm
21 mm
13 mm
14 mm
25 mm
11 mm
15 mm
26 mm
20 mm
30 mm
FWHM spatial resolution, 1 cm distance
10
12
33
19
14
11
40
2
12.0
30.0
3.0
9.8
54
11
44.5
Max. sensitivity of a pointsource (cps/ kBq)
5 (0.5 cm behind probe tip)
12 (1 cm behind probe kink)
34 (2 cm behind probe tip)
34 (2 cm behind probe tip)
34 (2 cm behind probe tip)
34 (2 cm behind probe tip)
60 (11 cm behind probe tip)
10 (1.5 cm behind probe tip)
0.4 (1.5 cm behind probe tip)
45 (0.5 cm behind probe tip)
0.4 (2 cm behind probe tip)
14 (4 cm behind probe tip)
14 (4 cm behind probe tip)
318 (at probe kink)
318 (at probe kink)
Max. sensitivity outside measurement-field (leak sensitivity) (cps/MBq)
0.5%
0.1%
0.1%
0.2%
0.2%
0.3%
0.1%
0.5%
0.003%
0.15%
0.01%
0.14%
0.03%
2.9%
0.7%
Ratio of leak sensitivity to max. sensitivity
13 mm
16 mm
18 mm
18 mm
18 mm
18 mm
18 mm
22 mm
19 mm
16 mm
15 mm
16 mm
14 mm
26 mm
23 mm
Diameter
Probe shape
No
Yes
No
No
No
No
Yes/no
No
Yes
Yes
Yes
No
No
Yes
Yes
Kinked
122 Chapter 12 Quality Criteria of Gamma Probes: Requirements and Future Developments
38 8 66 8 54 8 30 8 778/658
778/628
568
C-Trak laparoscope
ScintiProbe 11L
ScintiProbe 11/20 inclined measurement direction
Crystal, probe with perpendicular (908) measurement direction
Crystal, probe with inclined (428) measurement direction
Crystal, probe with forward (08) measurement direction
FWHM, radial sensitivity distribution 30 cm distance
Stratec laparoscope
Laparoscopic probes
Gamma probe system
Table 3 (cont.)
18 (1 cm behind probe tip) 3.9 (3 cm behind probe tip) 16 (1.5 cm behind probe tip) 18 (1.5 cm behind probe tip) 55 (opposite to measurement direction) 120 (opposite to measurement direction) 140 (1 cm behind probe tip)
9.5 5.6 5.6 22.5
16.5
13.5
16 mm 19 mm 10 mm 18 mm
17 mm/15 mm
14 mm
Max. sensitivity outside measurement-field (leak sensitivity) (cps/MBq)
6.2
Max. sensitivity of a pointsource (cps/ kBq)
13 mm
FWHM spatial resolution, 1 cm distance
1.0%
0.7%
0.24%
0.3%
0.3%
0.04%
0.3%
Ratio of leak sensitivity to max. sensitivity
10 mm
10 mm
10 mm
11 mm
12 mm
10 mm
11 mm
Diameter
Probe shape
No (08)
Yes (428)
Yes (908)
No
No
No
No
Kinked
Future Developments 123
124
Chapter 12 Quality Criteria of Gamma Probes: Requirements and Future Developments Table 4. Measurement conditions for standard lymph node (SLN)-ectomy at different cancer entities Melanoma Most often long distance between SLNs and injectionspot Good radionuclide accumulation in the SLNs Mamma carcinoma Short distance between SLNs and injection site Poor uptake in the SLNs Prostate carcinoma High background out of prostate, bladder and bone marrow Varying uptake in the SLNs Large lymph node regions to be scanned Head and neck tumors High background out of injection spot and contamination of oral cavity Small target-volume with poor radionuclide accumulation Short distance between SLNs and injection site
from bone marrow, urinary bladder, and prostate. Because of the different measurement conditions, the quality parameters described vary in importance, as indicated by the plus signs in Table 5. In view of upcoming medical demands the following improvements and de novo developments that will make it more likely that they can be met are highly appreciated: · Probes used in laparoscopic evaluations should have movable tips to allow measurements at variable angles. · The scope and the probe should be fitted together to allow viewing and measuring simultaneously in the viewing channel. · For precise indication of the distance away from a small target structure in the presence of a high background signal, ªsandwich detectorsº could be used to differentiate between electrons and gamma rays. Intraoperative measurement systems for PET nuclides could also be improved by the use of sandwich detectors.
The measurement conditions for SLNE are very different in different tumor entities (Table 4). The distance between SLN and tumor (injection site) is usually further in the case of a melanoma than in most other tumors. The activity enrichment is also normally better in SLN of the skin than in other tumors. In prostate cancer, for example, the radionuclide uptake of an SLN varies between only 0.001% and 1%. In addition, the intraoperative measurement is disturbed by background activity
Table 5. Search for quality control parameters
Sensitivity
Melanoma
Breast carcinoma
Prostate carcinoma
Head and neck tumors
(+)
+
+
+
+
+
+
Spatial selectivity (radial sensitivity distribution) Spatial resolution
+ (Head, neck, supraclavicular region)
+
Shielding
+
+
+
Energy discrimination
+
+
+
References
References Albertini JJ, Cruse CW, Rapaport D et al. (1996) Intraoperative radiolymphoscintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223(2):217±224 Alex JC, Weaver DL, Fairbank JT, Rankin BS, Krag, DN (1993) Gamma-probe-guided lymph node localization in malignant melanoma. Surg Oncol 2:303±308 Alex JC, Sasaki CT, Krag DN, Wenig B, Pyle PB (2000) Sentinel lymph node radiolocalization in head and neck squamous cell carcinoma. Laryngoscope 110:198±203 Bachter D, Balda BR, Vogt H, Bçchels H (1996) Die ªsentinelº Lymphonodektomie mittels Szintillationsdetektor. Hautarzt 47:754±758 Bachter D, Balda BR, Vogt H, Bçchels H (1998) Primary therapy of malignant melanomas: sentinel lymphadenectomy. Int J Dermatol 37:278±282 Britten AJ (1999) A method to evaluate intraoperative gamma probes for sentinel lymph node localisation. Eur J Nucl Med 26:76±83 Bçchels HK, Vogt H, Bachter D (1997) Szintillationsgesteuerte Sentinel-Lymphadenektomie beim malignen Melanom. Chirurg 68:45±50 Bçchels HK, Vogt H, Wagner T, Steinfeld D, Sagasser J (1999) Sentinel Lymphonodektomie beim Mammakarzinom. Nuklearmediziner 4:261±267 De Cicco C, Sideri M, Bartolomei M, Grana C, Fiorenza M, Maggioni A, Bocciolone L, Mangione C, Colombo N, Paganelli G (2000) Sentinel node biopsy in early vulvar cancer. Br J Cancer 82:295±299 Heidenreich P, Bares R, Brenner W, Grçnwald F, Kopp J, Lottes G, Munz L, Reiners C, Risse JH, Schober O, Schçmichen C, Vogt H, Wengenmair H, Werner E (2001) Verfahrensanweisung fçr die nuklearmedizinische WåchterLymphknoten (sentinel lymph node; SLN)-Diagnostik. Nuklearmedizin 3:98±101
Krag DN, Weaver DL, Alex JC, Fairbank JT (1993) Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 2:335±340 Perkins A (1993) Peroperative nuclear medicine. Eur J Nucl Med 20:573±575) Tiourina T, Arends B, Huysmans D, Rutten H, Lemaire B, Mçller S (1998) Evaluation of surgical gamma probes for radioguided sentinel node localisation. Eur J Nucl Med 25:1224±1231 Vogt H, Bachter D, Bçchels H, Wengenmair H, Dorn R, Heidenreich P (1999 a) Nachweis des Sentinel-Lymphknotens mittels pråoperativer Lymphszintigraphie und intraoperativer Gammasondenmessung beim malignen Melanom. Nuklearmedizin 38:95±100 Vogt H, Wengenmair H, Kopp J, Dorn R, Græber S, Heidenreich P (1999 b) Der Sentinel-Lymphknoten (SLN): pråund intraoperative nuklearmedizinische Diagnostik. Der Nuklearmediziner 22:233±252 Wawroschek F, Vogt H, Weckermann D, Wagner T, Harzmann R (1999 a) Identifikation der SchildwåchterLymphknoten des Prostatakarzinoms ± Ergebnisse eines neuen Staging-Verfahrens. Der Nuklearmediziner 22:283±291 Wawroschek F, Vogt H, Weckermann D, Wagner T, Harzmann R (1999 b) The sentinel lymph node concept in prostate cancer ± first results of gamma probe guided sentinel lymph node identification. Eur Urol 36:595±600 Wawroschek F, Vogt H, Bachter D, Weckermann D, Hamm M, Harzmann R (2000) First experience with gamma probe guided sentinel lymph node surgery in penile cancer. Urol Res 28:246±249 Wengenmair H, Kopp J, Vogt H, Heidenreich P (1999 a) Qualitåtskriterien fçr Meûsonden zur intraoperativen Lokalisation Tc99m markierter Lymphknoten. Z Med Phys 2:122±128 Wengenmair H, Kopp J, Vogt H, Heidenreich P (1999 b) Qualitåtskriterien und Vergleich von Gammasonden zur Sentinel-Lymphonodektomie. Nuklearmediziner 4:271± 280
125
Chapter 13
Statistical Evaluation in Detection of the SLN(s)
Statistical analysis of any suspicious radioactive tissue components is difficult and must be critically evaluated, especially with a view to intraoperative assessments. As long ago as in 1989, Barber et al. compared different in vivo scintillation probes and the gamma cameras used for the detection of small, deeplocated cancers; shortly afterwards Waddington et al. (1991) analyzed the techniques applied in the intraoperative detection of radiolabeled monoclonal antibodies directed to colon cancer cells. Partly based on these earlier investigations, Gulec et al. (1997) started statistical analysis with reference to the sentinel node concept in breast cancer patients. Further studies were necessary before it was possible to evaluate the imaging results against the background of radioactive decay. Meanwhile, such investigations have been performed extensively and clearly evaluated by Veal (1971) and by Evans (1981). As already pointed out by Keshtgar and Ell, an important and suitable criterion of statistical significance can be derived by implicating the significant basic values, such as radioactive decay rates, and relating them to the difference between the counts measured over the sentinel node region (N) and the background (B). According to the analytic results of Peter Ell's group, the variance of any single measured count is numerically equal to the recorded count itself, and the variance of the difference between these counts is defined as: variance r2
N B
and in consequence of these facts the standard deviation is r
p N
N B
Peter Ell's group explains: If a threshold of three standard deviations, 3 r is adopted as a criterion for the statistically signif-
13
icant detection of a sentinel node by virtue of its radioactivity, then there is greater than 99.7% chance that this is not due to the random error in detected counts alone. Thus, it is required that:
N
B 3
p
N B :
If the mean of multiple counts is used then this criterion should be modified to meet the requirement that: ~
N
~ 3 B
q ~ B=b ~
N=n ;
~ is the mean node count and n the number were N ~ is the mean backof node counts performed, B ground count, and b the number of background counts performed. This knowledge is relevant from the practical point of view. In contrast to the given statements, in simple evaluations not based on statistically supported programs there is no input of factors which can influence the reliability of the measurements. Such relevant influences can be: · Longer time units for counting · Usage of a more sensitive detector · Multiple sampling of counts In cases with very low count rates over the sentinel node or a node group, leading to an uncertain result, count rates can be accumulated for 10±20 s directly over the suggestive area and the result compared with a significant background area. When these evaluations lead to statistically significant results derived from the difference between the count values in the suggestive area investigated and the background control area, a decision for local surgical exploration to find the SLN(s) can be made.
128
Chapter 13 Statistical Evaluation in Detection of the SLN(s)
References Barber et al (1989) Comparison of in vivo scintillation probes and gamma cameras for detection of small deep tumors. Phys Med Biol 34:727±739 Evans AL (ed) (1981) The evaluation of medical images, chapter: The quest for a ªfigure of merit.ª Adam Hilger, Bristol
Gulec SA, Moffat FL, Carroll RG, Krag DN (1997) Gamma probe guided sentinel node biopsy in breast cancer. Q J Nucl Med 41:251±261 Veal N (1971) Statistical factors affecting radioactivity measurements. In: Belcher EH, Vetter H (eds) Radioisotopes in medical diagnosis. Butterworth, London, pp 1±18 Waddington WA, Davidson BR, Todd-Pokropek A, Boulos PB, Short MD (1991) Evaluation of a technique for the intraoperative detection of a radiolabeled monoclonal antibody against colorectal cancer. Eur J Nucl Med 18:964±972
Chapter 14
Are the Technical Conditions for SLN Detection Satisfactory?
Investigations of Breast Cancer Cases As a Basic Parameter In the year 2001 there was still a high degree of uncertainty about the safety of the SLN concept in breast cancer treatment; many institutions are involved in clinical, partly multicenter, studies, but definitive results answering the most important question, that of the false-negative rate and its implications, are not yet available. One of the latest fairly extensive studies to be performed was carried out in 466 cases by Cox et al. (1998), who give a preliminary answer on the relative success rates of the different methods of diagnosis in ensuring correct diagnosis of the primary. The percentage ratio of stereotactic biopsy to excision biopsy found by Cox et al. was 46.2% to 53.8%. The failure rate for identification of a sentinel node in the axilla was 5.6%. The failures were compensated by axillary revisions, in 15.4% of which cancer involvement was detected. In Cox's series there was only one case with skip metastasis, which developed after prior excisional biopsy. The results of Cox's investigations, published under the senior authorship of Reintgen, give an overview and are obviously representative for many investigations of other groups in this field. They can be a measure of information to patients and of further improvements. The main data are listed in Table 1. With respect to the current constant and steadily discussed problem of how to treat DCIS cases in
14
which, because of early stromal invasion that has not been detected histologically, the disease cannot be safely resected, even when the Van Nuys (Silverstein et al. 1995) or Holland (Holland et al. 1994) classification of DCIS following identification of high-grade types (see also International Consensus Conference (2002) is applied, the results of Cox et al. (1998) are of special interest. These authors had 87 cases with noninvasive ductal breast cancer (DCIS) in their series of 466 cases. In 4 of these cases (4.6%) cancer-positive SLNs were found. This rate is in keeping with most percentages presented in evaluations already published. With respect to these results, it would have been dangerous to omit the check on the axillary nodes in all cases of DCIS. Therefore, in DCIS cases investigation of the SLN(s) with avoidance of full axillary revision could become the method of choice in the future. In enquiries into the value of our imaging systems in addition to the primary physical examination, our experience and the results of clinical studies have shown that we have to extend our evaluation procedures intensively to include DCIS and, because in these cases the putative invasion rate is low, also to include a search for the SLN(s), which can more easily be found than in the case of highly extended invasive cancers. In contrast to this constellation stands the question of the security of the results obtained in the search for the SLN(s) as a function of pT stage. Schlag and Bembenek (2000) have tried to find an answer to this problem, which has often been discussed. Their results are shown below.
Table 1. Important factors for determining significance of sentinel lymph node (SLN) investigations in breast cancer cases (n=422) Mean value of harvested nodes
Cancer infiltration rate of the harvested nodes
Rate of cases with positive nodes
Hot nodes
Blue nodes
Hot and blue nodes
Positive nodes in DCIS
1.92
20%
105/440 23.8%
339/884 40.2%
272/844 32.2%
233/844 27.6%
4/87 4.6%
130
Chapter 14 Are the Technical Conditions for SLN Detection Satisfactory? Table 2. Identification and sensitivity rates in the learning stages of a study of SLNs in breast cancer Reference
Rubio et al. (1998)
No. of cases
55
Tracer used
99m
Tc
Identification of SLN(s) n
%
53
96.3
Detection Rate and Accuracy of SLN Detection in Dependence on Tumor Diameter (Schlag and Bembenek 2000) In an investigation carried out by Schlag and Bembenek (2000) in 146 patients with breast cancer it was found by use of the radionuclide method on the basis of preoperative lymphoscintigraphy and intraoperative gamma probe evaluation that the detection rate varied with tumor size. The detection rates obtained were: · 94% for tumors with 1 cm diameter · 85% for tumors 1±3 cm in diameter · 70% for tumors 3±5 cm in diameter · 63% for tumors >5 cm in diameter The accuracy of sentinel node detection for prediction of the nodal status also varied with tumor diameter: · 100% for tumors < 1 cm · 97% for tumors 1±3 cm · 88% for tumors 3±5 cm · 67% for tumors >5 cm Among pT1±2 tumors, 53% showed true negative sentinel nodes. In 38% of cases tumor cells were detected by HE staining, and in 7%, exclusively by immunohistochemical staining. The authors report that in 4% of cases false-negative results were found, all in the first half of the study. All these cases showed lymphangiosis carcinomatosa or extensive metastatic node infiltration. The conclusion reached by the authors is that in
Sensitivity (%)
Specificity (%)
Positive predictive value 100%
88.2
100
Accuracy of the study
approximately 50% of patients with stage pT1±2 axillary revision could be avoided. This rate corresponds with my own experience, but up to now there is no diagnostic scheme for finding this group. Table 2 demonstrates the percentage SLN identification rate obtained by Rubio and her colleagues in the course of their learning process. All pT stages are included. The 96% detection rate is very high already in the learning stage.
References Cox CE, Pendas S, Cox JM, Joseph E, Shons AR, Yeatman T, Ku NN, Lyman GH, Berman C, Haddad F, Reintgen DS (1998) Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 227:645±651 Holland R, Peterse JL, Millis RR, Eusebi V, Faverli D, van der Vijver MJ, Zafrani B (1994) Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 11(3):167±180 International Consensus Conference (2002) Image detected breast cancer: state of the art, diagnosis and treatment. Breast J 8(2):70±76 Rubio IT, Korourian S, Cowan C, Krag DN, Colvert M, Klinberg VS (1998) Sentinel lymph node biopsy for staging breast cancer. Am J Surg 176:532±537 Schlag PM, Bembenek A (2000) Specification of potential indications and contraindications of sentinel lymph node biopsy in breast cancer. Recent Results Cancer Res 157:228±236 Silverstein MJ, Poller DN, Waisman JR, Colburn WJ, Barth A, Gierson ED, Lewinsky B, Gamagami P, Slamon DJ (1995) Prognostic classification of breast ductal carcinoma in situ (contains information on the Van Nuys DCIS classification). Lancet 345:1154±1157
Chapter 15
Breast Cancer Diagnosis Based on Histopathology and/or Cytopathology Before Sentinel Lymph Node Labeling
Reasons for Histology/Cytology-based Diagnosis of Breast Cancer Before Sentinel Lymph Node Labeling Most publications based on investigations aimed at sentinel lymph node (SLN) detection state that a clear-cut histology- or cytology-based diagnosis of breast cancer is required before SLN labeling (99mTc and/or patent blue injection) starts. Only when a palpable circumscribed solid tumor mass has been found on imaging and already ªcertifiedº as cancer can SLN labeling be started without preceding biopsy. In such cases, the often very sharply delineated and spherical medullary cancer must be examined by needle biopsy to exclude the differential diagnosis ªfibroadenomaº before the sentinel node labeling starts. When radioimaging-based results do no more than arouse a high level of suspicion of breast cancer, stereotactic needle biopsy with different principles is the method of choice to confirm the diagnosis ªbreast cancerº before SLN labeling. However, before any discussion of advantages and disadvantages of the different methods can be even started, it is necessary to emphasize that causation of large tissue defects in or around the tumor by biopsy techniques involving extraction of large cylinders (*1 cm) is not acceptable, because such defects can seriously hamper the ªperitumoralº or ªsubdermalº injection of the contrast-fluids for sentinel node detection. It also seems important to emphasize that even in tiny core biopsies containing cancer cell formations, in addition to confirmation of the cancer diagnosis by the mandatory HE staining, evaluation of important biological parameters with prognostic significance, such as tumor grading, proliferative activity revealed by MIBI staining, ER and PR status, overexpression of p185, expression of mutated p53, and coexpression of vimentin, is perfectly possible.
Early preoperative examination of such biopsy specimens can be helpful in the development of a comprehensive therapy plan.
Routine and Special Histopathological and Cytopathological Techniques Fine-needle Aspiration Cytology One of the most frequently used techniques has been and is still fine-needle aspiration cytology (FNAC); for many years it has been possible to apply this puncture method with ultrasound guidance. This method allows cellular material to be obtained from a circumscribed area when the needle is fanned during collection of the material, though it mostly produces only a few smears when compact tissue is punctured. This means that only a few parameters can be investigated by basic staining (e.g., Giemsa) and additional immunohistochemical stainings. In addition, this method does not allow ascertainment of the invasive tumor process as histopathological examination does (Frykberg 1999; Chapellier et al. 2000; O'Driscoll et al. 2000; Georgian-Smith and Lawton 2001; Guenin 2001; Uchiyama et al. 2001). Statements published by Tulusan et al. (1982) emphasize the difficulties in diagnosis of noninvasive and invasive lobular cancer. The cellular picture with dissociated small or intermediate-sized tumor cells with eccentric nuclei arranged in an ªIndian fileº pattern can be found only focally and is inconsistent. Variants have a rosette-like pattern (alveolar variant) or a large-cell pattern (pleomorphic variant). Because of the partly isomorphic cellularity the diagnosis can still be difficult, however. It means that the only statement possible is that ªmalignancyº cannot be definitely either confirmed or ruled out.
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In cases with a negative result but persisting suspicion based on radiological imaging methods this procedure can be repeated. To permit reliable and scientifically based recommendations, the following statements must be kept in mind: · Stereotactic fine needle aspiration cytology (SFNAC) and stereotactic (MR-guided) core needle biopsy (SCNB) are the methods of choice. (For evaluation of the advantages and disadvantages of these methods see next sections.) · Vacuum-assisted core biopsy, while coming more and more to the fore, seems not to be appropriate for cancers that have been diagnosed with near-certainty by imaging methods, because the defects within a solid growing cancer with a diameter >1 cm can disturb the SLN labeling (after peritumoral injection of the colloid solution) following the initial diagnostic procedure and can open veins within the cancer. Therefore, it is safe to say that this method is much more appropriate for obtaining a diagnosis in the case of tiny, unclear lesions, which may have multifocal localizations, in order to avoid one or multiple open surgical biopsies.
many groups. The values found by Abreu-e-Lima et al. (1999) were 90.7% and 98.4%, respectively. Pellets of SFNAC or SCNB material can also be used for quantification of p185: the material is extracted with a buffer containing Triton X-100, and the p185 receptor protein is measured with an enzyme immunoassay. When this procedure is used Herceptin can be proposed as a component of the adjuvant regimens even in the earliest phases of the diagnostic investigations (Dey et al. 2000; Wu et al. 2000).
Vacuum-assisted Core Biopsy The vacuum-assisted core biopsy (VAC-B) is the latest sophisticated development: it allows multiple tissue cores (11 G) to be taken in a circumferential manner from around the biopsy probe, which is inserted under stereotactic guidance. This method allows more extensive sampling of small suspicious lesions than core biopsy, and it yields fewer unsatisfactory core biopsies.
Advanced Breast Biopsy Instrumentation
Core Needle Biopsy The core needle biopsy (CNB) procedure has been improved by the availability of ultrasound and MR guidance. In addition, it was basic to the development of the vacuum-needle biopsy (VAC-NB) technique. All needle biopsy techniques performed with histological examination of the specimens in mind yield tissue cylinders that can be embedded in paraffin for investigation, as a rule, of all the aforementioned parameters in serial sections. In addition, the invasive cancer process can be confirmed in most cases. With a view to having a secure diagnosis before sentinel node labeling and an overview of the most important prognostic parameters, the needle biopsy methods have become increasingly good ways of obtaining optimal information on the tumor biology (the prognostic parameters themselves are already valuable) before the sentinel node labeling is started. The sensitivity and specificity of the stereotactic core biopsy technique have been investigated by
The advanced breast biopsy instrumentation (ABBI) uses stereotactic techniques combined with an oscillating-blade cutting mechanism to obtain single cylinders from 5 to 20 mm in diameter. These cylinders can be collected and give optimal conditions for intensive histopathological investigations (Wong et al. 2000). The three different methods briefly described above can be used as seems appropriate according to the different local conditions, but are much more frequently selected on the basis of the local findings and the planned schedule of further investigation and treatment.
Basic Need for Qualified Diagnostic Methods in the Context of the ªSLN Conceptº Diagnostic procedures should not be allowed to cause local tissue damage with necroses, bleeding and opening of veins within the infiltrative and growing cancer by diagnostic methods before SLN(s) are labeled by peritumoral or subdermal injection of the labeling fluids (blue dye, 99mTc-col-
Advantages of Using Combined Methods
loid solution); to this end the diagnosis of breast cancer must be confirmed by needle biopsy techniques when palpation and imaging methods do not allow a diagnosis that is beyond reasonable doubt. Needle biopsy methods are now highly developed and appropriate for this purpose. For these methods to fulfill their purpose the following requirements must be met: · They must guarantee balanced pressure during application to avoid translocation of cancer cells within the branch canal. · They must not cause tissue destruction, induce local opening of veins, or lead to local necroses or any bleeding worthy of mention. · They must be guaranteed to yield enough material for the investigations planned.
MR Imaging Support of Needle Biopsy for Preoperative Detection of Multifocality and/or Multicentricity of Breast Cancer In selection of the SLN imaging approach, it is essential to find out about any multifocality and/or multicentricity by exact localization of such lesions within the breast(s) as raise the suspicion of cancer at the earliest possible point in the diagnostic chain, and even before sentinel node localization. In this approach mammographic investigations and MR tomography give us the basic information needed, especially about the main tumor nodule. In the case of tumor multifocality and/or multicentricity, however, it means detecting additional tiny cancer foci in situ (DCIS or LCIS) or invasive cancers with an extension of only a few millimeters; MR tomography plus mammographic or ultrasound (US) guidance of the puncture is then very helpful in localization of such small cancer foci and confirmation of the cancer diagnosis by means of a needle biopsy procedure followed by histopathological and immunohistochemical investigations, as described above (Obdeijn et al. 2000).
Selective Use of the Different Needle Biopsy Techniques The three different needle biopsy techniques available are: · Fine-needle aspiration cytology (FNAC) · Core needle biopsy (CNB) · Vacuum-assisted needle biopsy (VAC-NB) In this section an analysis of the indications for each is attempted, based on points that are important for the choice of diagnostic system: · Keeping tissue damage ± especially in putative cancer regions ± as slight as possible. · Refraining from use of systems that can cause extensive damage and changes to tissue, such as VAC-NB or CNB with large-diameter needles, when cancer is already all but confirmed: ± With regard to the projected search for sentinel node(s). ± Because of the possibility of propagating hematogenous metastasis. The indications for use of the different types of needle-biopsy techniques and their alternatives are summarized in Fig. 1 a±c, which shows the principles of the needle biopsy subtypes in current use and the indications for their application in ascertaining a cancer diagnosis in the presence of different degrees of suspicion of cancer and different cancer types. The results obtained are valuable for recognizing the indications for carrying out the appropriate treatment and also as an aid in selection of the technique to be used in the subsequent search for the SLN(s).
Advantages of Using Combined Methods In the case of FNAC, all material is generally investigated using stained smears. In contrast, core biopsy and vacuum biopsy specimens are paraffin embedded and examined histologically in serial sections. It is possible to obtain imprint cytology smears from core and vacuum biopsy material, however. It follows from this that the imprint cytology examination allows a preliminary diagnosis within a few hours, whereas the process of fixation, paraf-
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Fig. 1. a Cancer largely already confirmed by palpation and imaging (nodular growth), showing unifocal or multicentric palpable tumor node(s). Core biopsy is useful in invasive, mostly uni- and sometimes multifocal/-centric breast cancers. The advantage is that cancer invasion can be verified even in low-grade cancer subtypes (tubular cancer lobular cancer types), in which it is hard to verify by aspiration cytology. The disadvantage is that there is more local tissue injury than in fine needle aspiration cytology (FNAC). As an alternative, FNAC can also be used, but this requires highly experienced cytologists. b In a diffusely growing cancer, mostly with a scirrhous growth pattern. Core needle biopsy (CNB) and FNAC are both possible. The advantages of CNB are that the invasiveness of the cancer cells can be verified. A relatively high number of sections for HE and immunohistochemical stainings (prognostic parameters, steroid receptors, delineation of histiocytes and histiocyte-like cancer cells using antibodies directed to histiocytes (CD 68) and cancer cells (anti-cytokeratin 8, 18 etc) are possible. The advantage of FNAC is that cells can be sampled from a more extensive field of the invasive cancer
process. Comparison of the two methods suggests that FNAC is less traumatic than CNB, while in a core biopsy a higher rate of ascertainment of malignancy (by proof of tumor invasion) and more extensive parameter investigations are possible. c In a vacuum biopsy, the puncture is made by pressure lower than atmospheric pressure and is guided by mammography; this is helpful in cases with low-grade suspicion, as surgical excision biopsy can then be avoided. This biopsy technique is optimal for evaluation of small foci with mammographically verified presence of microcalcifications that are the subject of lowgrade suspicion (Bi-RADS 3). The advantage of this is that single or multifocal foci with microcalcifications of different quality can be evaluated in one course or possibly in different successive courses. There are also disadvantages: this system should not be used in highly suspicious lesions (Bi-RADS 4) or cases in which a diagnosis of cancer is virtually confirmed by mammography or MRI. Note: Sclerotic, calcified microfibroadenomas or calcified sclerosing adenosis cannot easily be sucked up by the vacuum biopsy system. In such cases surgical excision is the method of choice
Advantages of Using Combined Methods
Fig. 2. Comparison and synopsis of cytology and biopsy techniques used for preoperative diagnosis of breast cancer. The main advantages and disadvantages of each method
must be considered before use of the system (see comments by the syringes)
fin embedding, sectioning, and staining needs much more time, usually 24 h. This has already been examined by Albert et al. (2000) and many others, who investigated imprint cytologies from core biopsies and found that double investigation in both systems ± imprint cytology and core
biopsy histology ± could reduce the number of biopsy specimens needed and increase safety during diagnosis. The different techniques used for exclusion or confirmation of the cancer diagnosis that are based on microinvasive methods and the avoidance
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of surgical intervention are summarized in Fig. 1 a±c. The synopsis below (Fig. 2) again shows the appropriate usage of each of the three different techniques. When high-grade cancer is suspected FNAC and CNB can both be used, but when the advantages and disadvantages are considered CNB is used more often. This is understandable, because highly experienced cytopathologists have become very few and far between in almost all countries. Vacuum needle biopsy seems not to be fully adequate for cancer diagnosis in general, specifically in view of the possibility of cancer propagation via veins opened by the biopsy procedure, as described above.
Suitability of These Minimally Invasive Diagnostic Methods for Confirmation or Exclusion of Breast Cancer The minimally invasive diagnostic methods described above should be used as dictated by individual circumstances, that means the results of the physical examination of the breast and the results of radiodiagnostic techniques (mammography, MRI, ultrasound).
Table 1. Results of physical and radiological prediagnosis linked with the most suitable puncture technique(s), which are necessary for histocytopathological diagnosis (FNAC fine-needle aspiration cytology, CB, VAC-B) 1. Solid palpable tumor, high suspicion of carcinoma already on mammography
1. Core biopsy 2. FNAC
2. Small focus seen on mammography leading to strong suspicion of cancer
1. Ultrasound- or MR-guided core biopsy 2. Ultrasound- or MR-guided FNAC
3. Nonpalpable, diffuse, highly suspicious lesions, e.g., assumed scirrhous tumor growth or inflammatory tumor growth
FNAC or small (mini-)biopsy in superficial tumor growth
4. One or more unclear or suspicious foci in mammography or MR tomography (large number of cases in screening programs)
Vacuum core biopsy, mammographically guided If possible, elimination of the whole focus
To make it easier to select the best diagnostic intervention, i.e. the one most specifically tailored to a particular patient's needs, the short overview summarized in Table 1 can be used for orientation.
Comparison of the Different Needle Biopsy Techniques by Proportion of Correct Diagnoses Stereotactic FNAC (SFNAC) and FNAC without guidance are the oldest well-developed cytological techniques and are used by many teams with a high level of expertise. The ªCamecoº syringe, a light but stable metal case into which one-way syringes are inserted, has long been the most frequently used system. With this special syringe it is possible to achieve a fan-shaped puncture of a suspicious lesion, so that with only one puncture of a lesion it is possible to obtain enough material for three or four, or even more smears. The rate of positive results in cases with breast cancer is approximately 98%. Ultrasound guidance was the first principle of guidance used (Obdeijn et al. 2000; Hatada et al. 2000, etc.), and this has now been in use for a long period. In investigations in 351 cases with FNAB diagnosis (Chieng et al. 2000), invasive breast cancer was found in the subsequent excision in 343 cases (= 97.7%). Only in 8 cases were other types of malignancy found: DCIS in 6 (1.7%) and DCIS arousing the suspicion of microinvasion in 2 (0.6%). Further investigations show similar results (See next chapter; Ruschenburg et al.). The disadvantages of SFNAC are that highly differentiated cancers, such as tubular cancer and differentiated subtypes of lobular cancer, often cannot be reliably diagnosed. In such cases, core biopsies seem to be much more effective, because the invasive behavior of the cancers can be documented in histological section. In the course of growing acceptance of the SLN concept, FNAC, ultrasound-guided automated percutaneous core needle biopsy, and, of late, the development of VAC-C are gaining increasingly in significance (Osanai et al. 2000). The advantage of histological evaluation over SFNAC, as already pointed out, is that stromal invasion of cancers can be confirmed and prognostic factors can be evaluated preoperatively in a higher rate.
Comparison of the Different Needle Biopsy Techniques by Proportion of Correct Diagnoses Table 2. Shifting of atypical lesions to higher degrees of malignancy and invasive cancers in 841 mammographic abnormalities. (Compiled using data from Burak et al. 2000) Atypical ductal hyperplasia (ADH)
Ductal carcinoma in situ (DCIS)
Invasive cancer
46
89
73
10 (11.2%) Including
2 (4.3%)
"Invasive cancer
"DCIS
4 (8.7%)
When no invasive cancer can be ascertained, it may be that only one of the following is revealed by the histopathological examinations: · Atypical ductal hyperplasia · Ductal carcinoma in situ (DCIS) · Extensive intraductal component (EIC) in the marginal areas of an invasive breast cancer It is easy to understand that cases with such lesions found in the needle biopsy can have invasive tumor parts in neighboring areas not included in the needle biopsy material. Studies testing the significance of this method have shown that the overall rate of diagnoses including all malignant invasive lesions and their prestages, such as ADH, DCIS, and invasive cancers, is very high, but the number of invasive cancers is underestimated within the collective when only a small part of the whole lesion, namely a cylinder of it, is investigated. Burak et al. (2000) have published impressive data on the material-dependent underestimation of malignant invasive lesions. The percentage underestimation can be derived from Table 2. This ªunderestimation of malignancyº is not too disturbing, because in DCIS cases the SLN(s) should be histologically investigated too, and in ADH cases the lesion must also be totally excised. When the initial core biopsy diagnosis of ADH has to be changed to one of invasive cancer, the subdermal injection for labeling the sentinel node(s) can already be given on the basis of the ADH diagnosis. When no DCIS or invasive cancer is found in serial sections of the excised lesion, sentinel node excision can be avoided. However, this decision needs very fast serial sectioning and histopathological exclusion of an
"Invasive cancer
invasive cancer, to keep up with the labeling procedure for localization of the SLN(s). Because extensive intraductal component (EIC) is also an important factor that has to be considered intraoperatively when wide excision of the primary is performed, attempts have been made to find information on EIC preoperatively in serial sections of the CNB specimen (Jimenez et al. 2000). The formula established for calculation of the EIC in a core biopsy is: Number of ducts containing EIC divided by the total number of tissue cores A ratio of more than 0.5 is classed as EIC. Preoperative diagnosis of EIC helps the surgeon to be informed and to control the marginal areas for tumor-free margins on the basis of the results of intraoperative investigations. This must be carefully timed to fit into the sequence of radio- and histo-/ cytopathological diagnostic procedures and the surgical search for the SLN(s). Besides histo- and/or cytopathological confirmation of the cancer diagnosis a quick overview of biological tumor parameters can be very valuable with a view to further treatment strategies. Ultrarapid immunohistochemical stainings also contribute to support for these aims. It is also helpful to obtain information about proliferation factors connected with higher degrees of hematogenous spread (e.g. c-erb B2 overexpression, p53 mutation, etc.). Nåhrig et al. of the Munich group (see Chapter 17) have developed a sophisticated immunohistochemical technique that allows results within less than 20 minutes; such contributions are much appreciated within the important concept of optimizing interdisciplinary cooperation. They support the current goal of making interdisciplinary cooperation more efficient and reduc-
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ing costs in our treatment protocols (e.g., shorter length of stay in hospital, etc.). The staining method is described and discussed in the next chapter with reference to some classic cancer types.
References Abreu-e-Lima MC de, Maranhao N, Costa I, Abreu-e-Lima M, Abreu-e-Lima P, Carvalho AR de (1999) Sensitivity and specificity of sterotaxic core biopsy in the diagnosis of non palpable lesions of the breast. Rev Assoc Med Bras 45:290±294 Albert US, Duda V, Hadji P, Goerke K, Hild F, Bock K, Ramaswamy A, Schulz KD (2000) Imprint cytology of core needle biopsy specimens of breast lesions. A rapid approach to detecting malignancies, with comparison of cytologic and histopathologic analyses of 173 cases. Acta Cytol 44:57±62 Burak WE Jr, Owens KE, Tighe MB, Kemp L, Dinges SA, Hitchcock CL, Olsen J (2000) Vacuum assisted sterotactic breast biopsy: histologic underestimation of malignant lesions. Arch Surg 135:700±703 Chapellier C, Balu-Maestro C, Bleuse A, Ettoro F, Bruneton JN (2000) Ultrasonography of invasive lobular carcinoma of the breast: sonographic patterns and diagnostic value: report of 102 cases. Clin Imaging 24:333±336 Chieng DE, Fernandez G, Cangiarella JF, Cohen JM, Waisman J, Harris MN, Roses DF, Shapiro RL, Symman WF (2000) Invasive carcinoma in clinically suspicious breast masses diagnosed as adenocarcinoma by fine needle aspiration. Cancer 90:96±101 Dey P, Luthra UK, George SS, Prasad A (2000) c-erb-B2-expression and DNA ploidy in breast cancer on fine needle aspiration cytology material. Diagn Cytopathol 22:261± 262 Frykberg ER (1999) Lobular carcinoma in situ of the breast. Breast J 5:296±303
Georgian-Smith D, Lawton TJ (2001) Calcifications of lobular carcinoma in situ of the breast: radiologic-pathologic correlation. AMJ Am J Roentgenol 176:1255±1259 Guenin MA (2001) Is excision of all lobular carcinoma in situ really necessary? Radiology 219:295±297 Hatada T, Ishii H, Ichii S, Okada K, Fujiwara Y, Yamamura T (2000) Diagnostic value of ultrasound-guided fine-needle aspiration biopsy, core needle biopsy and evaluation of combined use in the diagnosis of breast lesions. J Am Coll Surg 190:299±303 Jimenez RE, Bongers S, Bouman D, Segel M, Visscher DW (2000) Clinicopathologic significance of ductal carcinoma in situ in breast core needle biopsies with invasive cancer. Am J Surg Pathol 24:123±128 O'Driscoll D, Britton P, Bobrow L, Wishart GC, Sinnatamby R, Warren R (2001) Lobular carcinoma in situ on core biopsy what is the clinical significance? Clin Radiol 56:216±220 Obdeijn IM, Brouwers-Kuyper EM, Tianus-Linthorst MM, Wiggers T, Oudkerk M (2000) MR-Imaging-guided sonography followed by fine needle aspiration cytology in occult carcinoma of the breast. AMJ Am J Roentgenol 174:1079±1084 Osanai T, Gomi N, Wakita T, Yamashita T, Ichikawa W, Nihei Z, Sugihara K (2000) Ultrasound guided core needle biopsy for breast cancer: preliminary report. Jpn J Clin Oncol 30:65±67 Tulusan AH, Egger H, Schneider ML, Willgeroth F (1982) A contribution to the natural history of breast cancer. IV. Lobular carcinoma in situ and its relation to breast cancer. Arch Gynecol 23(3):219±226 Uchiyama N, Miyakawa K, Moriyama N, Kumazaki T (2001) Radiographic features of invasive lobular carcinoma of the breast. Radiat Med 19:19±25 Wong AY, Salisbury E, Bilous M (2000) Recent developments in sterotactic breast biopsy methodologies: an update for the surgical pathologist. Adv Anat Pathol 7:26±35 Wu JT, Than P, Benth JS (2000) Quantification of HER2 oncoprotein in fine needle aspirates of the breast. Ann Clin Lab Sci 30:59±56
Chapter 16
Success of Stereotactic Fine-Needle Aspiration Cytology Depending on Quality of Sampling I. Ruschenburg, B. H. Kamphausen, T. Tællner
Many investigations have documented the value of breast fine-needle aspiration cytology (FNAC) in the treatment of patients with palpable and impalpable breast lesions (Barrows et al. 1986; Wilkinson et al. 1989; Giard and Hermans 1992; Willis and Ramzy 1995; Anonymous 1996; Feichter et al. 1997; Park and Ham 1997; Klijanienko et al. 1998; Bærner et al. 1999; Leifland et al. 2000). The Swedish Cameco syringe has long been used in many European countries and also in other continents (Fig. 1). Ultrasound guidance supports the success of the puncture, which may for instance take the form of confirming a diagnosis of breast cancer. This syringe is also often used
Fig. 1. The Cameco system used in fine-needle aspiration cytology (FNAC). The syringe is a one-way type, which can easily be removed from the frame. The system has a light metal frame. It is light and practical in use
in other fields, e.g. in the diagnosis of head and neck tumors. A collection of fine needles that can be used with the Cameco-system is shown in Fig. 2. With regard to general immunohistochemical developments, it is also possible to evaluate special biological features such as overexpression of c-erb B2 (p185) and DNA ploidy (Dey et al. 2000; Wu et al. 2000). However, especially in large clinics with high medical staff turnover, long-term training and experience in handling the SFNAC techniques are in decline. The same applies when the cytopathology team has frequent changes in the medical staff and also in the laboratory staff. Therefore, results obtained by a single clinic with the same cytopathologists throughout are presented. Certainly most investigators agree that to avoid missing a malignant lesion absolute and complete sensitivity must be high and the false-negative rate must be low. When results from the literature are calculated in the same way as in this series (Zakhour and Wells 1999 a), absolute and complete sensitivity lie in the ranges of 50.3±82.6% and 76.9±98.0%, respectively, and the false-negative rate is between 2.6% and 12.1%. Our data show an absolute sensitivity of 63.3%, a complete sensitivity of 83.3%, and a false-negative rate of 6.7%, representing two aspirates. Table 1 summarizes the cytologic results from all 355 aspirations. Solid breast lesions were considered malignant, benign, suspicious or inadequate in 8.7%, 66.9%, 5.8%, and 18.6% of cases, respectively, whereas cystic lesions were considered malignant, benign, suspicious, or inadequate in 0.9%, 96.5%, 0.9%, and 1.8%, respectively. In 7 of the 22 aspirates containing malignant cells a ductal tumor subtype was recognized, and in 3, a mucinous subtype. There were 2 false-negative results, 1 from a solid and 1 from a cystic lesion. The cystic lesion was not palpable, and the clinical and imaging findings, including MR mam-
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Chapter 16 Success of Stereotactic Fine-Needle Aspiration Cytology Depending on Quality of Sampling
Fig. 2. Fine needles, some of which can be used for breast puncture and some also for organ punctures (the longer needles are adequate for lung and liver punctures Table 1. Cytological findings (n =355) Tissue
Malignant
Benign
Suspicious
Inadequate
Total
Breast
22 (6.2%)
271 (76.3%)
15 (4.2%)
47 (13.2%)
355
Solid
21 (8.7%)
162 (66.9%)
14 (5.8%)
45 (18.6%)
242
Cystic
1 (0.9%)
109 (96.5%)
1 (0.9%)
2 (1.8%)
113
mography, had not raised suspicion. The cytological diagnosis was ªfibrocystic change.º Biopsy and histological examination were performed 8 months after fine-needle aspiration and cytological analysis. A diagnosis of a ductal carcinoma in situ (DCIS) with minimal stromal invasion was made. Reexamination of the smears showed a very few suspect cells, which had been underdiagnosed as apocrine cells with marked degeneration in the first evaluation. The solid lesion had been palpable, but neither the clinical nor the imaging findings were suspicious. The initial cytology-based diagnosis was ªfibrocystic change, fibroadenoma possible.º Histology showed an invasive ductal carcinoma (pT1c N0). Fibrocystic change was found close to the carcinoma. The results of all cases based on FNAC were compared and checked against those of the subse-
quent histopathological examinations. The results of the comparison are summarized in Table 2. In cases with a benign cytological diagnosis the rate of malignant events in the following 2.5 years was very low (Table 3). Successive evaluations in the same collective of patients have shown that FNAC alone does not give optimal results; rather it must be combined with radioimaging systems and ultrasound methods (Table 4). The highest rates of cancer detection were obtained when clinical appearance, ultrasound, and FNAC were used for diagnosis in a synergistic manner. These rates were 89.7% on average. This is comparable to the rate achieved with the well-known so-called triple test when used in clinics as a basis for deciding whether an operation is indicated (O'Neil et al. 1997; Rocha et al. 1997; Rubenchik et al. 1997; Wang and Ducatman
Chapter 16 Success of Stereotactic Fine-Needle Aspiration Cytology Depending on Quality of Sampling Table 2. Correlation of cytological and histological findings in breast aspirates Histology
Cytology
Solid
Cystic
Total
Malignant
Malignant
18
1
19
Suspicious
5
1
6
Benign
1
1
2
Inadequate
3
All Benign
27
3
30
Malignant Suspicious
7
Benign
7
16
Inadequate
2
18
6
All Not available
3
6
29
2
31
Malignant
3
3
Suspicious
2
2
Benign
145
106
251
36
2
38
186
108
294
Inadequate All
Table 3. Follow-up from benign breast aspirates Solid
Cystic
Total
162
109
271
Histological follow-up data available
17
3
20
Clinical follow-up data available
41
36
77
104
70
174
Spontaneous recovery
4
2
6
Diagnosis confirmed by repeat aspiration biopsies
3
2
5
No sign of malignancy, follow-up at least 1 year
20
23
43
No sign of malignancy, follow-up less than 1 year
13
8
21
1
1
All aspirates
No information
Cyst recurrence Malignant tumor 2.5 years after fine-needle aspiration
1998; Collao et al. 1999; Masood 1999; Reinikainen et al. 1999; Salami et al. 1999; Waisman 1999; Zardawi et al. 1999; Bonk et al. 2000; Chieng et al. 2000; Cytology Subgroup 2000; Obdeijn et al. 2000). In addition, SFNAC, or alternatively core biopsy, can be used for preoperative M-staging before the SLN labeling starts. Pleural effusions or liver metastases, in particular, can be confirmed by these meth-
1
1
ods. In our statistical evaluations of the whole collective, the following results are of special interest. The false-negative rate is only 6.7% and the false-positive rate, 0%; the predictive value is 100% (see Table 5). In conclusion, it must be emphasized that on the basis of the FNAC results, the next step(s), namely: breast-conserving surgery or ablative therapy and sentinel node labeling, can already be dis-
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Chapter 16 Success of Stereotactic Fine-Needle Aspiration Cytology Depending on Quality of Sampling Table 4. Comparison between cytology, clinical and imaging findings Carcinomas detected Clinical appearance
44.8%
Mammography
57.1%
Ultrasound
62.1%
Cytology
83.3%
Clinical appearance + mammography
90.5%
Clinical appearance + ultrasound
75.9%
Clinical appearance + cytology
86.2%
Mammography + ultrasound
81.0%
Mammography + cytology
90.5%
Ultrasound + cytology
93.1%
Clinical appearance + mammography + ultrasound
85.7%
Clinical appearance + mammography + cytology
90.5%
Clinical appearance + ultrasound + cytology
96.6%
Mammography + ultrasound + cytology
95.2%
Clinical appearance + mammography + ultrasound + cytology
95.2%
Table 5. Statistical evaluation Absolute sensitivity
63.3%
Complete sensitivity
83.3%
Specificity (biopsied cases)
51.6%
Specificity (full)
84.1%
Positive predictive value
100.0%
False-negative rate
6.7%
False-positive rate
0.00%
Inadequate material (all cases)
13.2%
Inadequate material in cases with histologically confirmed
10.0%
Suspicious findings rate
4.2%
cussed with the patient at that time point, in order to find the safest and cosmetically best operative strategy for further treatment (Zakhour and Wells 1999 b).
References and Further Reading Anonymous (1996) The uniform approach to breast fine needle aspiration biopsy: a synopsis. Acta Cytol 40:1120±1126 Barrows GH, Anderson TJ, Lamb JL, Dixon JM (1986) Fineneedle aspiration of breast cancer: relationship of clinical factors to cytology results in 689 primary malignancies. Cancer 58:1493±1498 Boerner S, Fornage BD, Singletary E, Sneige N (1999) Ultrasound-guided fine-needle aspiration (FNA) of nonpalpable breast lesions: a review of 1885 FNA cases using the National Cancer Institute-Supported Recommendations on the Uniform Approach to Breast FNA. Cancer (Cancer Cytopathol) 87:19±24 Bonk U, Degrell I, Gohla G, Hanisch P (2000) Fine needle aspiration cytology of the breast. In: Bonk U (ed) Breast cancer ± international recommendations for an objective diagnosis. Urban & Fischer, Munich Jena, pp 57±67 Chieng DE, Fernandez G, Cangiarella JF, Cohen JM, Waisman J, Harris MN, Roses DF, Shapiro RL, Symman WF (2000) Invasive carcinoma in clinically suspicious breast masses diagnosed as adenocarcinoma by fine needle aspiration. Cancer 90:96±101 Collao LM, Lima RS, Werner B, Torres LFB (1999) Value of fine needle aspiration in the diagnosis of breast lesions. Acta Cytol 43:587±592 Cytology Sub-Group of the National Coordinating Committee for Breast Screening Pathology (2000) Guidelines for cytology procedures and reporting in breast cancer screening. In: Bonk U (ed) Breast cancer ± international recommendation for an objective diagnosis. Urban & Fischer, Munich Jena, pp 70±94 Dey P, Luthra UK, George SS, Prasad A (2000) c-erb-B2-expression and DNA ploidy in breast cancer on fine needle aspiration cytology material. Diagn Cytopathol 22:261±262 Feichter GE, Haberthçr F, Gobat S, Dalquen P (1997) Breast cytology: statistical analysis and cytohistologic correlations. Acta Cytol 41:327±332 Giard RWM, Hermans J (1992) The value of aspiration cytologic examination of the breast. Cancer 69:2104±2110 Klijanienko J, CÖt J-F, Thibault F, Zafrani B, Meunier M, Clough K, Asselain B, Vielh P (1998) Ultrasound-guided fine-needle aspiration cytology of nonpalpable breast lesions: Institut Curie's experience with 198 histologically correlated cases. Cancer [Cancer Cytopathol] 84:36±41 Leifland K, Lundquist H, Mare K, Erhardt K, Fernstad R (2000) Pre-operative simultaneous sterotactic core biopsy and fine needle aspiration biopsy in the diagnosis of invasive lobular breast carcinoma. Acta Radiol 41:57±60 Masood S (1999) Diagnostic terminology in fine-needle aspiration biopsy of the breast. Cancer [Cancer Cytopathol] 87:1±4 O'Neil S, Castelli M, Gattuso P, Kluskens L, Madsen K, Aranha G (1997) Fine needle aspiration of 697 palpable breast lesions with histopathologic correlation. Surgery 122:824±828 Obdeijn IM, Brouwers-Kuyper EM, Tianus-Linthorst MM, Wiggers T, Oudkerk M (2000) MR-Imaging-guided sonography followed by fine needle aspiration cytology in occult carcinoma of the breast. AJR Am J Roentgenol 174:1079±1084
References and Further Reading Park IA, Ham EK (1997) Fine needle aspiration cytology of palpable breast lesions: histologic subtype in false negative cases. Acta Cytol 41:1131±1138 Reinikainen HT, Rissanen TJ, Piippo UK, Påivånsalo MJ (1999) Contribution of ultrasonography and fine needle aspiration cytology to the differential diagnosis of palpable solid breast lesions. Acta Radiol 40:383±389 Rocha PS, Nadkarni NS, Menezes S (1997) Fine needle aspiration biopsy of breast lesions and histopathologic correlation: an analysis of 837 cases in four years. Acta Cytol 41:705±712 Rubenchik I, Sneige N, Edeiken B, Samuels B, Fornage B (1997) In search of specimen adequacy in fine-needle aspirates of nonpalpable breast lesions. Am J Clin Pathol 108:13±18 Salami N, Hirschowitz SL, Nieberg RK, Apple SK (1999) Triple test approach to inadequate fine needle aspiration biopsies of palpable breast lesions. Acta Cytol 42:339± 343 Tabbara SO, Frost AR, Stoler MH, Sneige N, Sidawy MK (2000) Changing trends in breast fine needle aspiration: results of the Papanicolaou Society of Cytopathology Survey. Diagn Cytopathol 22(2):126±130 Waisman J (1999) Criteria for cytologic reporting of breast fine needle aspiration. Acta Cytol 43:1200
Wang HH, Ducatman BS (1998) Fine needle aspiration of the breast: a probabilistic approach to diagnosis of carcinoma. Acta Cytol 42:285±289 Wilkinson EJ, Schuettke CM, Ferrier CM, Franzini DA, Bland KI (1989) Fine needle aspiration of breast masses. Acta Cytol 33:613±619 Willis SL, Ramzy I (1995) Analysis of false results in a series of 835 fine needle aspirates of breast lesions. Acta Cytol 39:858±864 Wu JT, Zhang P, Bentz JS (2000) Qualification of HER2 oncoprotein in fine needle aspirates of the breast. Ann Clin Lab Sci 30:49±56 Zakhour H, Wells C (1999 a) Diagnostic cytopathology of the breast, chapter: Audit of statistical data and quality assurance. Churchill Livingstone, London, pp 241±252 Zakhour H, Wells C (1999 b) Diagnostic cytopathology of the breast, chapter: The value of fine needle aspiration. Churchill Livingstone, London, pp 1±10 Zardawi IM, Hearnden F, Meyer P, Trevan B (1999) Ultrasound-guided fine needle aspiration cytology of impalpable breast lesions in a rural setting: comparison of cytology with imaging and final outcome. Acta Cytol 52:163±168
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Use of a Newly Developed Ultrarapid Immunohistochemical Method to Improve Security in Sentinel Node Investigation and Timing in Interdisciplinary Cooperation J. Nåhrig, H. Hæfler
In the strategies to detect SLNs in different primaries, such as breast cancer, melanoma, lung and gastrointestinal carcinomas and also neuroendocrine tumors and urogenital cancers, exact timing of the various diagnostic and therapeutic procedures has an important role. As a general rule, it is extremely helpful to have an exact histopathological and/or cytopathological diagnosis before sentinel lymphadenectomy is performed. In certain tumor entities, such as melanoma, primary biopsies before radioactive SLN labeling cannot be recommended because the procedure entails a high risk of tumor spread in these. However, in breast cancer, oropharygeal cancer, lung cancer, and gastrointestinal tumors, for example confirmation of the cancer diagnosis is the basis for all further labeling and treatment procedures. Whereas biopsies can be taken directly from organ tissues that are covered by mucosa and from the gastrointestinal tract, in the case of a deeper location of a suspected cancer (e.g. breast cancer), it is necessary to use puncture methods to take the specimens. The most common and best evaluated methods are: fine needle aspiration biopsy (FNAB), core biopsy and, for limited indications, vacuum biopsy (see Chapters 15, 16). In this context it must be stated that FNAC is also appropriate during follow-up for the evaluation of small, suspicious lesions, some of which may not be palpable. However, in highly suspicious cases, when a primary is palpable or has been disclosed by mammography or MRI, core biopsy methods are now increasingly preferred. With these methods, it is possible to check the cancer diagnosis, on the one hand, and on the other to perform additional immunohistochemical evaluations for prognostic factors in addition. However, routine immunohistochemical techniques are time consuming; they take at least 1 day. A newly developed method, the ªultrarapid immunohistochemical staining procedure,º makes it possible to obtain results within approximately
20 min. With this faster availability of the results, the method offers the opportunity of developing an exact time schedule for confirmation of the diagnosis, nuclear medical labeling and surgical excision (interdisciplinary timing). A second problem, in addition to the initial confirmation of the diagnosis, is the question of whether the lymph nodes can already be investigated intraoperatively to look for cancer cell infiltration, especially by means of techniques that help to detect isolated cancer cells or small cancer cell clusters. These methods are used in many pathology laboratories and their use is acceptable for differentiated cancers with high cancer cell adhesion (differentiated adenocarcinomas or squamous cell carcinomas). However, HE staining alone is insufficient in intraoperative evaluations, especially in cases with a high degree of tumor cell dissociation. Therefore, the use of frozen sections for intraoperative lymph node examination can hardly be recommended in cases without macroscopically obvious clear-cut cancer infiltration and with high-grade tumor cell dissociation. The degree of high-grade dissociation can be detected even in the initial investigations of the primaries and can also be suspected from the behavior of the cancer within the nodes. Because intraoperative sectioning of small lymph nodes with diameters of 3±5 mm leads to the loss of parts of the lymph node tissue and further loss must be expected after paraffin embedding, the intraoperative search for single tumor cells or small clusters of tumor cells must be regarded very critically within the SLN concept. In these circumstances it seems advisable never to investigate the sentinel nodes except after paraffin embedding in serial and step sections by the newly elaborated immunohistochemical method, because a falsenegative diagnosis can lead to a fatal outcome for the patient. Because the histopathological investigations of the tumor tissue from the primaries and of the sentinel node(s) must fit in with the time schedule
17
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Chapter 17 Use of a Newly Developed Ultrarapid Immunohistochemical Method to Improve Security
for clinical labeling, imaging and operative procedures and accelerated staining procedures, especially those for immunohistochemical staining of cancer cell markers, are highly valued. An ªultrarapid staining methodº newly developed in the research laboratories of Hæfler and Nåhrig supports this ambition fundamentally. To give readers an idea of the practical management of this accelerated, very fast-working, immunohistochemical staining procedure (e.g., demonstration of cytokeratins in epithelial cancer cells and vimentin in soft tissue tumors and differentiation products in neuroendocrine cancers) that gives satisfactory results within 2 h, the essentials of this method are described below.
Methodical Options The time required depends on whether frozen sections are used after ultrarapid immunohistochemical staining or paraffin sections requiring embedding. · When the ultrarapid immunohistochemical staining of frozen sections of sentinel node tissue (selection of cases see above) is used, a clear-cut result can be obtained according to the following time schedule. ± Transport from the operating room to the pathology laboratory: approx. 5±15 min ± Preparation of the frozen sections: approx. 10 min ± Staining procedure for different markers: approx. 1.5 h ± Evaluation of the stained sections: approx. 10±15 min According to this time schedule a significant result can be obtained within approximately 2 h. This means that further surgical treatment is possible on the same day. · When paraffin sections are used approximately 2±4 h must be added for quick embedding in paraffin, and 30 min for sectioning and drying of the sections.
Technical Procedure for Ultrarapid Immunohistochemistry Fresh SLN specimens are usually obtained within 10 min after surgical removal for frozen section examination. The number of lymph nodes resected generally varies from 1 to 3, and it is rare for more nodes to be identified. Each lymph node is cut through the longitudinal axis to give slices of 2± 3 mm. Specimens are snap-frozen and 5-lm cryostat sections are prepared. Fresh sections are fixed in 4% neutral buffered formalin for 2 min and then rinsed in Tris-buffered saline containing sodium chloride (TBS, 0.01 M, pH 7.4) for 15 s. Endogenous peroxidase is blocked using 1% H2O2 dissolved in methanol for 5 min. The fixed slides are then washed again with Tris buffer plus 1% Tween-20 detergent to reduce nonspecific background staining. A direct immunoperoxidase method is applied for ultrarapid immunostaining using the EPOS R system (DAKO, Copenhagen, Denmark). Prediluted EPOS antibodies are incubated in a humid chamber at 54 8C for 5 min. Then slides are rinsed in tap water and nuclear counterstaining of the specimens is done with hemalaun for 10 s. Finally, slides are rinsed in tap water and dehydrated through increasing concentrations of alcohol, isopropanol, and xylene and then coverslipped (Eukitt), or alternatively rinsed in tap water and coverslipped with Kaiser's glycerin gelatin (Merck, Darmstadt, Germany).
Preliminary Experience with Ultrarapid Immunohistochemistry Staining We conducted a clinical study to evaluate the ultrarapid immunohistochemistry method in the examination of sentinel nodes in primary breast cancer using pancytokeratin antibody clone MNF 166 (EPOS, DAKO; Fig. 1). The preliminary results suggest, first, that this technique can well be applied to intraoperative examination of lymph nodes, owing to its short turnaround time of about 20 min; and secondly, that its specificity and sensitivity were high. The major advantage of the method seems to be that it requires less time than microscopic screening. Especially in cases where metastatic disease presents with isolated tumor cells and in the case of lobular carcinoma infiltration, it may help to detect tumor cells more easily.
Preliminary Experience with Ultrarapid Immunohistochemistry Staining Fig. 1 a, b. Sentinel lymph node (SLN): strong immunostaining of a micrometastasis from an invasive ductal breast carcinoma. Frozen-section ultrarapid immunohistochemistry: direct immunoperoxidase staining with anti-pancytokeratin antibody clone MNF116 (EPOS system, DAKO, Denmark). Original magnification ´ 100 a Cancer cells or cell clusters are strongly stained; disseminated cancer cell material, with some cells weakly stained, can be found in macrophages (arrows). b The marginal sinuses of the lymph node are filled with cancer cells; disseminated, small, positively stained cancer cell clusters with strongly positive reaction for cytokeratins can be seen
In a pilot study we also applied the ultrarapid immunohistochemistry method to lymph nodes in patients with colorectal cancer and melanoma, using anti-pancytokeratin antibodies MNF 116, anti-melanoma (MEL) and anti-leukocyte antigen (LCA) antibodies. These antibodies also worked well in the detection of metastatic tumor cells in lymph nodes. A broad range of other markers is also available for this technique and offers the opportunity of studying lymph nodes in patients with primaries other than breast cancer, colorectal cancer and melanoma, e.g., cytokeratin 19 (code no. U 7035), epithelial membrane antigen (code no. U7037), neuroendocrine tumors (Synaptophysin; code no. U0037), chromogranin A (code no.
U7030), and neuron-specific enolase (NSE; code no. U 7026), and prostate-specific antigen (code no. U0035) (Fig. 2). However, it must be considered that there may be a significant rate of false negatives when the SLN has been examined by frozen section techniques in only a few sections. The rates may range from 10% to 20%. In these cases micrometastases or isolated tumor cells are typically found. However, even patients with isolated tumor cells may be found to have positive lymph nodes after paraffin embedding and serial step sectioning. Therefore, meticulous and extensive examination of the sentinel nodes is required to rule out such findings.
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Chapter 17 Use of a Newly Developed Ultrarapid Immunohistochemical Method to Improve Security Fig. 2. Peripancreatic lymph node: strong immunostaining of metastatic low-grade neuroendocrine carcinoma. Frozen-section ultrarapid immunohistochemistry: direct immunoperoxidase staining with anti-chromogranin A antibody clone DAKO-A3 (EPOS system, DAKO, Denmark). Note the far-reaching isomorphism of the tumor cell nuclei. The staining of the cancer cell cytoplasm is moderate but specific. Note also the absolutely negative background, which excludes nonspecific binding and incomplete washout of the immunoreagents. Original magnification ´ 400
Differences in Application In lymph node evaluations performed after immunohistochemical staining the procedures are fundamentally different when cancer cells or small cancer cell clusters are being looked for than when intermediary filaments (cytokeratins, vimentin or desmin) are stained or so-called differentiation products of the cancer cells, such as insulin, glucagon, gastrin, calcitonin and many others are being sought. It should be borne in mind that in most cases the intermediary filaments are expressed in all cancer cells and can therefore generally be detected in every single tumor cell within a node. In contrast, the expression of neurohormones or other substances is frequently inhomogeneously expressed. Therefore, it is only possible to search for these substances in the course of investigations of the primaries, where different parts can be evaluated, and not in single cells in lymph nodes, in which negative results do not exclude metastasis from a neuroendocrine cancer, because in many cases the neuroendocrine hormones are not homogeneously synthesized in all cancer cells. In these circumstances, in specific tumor categories different substances are immunohistochemically evaluated. For instance in:
Neuroendocrine tumors:
Malignant melanomas Prostate cancers (additional):
Chromogranin A S100 Protein Synaptophysin Neuron-specific enolase (NSE) S100 Protein HMB 45 Cytokeratin Prostate-specific antigen and acid prostate phosphatase
Planning for the Future One of the most time-consuming aspects of pathologists' work is the necessity of performing checks on very high numbers of SLN sections to look for single cancer cells or small cancer cell clusters. This very time-consuming work could perhaps be shortened by the use of a scanning program allowing the detection of single cancer cells that have been immunohistochemically stained an intense red by means of the APAAP technique and using the CASS 200 machine. It might also be possible to improve such programs by the development of an automatic slidechange program.
References
References Nåhrig J, Richter T, Kowolik J, Kuhn W, Avril N, Hæfler H, Werner M (2000) Comparison of different histopathological methods for the examination of sentinel lymph nodes in breast cancer. Anticancer Res 20(3B):2209±2212 Richter T, Nåhrig J, Komminoth P, Kowolik J, Werner M (1999) Protocol for ultrarapid immunostaining of frozen sections. J Clin Pathol 52(6):461±463
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Chapter 18
ªMicrometastasisº Versus ªMicroinvolvementº
Does This Discussion Hinder Decision Making? In order to come to a better understanding of biological significance of micrometastases and/or microinvolvement of regional lymph nodes (see also Wittekind 2001), including the sentinel lymph node, at least some points must be clarified once again: 1. Hermanek et al.'s statement (1999) that ªcancer cells in afferent or efferent lymphatic vessels or even in the marginal sinus of the lymph nodes cannot be considered as lymph node metastasis, neither are tumor cells revealed by immunohistochemistry using antibodies against cytokeratinº cannot be accepted in parallel with the sentinel lymph node (SLN) concept. a) When cancer cells are found in the marginal sinuses of a lymph node it is impossible to rule out local breakthrough into the surrounding lymphatic tissue with consecutive serial sectioning, because absolutely completely three-dimensional reconstructive investigation is not possible in routine investigations or even in scientific research studies. b) When we find cancer cells in the vasa afferentia or efferentia or in the sinus in one node, in our experience metastases with solid cancer growth can already have developed in the next (second) node. c) Immunohistochemical node investigation and RT-PCR needs special knowledge and experiences. It is possible that sinus histiocytes or macrophages in the parenchyma of the nodes phagocytose residual material after apoptosis or necrosis derived from cancer cells of the primary via lymphatics brought into the node or within the lymph node masking the macrophages with positive cytokeratin reaction (ªghost cellsº) or giving an uncontrolled positive RT-PCR reaction
2. a) Many recent investigations show a worse outcome in collectives with micrometastases than in collectives with absolute node scores of N0. b) Many statistical evaluations showing negative correlations are not conclusive, because the number of cases investigated has often been too low to document differences in the incipient stages of metastasis. The following scheme has been presented: N0 No cancer cells detectable on routine H-E stainings N0i+ Isolated cancer cells found in immunohistochemical investigations N0(mol+) RT-PCR positive This scheme, also based partly on immunohistochemical and molecular biological investigations, may be helpful in evaluation programs for clinical studies aimed at gathering further scientific information, but it does not help in decisions on whether elective lymphadenectomy should be performed following the SLN concept, or extensive lymphadenectomy of the whole lymphatic basin. Therefore, in daily clinical practice the benefit of this scheme is doubtful, and with reference to points 1 a±c it leads to misunderstandings. Especially in RT-PCR investigations, it is never safe to conclude that the substrate of positive results corresponds with vital cancer cells within the node. All N0, N0i+ and N0 (mol+) scores document at least a primarily N0 state, and discussion will arise in the treatment of individual case as to whether or not surgical clearance of the whole basin (e.g., axillary revision in breast cancer cases) is necessary. Therefore, in summary, most pathologists and their surgical colleagues decide on routine performance of axillary revision (levels I and II) in all cases with positive nodes in which cancer cells have been found by H-E staining and immunohistochemistry.
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Chapter 18 ªMicrometastasisº Versus ªMicroinvolvementº Table 1. Significance of micrometastases in breast cancer for survival Author
Year
Detection method
No. of cases
Percentage of micrometastases
Prognostic relevance
Haagensen
1971
Histology
175
12
+
Fisher et al.
1978
Histology
78
24
+
Friedmann et al.
1988
Histology
456
9
+
Neville et al.
1990
Histology
921
9
+
Chen et al.
1991
Immunohistology
80
29
+
Hainsworth et al.
1993
Immunohistology
343
12
+
Wilkinson et al.
1982
Immunohistology
525
17
±
Noel et al.
1991
Immunohistology
168
18
±
The question of whether micrometastases are of significance for survival in breast cancer cases has been frequently discussed. It is clear that the relevance cannot be striking, because initial lymph node involvement is obviously in its initial stages and therefore still limited in most cases. In a long series of investigations the significance of micrometastasis for prognosis has been documented by various investigators. These investigations were partly based on histology, and later on additional immunohistochemical analysis (Table 1). In the series of Wilkinson et al. 1982 and Noel et al. 1991, however, no prognostic relevance could be certified. The astonishing point that in the investigations published by Fellbaum et al. (1997), for instance, the proportion of gastric cancer cases with lymph node involvement was extremely high (90%), and the significance of these extreme results for the gastrointestinal sentinel node concept will not be discussed in depth at this point. It might be that 'such rates can be reached in undifferentiated (ªlymphoid cell likeº) cancer types, but not in more or less differentiated adenocarcinomas.' Nonetheless, since in all cancer types (breast, lung, gastrointestinal tract) higher rates of regional lymph node involvement are observed in immuno-
histochemical analysis of serial sections, we cannot avoid the conclusion that in every case treated according to the SLN concept both immunohistochemical analysis of the SLN(s) and H-E staining are conditiones sine quibus non. The results showing that the rates of micrometastasis are higher in immunohistochemically stained serial sections than in routine simple H-E evaluation are already familiar. With regard to the differences dealt with in the literature, however, it seems that when the differences between H-E stainings and immunohistochemically based results are very wide, the HEstained sections have not been intensively enough evaluated. The rates of positive node in local basins are summarized for most of the frequent solid cancers in Table 2, which is taken from Hermanek et al. (1997). In conclusion, with regard to the existing danger that nodes downstream of the sentinel node might be involved in cases in which the diagnosis reached on examination of a sentinel node is N0i+ (for definition see above), in cases with immunohistochemically invested nodes this result should be accepted as an indication for revision of the entire basin (e.g., axillary revision in the case of breast cancer cases).
References Table 2. Detection of cancer cells by immunohistochemical analyses in primarily ªtumor-freeº regional lymph nodes. (After Hermanek et al. 1997) Primaries
Regional nodes immunohistochemically positive (%)
Reference
Breast cancer
15%
Wells et al. (1984) Stosiek et al. (1996)
Gastric cancer
90%
Fellbaum et al. (1997)
Colorectal cancer
25±30%
Greenson et al. (1994) Jeffers et al. (1994)
Prostate cancer
45%
Edelstein et al. (1996)
Non-small-cell lung cancer
15%
Passlick et al. (1996)
Ductal pancreatic cancer
75%
Hosch et al. (1997)
Esophageal cancer
50%
Izbicki et al. (1997)
References Chen ZL, Wen DR, Coulson WF, Giuliano AE, Cochran AJ (1991) Occult metastases in the axillary lymph nodes of patients with breast cancer node negative by clinical and histologic examination and conventional histology. Dis Markers 9:239±248 Edelstein RA, Zietman AL, De las Morenas A, Krane RJ, Babayan RK, Dallow KC, Traish A, Moreland RP (1996) Implications of prostate micrometastasis in pelvic lymph nodes: an archival tissue study. Urology 47:370±375 Fellbaum C, Kestlmeier R, Busch R, Bættcher K, Siewert JR, Hæfler H (1997) Prognostic relevance of microcarcinosis (ªmicroinvolvementº) in lymph nodes in gastric cancer. In: Siewert JR, Roder JD (eds) Progress in gastric cancer research. Monduzzi, Bologna, pp 235±236 Fisher ER, Swamidoss S, Lee CH, Rockette H, Redmond C, Fisher B (1978) Detection and significance of occult axillary node metastases in patients with invasive breast cancer. Cancer 42:2025±2031 Friedmann S, Bertin H, Mauriesse H, Benchabat A, Genin J, Sarazzin D, Contesso G (1988) Importance of tumor cells in axillary node sinus margins (ªclandestineº metastases) discovered by serial sectioning in operable breast carcinoma. Acta Oncol 27:483±487
Greenson JK, Isenhart CE, Rice R, Mojzisik C, Houchens D, Martins EW Jr (1994) Identification of occult micrometastasis in pericolic lymph nodes of Dukes B colorectal cancer patients using monoclonal antibodies against cytokeratin and CD49. Cancer 73:463±569 Haagensen CD (1971) Diseases of the breast. Saunders, Philadelphia London Toronto Hainsworth PJ, Tjandra JJ, Stillwell RG, Machet D, Henderson MA, Bennett RC (1993) Detection and significance of occult metastases in node-negative breast cancer. Br J Surg 80:459±463 Hermanek P, Hutter RVP, Sobin LH, Wittekind C (1999) Classification of isolated (disseminated, circulating) tumor cells and micrometastasis. Cancer 86:2668±2673 Hosch STB, Knoefeld WT, Metz S, Stoecklein N, Niendorf A, Broelsch CE, Izbicki JR (1997) Early lymphatic tumor cells dissemination in pancreatic cancer: frequency and prognostic significance. Pancreas 15:154±159 Izbicki JR, Hosch STB, Pichlmeier U, Rehders A, Busch C, Niendorf A, Passlick B, Broelsch CE, Pantel K (1997) Prognostic value of immunohistochemically identifiable tumor cells in lymph nodes with completely resected oesophageal cancer. N Engl J Med 337:1188±1194 Jeffers MD, O'Dowd GNI, Mulcahy H, Stagg M, O'Donoghue DP, Toner M (1994) The prognostic significance of immunohistochemically detected lymph node micrometastases in colorectal carcinoma. J Pathol 172:183±187 Neville AM for the International (Ludwig) Breast Cancer Study Group Writing Committee: Bettelheim R, Price KN, Gelber RD, Davis BW, Castiglione M, Goldhirsch A, Neville AM (1990) Prognostic importance of occult axillary lymph node micrometastasis from breast cancers. Lancet 335:1565±1568 Noel P, Chauvin F, Minot JBP, Catimel G, Hesch M, Grollas M (1991) Prognostic value of lymph node micrometastases detected by immunohistochemistry. Ann Pathol 11:309±315 Passlick B, Izbicki JR, Kubuschok B, Thetter O, Pantel K (1996) Detection of disseminated lung cancer cells in lymph nodes: impact on staging and prognosis. Am Thorac Surg 61:177±183 Stosiek P, Gerber B, Kasper M (1996) Zur prognostischen Bedeutung von Mikrometastasen in axillåren Lymphknoten beim Mammacarcinom. Pathologe 17:433±439 Wells CA, Heryet A, Brochier J, Gatter KC, Mason DY (1984) The immunocytochemical detection of axillary micrometastases in breast cancer. Br J Cancer 50:193± 197 Wilkinson EJ, Hause LL, Hoffmann RG, Kuzma JF, Rothwell DJ, Donegan WL, Clowey LJ, Almagro UA, Choi H, Rimm AA (1982) Occult axillary lymph node metastases in invasive breast carcinoma: characteristics of the primary tumor and significance of the metastases. Pathol Annu 17:67±91 Wittekind C (2001) Diagnosis and staging of lymph node metastasis: morphologic and nonmorphologic methods of detection and principles of classification. In: Munz DL (ed) International forum of nuclear medicine. Zuckschwerdt, Munich, pp 26±34
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Chapter 19
Preoperative Axillary Lymph Node Diagnosis Using Ultrasmall Particles of Iron Oxide Combined with MRT
19
S. H. Heywang-Kæbrunner, C. Stets, J. Buchmann, C. Lautenschlåger, F. Gilbert, F. Wallis, 0A. Hupperts, M. Reiser, A. Schauer
In basic comparative studies (Mohr and Weiûleder 1996), lymphotropic iron oxide compounds with storage in sinus histiocytes of lymph nodes and gadolinium (iD) DTPA-PGM were tested; the results indicated that both categories of compounds improved the differential diagnosis between tumor-free and cancer-infiltrated lymph nodes, irrespective of size. While iron oxides are already in uses in clinical studies, GDDTPA-PGM is still being evaluated in preclinical study programs. After various experimental studies on different sites of primaries, a first stringently statistically controlled study has been now performed to evaluate USPIO in the diagnosis in breast cancer patients (Stets et al. 2000, 2002). Qualitative and quantitative parameters were evaluated in axillary lymph nodes by USPIO contrast agent and MR. The studies were planned on the basis of experience in different lymph node basins, referred to other tumor categories. Data from two scientific centers taking part in a multicenter trial were obtained (Heywang-Kæbrunner et al. 2002). Each of the diagnostic centers used the same techniques. This made it possible to pool the cases. It was shown that cancer-infiltrated node areas with destruction of the pre-existent node architecture were characterized by markedly less iron oxide storage than elsewhere, caused by the loss of the so-called sinus histiocytes that are active in
phagocytosis. According to experiences already available, the presence of USPIO in preserved lymph node structures can be detected with optimal accuracy by MRI. Iron oxide acts as a paramagnetic agent and causes signal drop out, particularly in T2-weighted and T2-sequences. In the two radiodiagnostic institutes taking part in the study, 21 patients were collected for the planned investigations. The inclusion criteria were breast cancer and scheduled axillary dissection after informed consent. Standardized MR without contrast agent (plain MRI) was followed by intravenous administration of 2.6 mg USPIO/kg bodyweight (30-min infusion with filtration). Postcontrast MRI (using the same pulse sequences as for the precontrast studies) was performed 24±36 h after USPIO administration. The en bloc axillary specimens were precisely marked for comparative studies with the imaging analyses. Deviations from standard axillary dissection were only allowed when suggestive lymph nodes were located outside the anticipated surgical field of axillary exploration. There was a high drop-out rate among patients in the study, for various reasons. In the preliminary study only 9 cases (52 lymph nodes) could be evaluable. Table 1 summarizes the results of lymph node evaluation by two radiologists and the investigating site pathologists.
Table 1. Histology and size of the 52 lymph nodes used in the statistical analysis Maximum transverse diameter of the lymph nodes Size category Histology
All
< 5 mm
5 mm to < 10 mm
Benign
14
10
Malignant
10
8
24
18
10 mm to < 15 mm
>15 mm
All
1
25
5
4
27
5
5
52
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Chapter 19 Preoperative Axillary Lymph Node Diagnosis Using Ultrasmall Particles of Iron Oxide Combined with MRT
The evaluation procedure that gave the best results for combined pre- and postcontrast MRI was based on the following parameters: · Transverse lymph node diameter £ 6 mm rather than > 6 mm · Visual assessment of signal change on T1 SE, T2 FSE and PSIF · Quantitative ratios of signal change SCR to T1 SE, T2 FSE, and PSIF. On the basis of these parameters, 88% of the lymph nodes were correctly classified with a sensitivity of 85% and a specificity of 92%. Finally, an accuracy of 87% was obtained when transverse diameter, SCR T2 FSE and visual assessment of signal change on T2 FSE were used as classification parameters. Among these single parameters, only the transverse diameter and the visual assessment of signal change on T2FSE proved to be significant discriminators of benign versus malignant lymph nodes (P = 0.013 and P = 0.007, respectively). The most suggestive area of the lymph nodes was determined visually. The procedures for determination of these areas were as follows: Comparison of pre- and postcontrast scans revealed differences. When no suspicious areas could be detected, areas showing either no change or signal intensification were chosen. If neither of these applied, the areas of the lymph node with the widest transverse diameter were chosen. For evaluation of significance of pre- and postcontrast results areas with iso- or hyperintense signal (referred to muscle) on T2 FSE were searched for. If this was not successful, areas with the same characteristics were searched for on FISP. The signal intensity on the postcontrast T2 FSE scans and the change between pre- and postcontrast T1 SE, T2 FSE and the FISP was recorded as a signal increase, no change, or a signal decrease. Quantitative evaluations were performed in regions of interest (ROIs): · Measurement of the representative ROI, care being taken that ROIs were included only on tissue type · As a control, a second ROI sited in the fatty tissue around the lymph node was examined, in
order to normalize inhomogeneous reception of the surface coil and differences in the adjustment of the MR unit between the examinations. The following ratios were calculated: · Signal intensity ratio (SIR) in the precontrast study: ± SIR pre+=(SIR lymph node) pre · SIR on the postcontrast study: ± SIR post++=(SI lymph node) post ± (SI adjacent fat) post The histopathological examination was based on systematic work-up of the entire dissection bloc in one site. In the other site the nodal sampling was performed by the surgeon, giving the exact position of the node to the pathologist. The following features of each lymph node were included in the statistical evaluation in an SPSS for Windows, vers. 9.0 database: Precontrast: homogeneity, SIR T1 SE, SIR T2 FSE, SIR FISP visual assessment of signal intensity Postcontrast: homogeneity SIR T1 SE, SIR T2 FSE, SIR FISP, visual assessment of signal on T2 FSE The histopathological classification of each single lymph node as · Completely involved · Partly involved · Not involved The data were entered in a logistic regression analysis. The best results were obtained with the following parameters: · Transverse lymph node diameter (£ 6 mm rather than >6 mm) · Visual assessment of signal change on T1 SE, T2 FSE and PSIF · Quantitative ratios concerning signal change SCR on T1 SE, T2 FSE, and PSIF On the basis of these parameters 88% of the lymph nodes were correctly classified (sensitivity 85%, specificity 92%). By backward selection the following parameters were eliminated: · SCR of PSIF · SCR of T1SE and visual assessment of signal change on T1-SE and on PSIF
Evaluation of Value
When these conditions were applied an accuracy of 87% was obtained when transverse diameter SCR T2 FSE and visual assessment of signal change on T2 FSE were used as classification parameters. Among these single parameters only the transverse diameter and the visual assessment of signal change on T2 FSE proved to be significant discriminators of benign versus malignant lymph nodes (P = 0.013 and P = 0.007, respectively). Quantitative assessment of signal change on FSE proved not to be a statistically significant discriminator (P=0.14). Therefore, it was possible to eliminate this third parameter with no deterioration in the results. For the postcontrast study the following parameters were available: · Transverse diameter · Homogeneity on the postcontrast images · SIR T1 SE · SIR T2 FSE · SIR FISP · Visual assessment of the signal intensity on T2 FSE In these evaluations the only parameter that proved statistically significant was the transverse diameter (P = 0.002). When this parameter was used an accuracy of 75% was obtained (sensitivity 56%, specificity 96%). Among these parameters, SIR PSIF performed best, but its discrimination capability did not reach statistical significance (P = 0.2). In the precontrast study, too, only the transverse lymph node diameter proved to have a statistically significant discrimination capability (P = 0.003). When these parameters were used a maximum accuracy of 75% was reached (sensitivity 63%, specificity 88%).
Evaluation of Value The purpose of this first study evaluating the use of USPIO in MRI was to obtain quantitative and qualitative, statistically underpinned parameters which could support standardization of interpretation. In order to allow evaluation on the basis of the lymph nodes only those nodes were to be evaluated for which histopathological investigations were also available.
There were two points hampering results in the comparative studies that can be incorporated into routine usage: · Very small lymph nodes, which are sometimes the only ones showing cancer infiltration, cannot be detected. · Some of the lymph nodes are packed very close together or overlapping. However, with the current technical conditions, the investigators regard the obtained results as ªfairly representativeº of most of the axillary lymph nodes in the eligible patients. The study is not ªpatient based.º However, at least a sufficient number of lymph nodes of all sizes was included in the evaluation. Therefore, the results must be accepted as a ªtest setº in order to determine the value of the various potential diagnostic parameters and to find thresholds for important parameters and the optimum effective combination of these parameters. The following points are of interest for further approaches: · Only a few parameters are necessary for optimal accuracy. · Quantitative evaluation of the signal change (even on FSE) is inferior to visceral assessment of the signal change and therefore not even necessary. · Lymph node homogeneity seems not to be an important discriminator in any type of study (precontrast, postcontrast or combined). · A clear advantage over plain MR in terms of accuracy, especially concerning sensitivity, is obvious (12%). · Comparison of post- and precontrast study results showed increased specificity at cost of sensitivity. Thus, overall accuracy was not improved. Overall, with all facts taken together, in cases in which imaging detects macroscopic lymph node involvement with sufficiently high specificity immediate axillary dissection could be chosen as the more appropriate, more cost-effective and less time-consuming method. Since the combined analyses provide good specificity and allow further development, the combination may become a valuable adjunct to support diagnostic and surgical strategies at an early stage. In a further preliminary study of the two sites carried out by the same research groups the same
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pulse sequences and field strength as in the precursor study (pre- and postcontrast MR) were used. T1-weighted and T2-weighted SE and 3D PSIF obtained in 88 lymph nodes (39 benign, 49 malignant) in 14 patients were histopathologically correlated and evaluated visually and quantitatively in a double-blind controlled investigation. Combinations of diagnostic parameters were compared and evaluated in logistic regression analysis. The best accuracy (85%: sensitivity 77%, specificity 92%) was obtained with transverse lymph node diameter (> 6 mm): visual assessment and signal intensity ratios (SI lymph node/SI fat) of T2-weighted SE and 3D-PSIF before and after CM and the (SI ratio after CM/SI ratio before CM). Without quantitative parameters accuracy was 81%. Precontrast data alone yielded 59% accuracy, postcontrast data alone 62%. The authors summarize from these data that both pre- and postcontrast scans are needed. In addition, CM improves accuracy significantly and quantitative evaluation improves accuracy slightly over visual evaluation. In a phase III study carried out by Taupitz et al. (1999) of the aforementioned international research group, Sinerem given as an i.v.-injected contrast medium for MRI was tested for lymph node imaging in patients with suspected breast cancer. In 35 patients breast surgery and axillary lymphadenectomy were performed within 10 days of each other. Plain MRI examination of the axilla was performed before an i.v. Sinerem infusion. The contrast medium was infused at a dosage of 2.6 mg Fe/kg within 30 min. Patients had a second comparative MRI within 24±36 h after the infusion (Taupitz et al. 1999). MRI was performed at 1.0 or 1.5 T. All patients were examined with three sequences before and after Sinerem application: Axial T1-weighted Se, axial T2-weighted SE or T2-weighted fast SE, axial or coronal conventional T2-weighted GRE or T2-weighted 3D-PSIF. Lymph node assessment was based on · Lymph node size for plain MRI · Signal variations for Sinerem-enhanced MRI. The results were correlated with histopathological findings. The preliminary results recorded by the group are summarized in Table 2. For all patients, with plain MRI there were 7/9 true-positive and 7/5 false-positive results, while with Sinerem-enhanced
Table 2. Results when Sinerem by i.v. injection as contrast medium for MRI was tested for lymph node imaging in patients with suspected breast cancer (Taupitz et al. 1999)
a
Lymph node detection according to MRI and after Sinerem infusion
Plain MRI
After Sinerem infusion
Lymph node detection according to MRI and after Sinerem infusion
N=234 lymph nodes
N=244 lymph nodes
Total removed by surgery
N=501 a lymph nodes
Possible comparison of lymph nodes MRI/ histology
N=144 lymph nodes
Lymph nodes not detected were mostly smaller than 9 mm
MRI there were 12/15 true-negative and 1/4 falsenegative results. When a lymph node was considered nonmetastatic (short axis < 10 mm) on plain MRI or showing a signal decrease in at least one sequence on Sinerem¾ enhanced MRI, plain MRI and Sinerem enhanced MRI showed sensitivity of 50% and 64% and specificity of 75% and 94%, for the detection of lymph node involvement, respectively. The conclusion drawn from this phase III study agrees with the judgment already presented in the main chapter insofar as Sinerem-enhanced MRI performs better than MRI alone, according to size criteria alone, in identification of metastatic lymph node involvement. This seems to be an important development as far as the four imaging-systems are concerned, which can never totally exclude metastatic processes. This clear statement can be given without any restrictions, because even with all our experience it is difficult to exclude metastatic processes. Such early metastatic processes can be detected by combined histological and immunohistochemical microscopically based examinations in serial sectioning the nodes. But in cases, in which Sinerem oxide labeling indicates already a metastatic node process already preoperatively decision for total axilla revision (level I and II) can be made. In addition Sinerem labeling in optimal performance could also help to detect parasternal lymph node involvement, which is in relation to additional parameters important for decision making of adjuvant therapeutic regimens.
References
Lymph Node Staging by Means of USPIO in Lung Cancer Patients A. Schauer
In a first multicenter clinical trial of USPIO in the evaluation of mediastinal lymph nodes in patients with primary non-small-cell lung cancer, Nguyen et al. (1999) tested 18 patients with primary lung malignancies and suspected regional lymph node metastases. After the initial performance of MR sequences, each patient was evaluated for the number and location of the mediastinal lymph nodes, their homogeneity based on the nodal signal, and possible change of the MR signal postcontrast application. The lung resections and sampling of the MRidentified nodes or node groups were performed 1±35 days after contrast MR imaging. There were 27 lymph nodes or node groups available for histopathological correlation. The combined MR imaging had a sensitivity of 92% and a specificity of 80% in confirming mediastinal lymph node(s) involvement. The authors conclude that combined MR imaging can support mediastinal lymph node staging.
Such preoperative evaluations and the knowledge gathered from them can support decision making about surgical treatment even in the treatment planning phase and possibly also in the planning of additional adjuvant therapeutic efforts.
References Mohr U, Weiûleder R (1996) Lymph node diagnosis with imaging methods. An overview with special reference to recent developments in the area of contrast media. Z Lymphol 20:15±20 Nguyen BC, Stanford W, Thompson BH, Rossi NP, Kernstine KH, Kern JA, Robinson RA, Amarosa JK, Mammone JF, Outwater EK (1999) Multicenter clinical trial of ultra small superparamagnetic iron oxide in the evaluation of mediastinal lymph nodes in patients with primary lung cancer. J Magn Reson Imaging 10:468±473 Stets C, Wallis F, Pickuth D, Lautenschlåger C, Murray AD, Heywang-Kæbrunner SH (2000) Iron oxide enhanced intravenous MR-lymphography in breast cancer: comparative value of precontrast, postcontrast and combined evaluation (abstract). RSNA, December 2000, abs 878 Stets C, Brandt S, Wallis F, Buchmann J, Gilbert FJ, Heywang-Kæbrunner SH (2002) Axillary lymph node metastasis: a statistical analysis of various parameters in MR with USPIO. J Magn Reson Imaging 16(1):60±68 Taupitz M, Wallis F, Heywang-Kæbrunner SH, Thibault F, Gilles R, Tardivon AA (1999) Axillary lymph node MR imaging with Sinerem in patients with suspected breast cancer (abstract). RSNA, December 1999, abs 1172
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Chapter 20
New Strategies and Devices for Combined Radiological and Histological Cancer Diagnosis ± Exclusion or Confirmation
The simplest system that is only minimally invasive is ultrasound-guided or mammographically controlled fine-needle aspiration cytology (FNAC), which is very successful in highly experienced hands. In the past few years, however, international companies such as Fischer-Techniques, Siemens
and others have developed new, electronically guided machines for taking core or vacuum biopsies from tiny suspicious foci; these are steered mammographically or by magnetic resonance tomography (MRT).
Fig. 1. The five important steps necessary for the extraction of one biopsy cylinder. Rotation through up to 360 8 makes sampling of many cylinders possible
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The system to be used for diagnosis in any individual case must be selected from the systems presented with due consideration for the necessity of avoiding any damage to the structure of the cancer. This means not increasing the pressure within the cancer tissue structures and not using large trocars in cases with more extended cancers, as these can open veins directly within the cancer formation. It would be depressing in the extreme if a patient's life expectancy were shortened by early iatrogenically induced hematogenous metastasis. Following an explanation of how to obtain a definite and histologically confirmed diagnosis of ªbreast cancerº without surgical intervention, the current minimally invasive systems will now be briefly presented.
Fig. 2 a, b. Fischer biopsy table. a Overview of the table top, showing the cut-out through which the breast can depend for puncture. The puncture device is fixed below the cut-
Commercially Available Biopsy Systems Digital Stereotactic Biopsy System (Unit) Developed by Fischer-Imaging, USA In cases with low-grade suspicious lesions (e.g., BI-RADS III: risk 3±5%), the vacuum biopsy method is very useful for ruling out cancer or, in rare cases, for confirming preneoplastic stages (e.g., atypical ductal hyperplasia, or ADH) or neoplastic noninvasive or only minimally invasive stages (e.g., DCIS without or with early stromal invasion or LCIS). When radiodiagnosis indicates high suspicion (e.g., BI-RADS IV: risk = 40%; see also chapter 21) the vacuum biopsy should not be used, especially when the lesion seems to be extended. The reasons for the risk of spreading cancer by manipulation have already been explained above and are accepted in many radiodiagnostic centers.
out ready for direct action. b Electronic control system for exact guidance of the puncture cannula to the focus of interest
Commercially Available Biopsy Systems
When the region of interest containing suspicious microcalcifications cannot be removed it is necessary to consider the possibilities that they are (a) larger foci of calcified strongly sclerosing adenosis or (b) calcified, long-existing and strongly sclerosed fibroadenomas, neither of which can be sucked up in parts into the cannula. The explanation for this is that when highly sclerosed, larger lesions cannot be sucked into the cannula in toto, it is also not possible for segments of them to be sucked through the window of the cannula, because of the low deforming capacity and high cohesion of the whole lesion, The biopsy device is demonstrated in Figs. 1±4. Figure 1 demonstrates the principles of how cylinders of suspicious tissue can be sucked into the lumen and cut off from the surrounding tissue structures under vacuum conditions. Step-for-step rotation through up to 360 8 and repeated cutting makes it possible to excise a full-circle block and collect approximately 10±15 cylinders. This new principle was born out of the development of the Fischer device. It uses the BIO PSYS puncture and cutting system.
Figure 2a illustrates the whole of the Fischer system, with the table on which the patient is lying prone. The breast is hanging through a cut-out positioned close to the vacuum biopsy cannula. In Fig. 2b the electronic control device is seen: this allows three-dimensional guidance of the puncture needle to the lesion recognized as suspicious by mammography or MRT. In Fig. 3 a, b the important components of the syringe-like puncture system are illustrated, especially the thumb-wheel, which can be rotated by hand, and the high-speed cutting knob for handling the excision of tissue cylinders. Figure 4 a±e illustrates the different steps in the excision process. In the particular case the lesion was found to be benign. The same principles underlie the Ethicon device. Both Ethicon and Fischer have now also developed a new strategy, which allows access to variously located lesions from any point on the entire circumference of the breast, which means it is possible to reach any lesion from the point where the distance from the skin surface is the shortest.
Fig. 3 a, b. Detailed view of the BIO PSYS puncture system in isolation. Note thumb-wheel, which is used to rotate the needle, and the cutter knob for handling the high-speed cutter
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Chapter 20 New Strategies and Devices for Combined Radiological and Histological Cancer Diagnosis Fig. 4 a±e. Sequential steps in vacuum biopsy using the Fischer technique, which in the case illustrated culminated in diagnosis of a tiny benign calcified fibroadenoma, a result making further surgical intervention unnecessary a Pre-biopsy mammogram b thorough biopsy of calcifications c deployment of MicroMark clip through probe d radiograph of specimen e post-biopsy mammogram
Commercially Available Biopsy Systems
Fig. 5. The Ethicon device. On the left, parts of the table are seen, with the cut-out for the dependent breast. The relatable puncture machine assembled with the swiveling plat-
form is seen connected with the table. On the right, the connected movable workstation is shown
Figure 5 gives an overview of the Ethicon device, demonstrating the possibility of moving the puncture machine around the entire breast dependent through the cut-out (360 8). This new development allows the suspicious lesion to be reached by the shortest distance from the skin surface of the breast. This is important, because it means a substantial reduction in post-puncture bleeding into the puncture channel and in the danger that infection might develop and spread around into the neighbouring tissue structures from infected blood coagula within the channel. Figure 6 is another illustraion of the BIO PSYS puncture machine, showing the inscriptions on the thumb-wheel more clearly; these are needed for handling the cutting system. In Figs. 7±9 the classic procedures of three-dimensional marking of the lesion (Fig. 7), postpuncture radiographic monitoring to check that the lesion is fully excised (Fig. 8), and additional radiographic control of the biopsies (Fig. 9) are illustrated. In the case of low-risk lesions the core needle biopsy procedure can also be used for analysis instead of the vacuum biopsy device. This method allows screening punctures of a circumscribed sus-
picious area with collection of biopsy material for radiographic control and subsequent histopathological examination (see Fig. 9 a). Benign intraductal proliferations such as papilloma, ADH, DCIS and early cancer with incipient stromal invasion can be diagnosed in this biopsy material (Fig. 9 b). In addition to the Fischer and Ethicon systems, a similar device has been developed by the Siemens Company in Germany: the Mammomat 3000. It is combined with Opdima digital imaging and sterotactic biopsy (Fig. 10). Figure 10 shows an overview of the Siemens Mammomat 3000 device. The system can be used with the patient standing or lying down. Figure 11 shows the Mammomat 3000 together with the workstation. The system is seen in use with a standing patient in Fig. 12 a and with a patient in the lying position in Fig. 12 b. Because of its versatility in use the Siemens device allows punctures from almost all directions around almost the whole of the circumference. This is an advantage over other systems, which can be adjusted only in the perpendicular direction. In addition, the Mammomat 3000 Nova gives optimal imaging quality and prevents too-strong compression of the breast, which is painful for patients.
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Fig. 6. Two views of the BIO PSYS vacuum puncture device, showing the possibility for cutting with safe equipment that can easily be handled with one hand
Fig. 7. Exact three-dimensional marking of a suspicious lesion. Note the black marked squares
Fig. 8. Post-puncture marking of the excision area as a control for total excision of the microcalcified lesion by the rotating puncture system
Commercially Available Biopsy Systems Fig. 9. a Radiographic examination of the biopsy cylinders. The suspicious calcified areas have been totally excised and are located in the central parts of the cylinders. b Radiographically detected, circumscribed microcalcifications in a strongly delineated area; core needle biopsies distributed over this area and subsequent histopathological examination of the paraffin-embedded cylinders allow an overview of the suspect area. c The most important possible findings are demonstrated. Total surgical excision for histopathological examination is indicated in all nonbenign lesions
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Chapter 20 New Strategies and Devices for Combined Radiological and Histological Cancer Diagnosis Fig. 10. Overview of the Siemens Mammomat 3000 (Siemens, Germany). This system can be used with the patient in a standing or a lying position
Fig. 11. The Siemens Mammomat 3000 (Siemens, Germany), together with the workstation
Minimally Invasive Excision Biopsy Using the ABBI Device Fig. 12. a Mammomat 3000 Nova (Siemens), here with a standing patient, allows guided puncture from medial to lateral and in diagonal directions. b The same system in use in a patient in a lying position; the puncture is carried out from a lateral approach
Figure 13 a, b demonstrates the control system, which allows the optimal degree of compression to be achieved in each case. The various elements of the Siemens Mammotest Pluss system and the procedures they allow are summarized in Table 1.
of its circumference of 360 8. Figure 14 gives an overview of the device set up and ready for use, while Figs. 15 and 16 show some of the components in more detail.
Lorad MultiCare
Minimally Invasive Excision Biopsy Using the ABBI Device
The Lorad MultiCare system is one of the newly developed devices designed to make it possible to reach suspicious foci by the shortest route through the parenchyma of the breast. The table has a 180 8 curve, which allows positioning of the breast in such a way as to permit access from the whole
Whereas vacuum biopsy devices (Fischer USA, Ethicon, Norderstedt, Germany) should only be used when the level of suspicion is low (as discussed above), the ABBI system (Figs. 17±21) has a different goal. This is to substitute for surgical biopsies in cases with small areas that have
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Chapter 20 New Strategies and Devices for Combined Radiological and Histological Cancer Diagnosis Fig. 13 a±c. a Photograph and b schematic of devices for optimal adjustment of breast compression. c Compression analysis curves
Fig. 14. Overview of the components of the Lorad MultiCare system set up and ready for use
Minimally Invasive Excision Biopsy Using the ABBI Device
Fig. 15. Computed guided syringe system used for puncture in the Lorad MultiCare device
Table 1. Mammotest Pluss: items of equipment and procedures they allow Equipment
Purpose/advantage
Fiberoptic CCD camera
For digital pictures with high dissolution (10 Ip/ mm), high contrast, and low irradiation dosage
Data indication at pressure-sensitive touch display at autoguide
For user-friendly operating
Mount for Mammotome vacuum biopsy system and various other adapters for biopsy systems
To allow performance of wire labeling as well as fine-needle aspiration TruCut, large core, and vacuum biopsies
Modern digital technology of Mammovision Plus Computer systems
For pictures of highest quality, with possibility of demonstrating microcalcifications and tiny suggestive lesions in tissue
Bipolar coordination (rotation and elevation)
Allows positioning of the biopsy system in such a way as to make it possible to biopsy lesions near the thoracic wall
aroused high-grade suspicion of a small DCIS focus or cancers with minimal extent (a few millimeters: e.g., microcarcinomas £ 5 mm). Overviews of the device and the puncture system can be seen in Figs. 17 and 18. Figure 17 is an overview of the entire ABBI device, showing the plate for the patient to lie on, which can be used in two directions to allow access to the breast from its whole circumference (360 8). In Fig. 18 the puncture device is shown in isolation. Note the localization needle, the cannula blade for cutting the tissue cylinder, and the levers
Fig. 16. Demonstration of the options for angular adjustment: ±15 8/0 8/+15 8
to effect knife return and withdrawal of the tissue specimen. When the goal is the one mentioned above the following reflections are relevant: · Excision biopsies 5±20 mm in diameter in one part are possible (Fig. 19), which means that tiny foci of ADH, DCIS, and small invasive cancers (microcarcinomas) can be totally removed en bloc, possibly with tumor-free margins, when the largest diameter is used. · In the case of DCIS or microcarcinoma consecutive sentinel node labeling by subdermal injection of 99mTc-nanocolloid is possible. It is clear that in the case of malignancy a second local wide excision must be performed in the course of sentinel node excision when it is not possible to confirm that the primary lesion has been removed with tumor-free margins. Figure 19 summarizes the different diameters of the instruments available, and the order code numbers are also given. When the ABBI system is used the following steps must be followed. · The patient lies on the ABBI table, which is positioned in the direction best allowing 360 8 access to the breast (Fig. 20 a, b).
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Fig. 17. Overview of the ABBI device, showing the plate on which the patient lies for removal of the biopsy specimens; the plate can be positioned in two directions to allow access to the breast from all round the cirumference (360 8)
Fig. 18. The puncture device in isolation. Note the localization needle, the cannula blade for cutting the tissue cylinder at the end, and the special parts designed to effect knife return and withdrawal of the sample
· The breast is positioned in the opening and compressed, with the targeted tissue centered within the biopsy window. · Digital stereotactic images are taken and the lesion's coordinates are calculated and transferred to the ABBI biopsy stage (Fig. 21).
· A motorized stage automatically positions the ABBI device. The site selected for the incision is prepared, and a small incision is made. · The needle is inserted and guided into the tissue in which malignancy is suspected. The ABBI cannula is advanced into the breast to excise the tissue sample.
Background to Presentation of the Various Devices
· Complete removal of suggestive tissue specimen in small biopsies is possible. · Exact imaging of area of interest and tissue excision accurate to 1 mm are possible (Fig. 21). · Orientation to excised specimen is possible. · The treatment period can be shorter.
Fig. 19. Summary of the different diameters of the instruments available. The corresponding order code numbers are: 080001 ABBI* system, 5-mm instrument; 080002 ABBI* system, 10-mm instrument; 080003 ABBI* system, 15-mm instrument; 080004 ABBI* system, 20-mm instrument
The instrument (Fig. 21) utilizes a cartesian XYZ coordinate system coupled with computer controlled targeting for automatic positioning of the biopsy device to give accurate localization of the lesion to Ô1 mm. Advantages for the patient are: · Better cosmetic results owing to micro-incisions. · Lower risk of scar formation. · Less fear about a surgical operation. · Lesser psychological and emotional trauma. · Possibility of physical activity immediately after the procedure, as it is done with local anesthesia.
Background to Presentation of the Various Devices
Fig. 20. a The ABBI device in use; the breast can be fixed under the table for the puncture-biopsy. b The segment of the device with the cut-out for the dependent breast
· Once the distal portion of the specimen has been cut through, the cannula and the biopsy sample are removed from the breast together. The specimen is evaluated, and the incision is inspected and closed with a few stitches. The ABBI device has various advantages in diagnosis: · No admission to a ward is necessary. · No general anesthesia is necessary; local anesthesia is enough.
The precise goals of the devices presented and briefly described above, which are used internationally to rule out or confirm precancerous or cancerous lesions, can be summarized as follows: · To try to analyze the spectra of indications for usage of the various devices. · To define useful applications for tiny lesions using the microinvasive radiodiagnostic instruments as carefully as possible and to differentiate them from necessary primary surgical interventions for cancer diagnosis in more extended lesions. · To answer the question of using the systems discussed before sentinel lymph node (SLN) labeling takes place. The last question can be answered as follows: subdermal injection for SLN labeling is possible in DCIS and invasive cancers when the diagnosis has been made by means of one of the systems described and no complications such as bleeding and infections have occurred. When larger biopsy specimens have been excised (using the ABBI device), peritumoral injections of the labeling solutions should be avoided because of bleeding in this area.
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When lesions are larger and it is not certain that it will be possible to excise them by means of the ABBI system before SLN labeling, confirmation of their cancerous nature by FNAC seems to be the method of choice. It is not possible to link the publications on this topic to the specific diagnostic systems. The relevant literature has therefore been collected and is presented in a single alphabetic list.
References Burbank F, Parker SH, Forgarthy TJ (1996) Stereotactic breast biopsy: improved tissue harvesting with the mammotome. Am Surg 62:738±744 Ferzli GS, Hurwitz JB, Puza T, Vorst-Bilotti S (1997) Advanced breast biopsy: a critique. J Am Coll Surg 185:145±151 Jackman RJ, Burbank F, Parker SH, Evans WP, Lechner MC, Richardson TR, Tocino I, Wray AB (1997) Atypical ductal hyperplasia diagnosed at sterotactic breast biopsy: improved reliability with 14-gauge, directional, vacuumassisted biopsy. Radiology 204(2):485±488 Jackman RJ, Nowels KW, Rodrigez-Soto J, Marzoni FA Jr, Finkelstein SI, Shepard MJ (1999) Stereotactic, automated, large-core needle biopsy of nonpalpable breast lesions: false-negative and histologic underestimation rates after long-term follow-up. Radiology 210(3):799±805
Krebs TL, Berg WA, Severson MJ, Magder LS, Goldberg PA, Campassi C, Sun CJ (1996) Large-core biopsy guns: comparison for yield of breast tissue. Radiology 200:365±368 Lamm RL, Jackmann RJ (2000) Mammographic abnormalities caused by percutaneous stereotactic biopsy of histologically benign lesions evident on follow-up mammograms. AJR Am J Roentgenol 174(3):753±756 LaRaja RD, Saber AA, Sickles A (1999) Early experience in the use of the advanced breast biopsy instrumentation: a report of one hundred twenty-seven patients. Surgery 125(4):380±384 Leibman AJ, Frager D, Cjoi P (1999) Experience with breast biopsies using advanced breast biopsy instrumentation system. AJR Am J Roentgenol 172(5):1409±1412 Liberman L, Dershaw DD, Rosen PP, Abramson AF, Deutsch BM, Hann LE (1994) Stereotaxic 14-gauge breast biopsy: how many core biopsy specimens are needed? Radiology 192:793±795 Meyer JE, Smith DN, DiPiro PJ, Denson CM, Frenna TH, Harvey SC, Ko WS (1997) Stereotactic breast biopsy of clustered microcalcifications with a directional, vacuumassisted device. Radiology 204:575±576 Nath ME, Robinson TM, Tobon H, Chough DM, Sumkin JH (1995) Automated large-core needle biopsy of surgical removed breast lesions: comparison of samples obtained with 14-, 16-, and 18-gauge needles. Radiology 197:739±742 Parker SH, Lovin JD, Jobe WE (1990) Stereotactic breast biopsies with a biopsy gun. Radiology 176:741±747 Parker SH, Lovin JD, Jobe WE, Burke BJ, Hopper KD, Yakes WF (1991) Nonpalpable breast lesions: stereotaxis automated large-core biopsies. Radiology 180:403±407 Parker SH, Jobe WE, Dennis MA et al. (1993) US-guided automated large-core breast biopsy. Radiology 187:507±511
Special Part
The Sentinel Node Concept Related to Main Tumor Types and Subtypes: Applicability in Daily Routine Work
Chapter 21
Breast Cancer
Development of the Sentinel Lymph Node Concept (Initial Approaches) There is some controversy about whether or not general axillary dissection has an influence on survival rates. In the National Surgical Adjuvant Breast and Bowel Project no. 4, it was concluded that axillary dissection was worthless in terms of any positive influence on survival rate. However, contradictory results were recorded by Dewar et al. (1987) and Moore et al. (1996). Veronesi et al. (1985, 1993) estimate that, according to the experience so far available, information on metastatic involvement of the parasternal lymph nodes can be obtained in 1±9% of cases by means of radiodiagnostic sentinel lymph node (SLN) investigation. The concept of (a) ªkey lymph node(s)º in incipient metastasis, the so-called sentinel lymph node(s) has been reactivated since 1993 (Mazzeo et al. 1986; Krag et al. 1993, 1998 a; Giuliano et al. 1994, 1995, 1996, 1997; Silverstein et al. 1994; Albertini et al. 1996; Statman et al. 1996; Chadh et al. 1997; Haffty et al. 1997; Nathanson et al. 1997; Pijpers et al. 1997; Veronesi et al. 1997; Offodile et al. 1998), when several groups tried to define the lymph node that had a direct connection to the primary. The high proportion of patients who underwent axillary revision without any findings of metastasis into the axillary nodes intensified the search for new possibilities. This is now more urgent than ever before, because among patients whose cancer is diagnosed as the result of early cancer detection programs the rate with a node-negative status is increasing steadily. Recent data show that in approximately 90% of cases the sentinel nodes in breast cancer are localized in the lower axilla. However, in less than 10% [8% in the report of Krag et al. (1998)] they can be localized outside the axilla, in the lateral area of the glandular part of the breast. Whereas the so-
21
called Sorgius lymph node with localization in the marginal area of the breast is a well-known localization of breast drainage from lateral breast parts, the extra-axillary SLNs seem to be located further cranially or within the breast. These facts of extraaxillary and marginal mammary localization are important in planning of the surgical procedures. This is in keeping with the advice we have long been giving: that the marginal area of lateral breast parts should also be checked for lymph nodes and, in the case of a subcutaneous mastectomy, the subcutaneous tissue should be eliminated from medial operation sites up to the marginal area of the pectoralis major muscle. The localization of hot spots at level II helps (in 4%) in operative clearance of the axilla (Krag et al. 1998) and confirms the frequency of skip metastasis, which according to our own experience is approximately 3%. Under these conditions SLN labeling seems to be important as a way of helping surgeons to find the first regional lymph node(s). To determine and find a direct connection with the primary is an additional goal for surgeons, because in cases with discontinuous extirpation of primary and lymph node(s), homogeneous postoperative radiation therapy may not be fully sufficient for tumor clearance. Tumor cells can then grow out of lymphatic vessels that have no connection with lymph nodes postoperatively. Nowadays, radiodiagnostic N-staging of breast cancer is performed by ultrasonography (US) or CT. Especially in the axillary region, US has a high sensitivity, whereas the specificity, like that of CT, remains unsatisfactory. New approaches are 18FFDG-PET (see also Chapters 5 and contributions by Avril et al. in chapters devoted to different cancer types) and the systemic application of Sinerem (see also Chapter 20) in breast cancer to evaluate all lymph nodes involved in drainage of the breast. Unpublished data have shown a higher specificity than shown by the earlier diagnostic results specified above, but no definite data have yet been reported.
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Is SLN Biopsy Indicated in Every Case with Suspect Lesion(s) of the Breast?
Complications After Axillary Revision ± an Argument for Limitation to Sentinel Biopsy Alone?
Figure 1 gives a rough answer to this question. It must be emphasized that vacuum biopsy (Mammotome, Fischer) is only indicated in the presence of moderately suspicious small lesions to exclude cancer [BI-RADS (Breast Imaging Reporting and Data System) 3]. It should not be used in the case of highly suspicious lesions (BI-RADS 4); in such lesions primary excision seems to be much more appropriate, as this makes it possible to avoid opening blood vessels by the vacuum procedure. Fine-needle aspiration cytology (FNAC) would also be far less traumatic.
It is easily understood that surgeons like to avoid performing axillary revision, in view of the different complications that can follow, such as those that can result from prolonged general anesthesia, development of postoperative seroma or bleeding, inflammatory processes with secondary abscess formation, areas of hypoesthesia, and painful neuromas; according to Larson et al. (1986) the complication rate with development of edema of the arm was 28% when more than ten axillary lymph nodes were removed. However, these complications, which have also been mentioned by Headiuk et al. (1992) and Maunsell et al. (1993), can be avoided or successfully
Fig. 1. Implications of the sentinel node concept in cancer screening and in surgical treatment of putative early cancer
cases. *Further discussion of axillary revision depending on result of sentinel lymph node (SLN) investigation
Primary- and Lymph Node-detecting Radiodiagnostic Systems Besides Mammography and Ultrasound
clinically treated to a high degree at least in some cases, and they do not compare with the problems of possibly incomplete operative tumor clearance after sentinel node biopsy alone and subsequent irreparable local and generalized tumor progression. Therefore, when the sentinel node concept is practiced, extreme care and a high quality of the working procedures performed by nuclear medicine specialists, surgeons, and pathologists are absolutely vital, as is good cooperation.
Skip Metastasis The sentinel node concept is closely connected with the problem of skip metastasis. According to the literature, the rate of skip metastasis (leaving out the first node without metastasis formation or bypassing the first node), was approximately 3% in earlier investigations. Similar results are also published in the current literature [Koller et al. (1998): 3.6%; Sandrucci and Mussa (1998): 4.6% in T1-2N0 breast cancers].
pT2 tumors than in pT3 or pT4 cancers (Graves et al. 1996; Cox et al. 1998 a, b; O'Hea et al. 1998; Reuhl et al. 1998). The identification of tumor-involved SLN also seems to influence adjuvant therapy in patients with pT1a, pT1b, and favorable pT1c tumors. It may also change the type and dose of chemotherapeutic regimens prescribed, especially in cases with pT1c tumors (Ollila et al. 1998). When breast cancer is staged, there is no point in SLN detection in cases with: · Large tumors when a metastatic process must be assumed on the basis of clinical examination; · Massive lymphangiosis carcinomatosa; · Inflammatory cancer; · Multicentric cancer in many cases.
Primary- and Lymph Node-detecting Radiodiagnostic Systems Besides Mammography and Ultrasound
Are Performance and Success of the SLN Biopsy Dependent on the Tumor Stage of the Primary?
Value of MRI for Cancer Detection and Injection Sites of the Nanocolloid Solution
In view of the uncertainty of physical examination of the axilla, the SLN concept is increasingly favored by physicians. The question is: Where is the ªstarting pointº for sentinel node biopsy in early lesions and where are the limits of applicability of the concept when lesions are more extensive?
In most cases with breast cancer, the findings established by palpation or mammography, sometimes complemented by ultrasound, are sufficient for more or less exact cancer localization and determination of the tumor margins. However, in some cases the cancer cannot be exactly located and cannot be delineated in the periphery, especially in breasts with higher density of the parenchyma. In such cases MRI is the most appropriate method to support accurate determination of the exact cancer localization and its extension and, in special cases, to confirm multifocality or multicentricity and locations of DCIS or EIC [Fischer et al. 1993, 1996 a; Orel et al. 1995; Heywang-Kæbrunner and Beck 1996; Abraham et al. 1996; German Roentgen Society 1996; Mumatz et al. 1997; Hrung et al. 1999; Heywang-Kæbrunner et al. 2001; the participating centers in the different countries (Germany, United States, United Kingdom, Sweden, The Netherlands, Belgium) are listed in Table 1]. These facts are of great importance for local subdermal or peritumoral (not intratumoral!) ad-
At present, the following statements can be given: · For ductal carcinoma in situ (DCIS) cases with minor extension up to 2.5, exclusion of sentinel node involvement should be recommended, because minimal invasion not suggested by the specimens of the primary lesion is possible and an SLN examination with negative results is safer. In the case of more extensive lesions SLN examination now seems to be obligatory, especially in high-grade types. · All investigators agree that in invasive breast cancers the accuracy of findings corresponds to the degree of extension of the primary. According to Giuliano et al. (1997), it is highest in lesions <10 mm in size, with 100% accurate prediction, and is much higher in pT1 and early
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Chapter 21 Breast Cancer Table 1. Researchers and institutes involved in the International Investigation Project on Diagnostic Parameters in Contrast-enhanced MRI of the Breast S. H. Heywang-Kæbrunner, Department of Diagnostic Radiology, Section Mammography, University Clinic/ Technical University, Ismaninger Street 22 81675 Munich, Germany
U. Bick, Department of Diagnostic Radiology, Westphalian Wilhelms University, Mçnster, Germany
W. G. Bradley Jr., Memorial Medical Center, Long Beach, California, USA
B. Bon, Department of Diagnostic Radiology, Huddinge University, Stockholm, Sweden
J. Casselman, Department of Diagnostic Radiology, A.Z. St. Jan, Brugge, Belgium
A. Coulthard, Department of Diagnostic Radiology, Royal Victoria Infirmary, Newcastle, UK
U. Fischer, Department of Diagnostic Radiology, Georg August University, Gættingen, Germany
M. Mçller-Schimpfle, Department of Diagnostic Radiology, Eberhard Karl University, Tçbingen, Germany
H. Oellinger, Department of Diagnostic Radiology, Rudolph Virchow University Clinic, Charit Berlin, Germany
R. Patt, Department of Diagnostic Radiology, Georgetown University, Washington, D.C. USA
J. Teubner, Department of Diagnostic Radiology, Mannheim Clinic, Heidelberg University, Heidelberg, Germany
M. Friedrich, Department of Diagnostic Radiology, Urban Hospital Berlin, Germany
G. Newstead, Faculty Practice Radiology, New York University, New York, New York, USA
R. Holland, Department of Pathology, University Hospital Nijmegen, Nijmegen, The Netherlands
A. Schauer, Department of Pathology, Georg August University, Gættingen, Germany
E. A. Sickles, Department of Radiology, University of California, San Francisco, California, USA
L. Tabar, Falun Central Hospital, Falun, Sweden
J. Waisman, Department of Pathology, New York University, New York, New York, USA
K. D. Wernecke, Institute of Medical Biometrics, University Charit, Berlin, Germany
ministration of the labeling solution injected for SLN(s) detection. The international investigation project on breast MRI, concerning diagnostic parameters for contrast-enhanced MRI (Heywang-Kæbrunner et al. 2001), has yielded valuable advice about more accurate delineation of cancer and of EIC foci, etc. Therefore, this method should be used in addition to US and mammography for more exact ªlabeling strategies.º The cited study correlated results of various examinations carried out in 519 histopathologically certified lesions and provided fundamentals for improved standardization and optimized interpretation guidelines for contrastenhanced MRI. The patients had standardized dynamic MRI on a Siemens 1.0- or 1.5-T appliance using the 3D fast low-angle shot (Flash 87s) technique before and five times after a standardized bolus of 0.2 mmol Gd-DTPA/kg. The best results were obtained by combining up to five wash-in or wash-out parameters. Different weighting of false-negative versus false-positive calls allowed to define a statistical interpretation for the highest possible sensitivity (specificity 30%) for moderate (50%) or high (64±71%) specificity. The sensitivities at the above-mentioned specificity levels were better, at 1.0 T (98%, 97%, or 96%) than at 1.5 T (96%, 93%, or 86%). In the search for milestones along the way of future use of MRI in our diagnostic concepts concerning breast cancer, the important aim of standardizing dynamic contrast-enhanced MRI was realized by this study. The results provide an additional fundamental basis for further clinical development of the SLN concept. This conclusion is of fundamental importance, because the contrast labeling solution needed for determination of the SLN(s) should be administered s.c. in superficially located palpable primaries, but must be injected exactly peritumorally, avoiding intratumoral injection, in the case of more deep-seated cancers. In these cases imaging systems, including MRI, are helpful in attaining precisely placed administration of the nanocolloid solution for SLN.
Role of PET in Breast Cancer Staging
Role of PET in Breast Cancer Staging N. Avril, W. Weber, M. Schwaiger Value in the Different pT Stages Initial studies involving patients with advanced disease found FDG-PET to be highly accurate in detecting primary breast carcinomas (Wahl et al. 1991; Adler et al. 1993). In the largest series so far, involving 185 breast tumors, Avril et al. (2000) identified primary breast cancer with a sensitivity ranging between 64.4% for conservative image reading (CIR: only definite FDG uptake regarded as positive) and 80.3% for sensitive image reading (SIR: either definite or probable FDG uptake regarded as positive) (Fig. 2 a±c). The increase in sensitivity (SIR) resulted in a noticeable decrease in specificity, specifically from 94.3% (CIR) to 75.5% (SIR). In stage pT1 (< 2 cm), only 30 (68.2%) out of 44 breast carcinomas were detected, as opposed to 57 (91.9%) out of 62 in stage pT2 (2±5 cm). In the
Fig. 2 a±c. Breast carcinoma. a Transaxial PET image of the upper thoracic region. There is an area of focally increased metabolic activity in the right breast, representing an invasive ductal carcinoma. b Lymph node metastases in left axilla and mammaria interna region. Transaxial PET image of the axillary region. There are areas of focally increased metabolic
false-negative group, invasive lobular carcinomas were overrepresented (34.8%) relative to invasive ductal carcinomas (11.3%). This difference can be explained by the frequent primary multifocality and the diffuse often scirrhous growth pattern with abundant collagenization of the cancerous region(s). Multicentric breast cancer is an important limitation for breast-conserving therapy. Even when SIR was applied in the above study, only 9 (50%) out of 18 patients with multifocal or multicentric breast cancer were identified. Overall accuracy in detecting noninvasive breast cancer was low, with a sensitivity of 25% (CIR) and 41.7% for SIR. Although the number of patients in this study was small, the data suggest that detection of in situ carcinomas may not be improved by PET imaging. Only 3 out of 53 benign breast masses presented with intense tracer uptake, suggesting that FDGPET has a high positive predictive value, with increased FDG accumulation indicating breast cancer. Only 1 out of 9 fibroadenomas showed increased tracer uptake. Moreover, dysplastic tissue,
activity in the left axilla and the mammaria interna region, indicating breast cancer metastases. c Axillary lymph node metastases. Coronal PET image of the body. There are multiple foci of increased metabolic activity in the right axillary region, indicating lymph node metastases
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which often accounts for false-positive results in MR imaging, mostly showed little or moderate and diffuse FDG uptake.
Value of PET in Staging: Conclusions Derived from Positive and Negative Results in Axilla Staging All available radioimaging systems (ultrasound, MRI, PET) are incapable of detecting incipient lymph node metastasis with loosely spread cancer cells or cancer cell clusters or even micrometastases. This statement also applies to the application of FDG-PET in cases with tiny incipient metastases. However, studies performed in recent years allow the conclusion that FDG-PET provides the highest diagnostic accuracy of all noninvasive diagnostic methods in axillary lymph node staging (Smith et al. 1998; Crippa et al. 1998). But, with view to the introductory remarks PET: · Is no substitute for histopathologically based lymph node staging. · Cannot give a significant answer to the question of how many lymph nodes are involved in the metastatic process. Therefore, SLN labeling and the subsequent histopathological examination of the node(s) cannot be fully substituted by PET. In these conditions, the demonstration of cancer infiltration of one or more regional lymph nodes by PET makes the clinical search for the SLN(s) useless. In conclusion, in cases with positive lymph node(s) in PET staging, axillary lymph node revision can be performed immediately without following the SLN concept. Conversely, when PETbased investigations give a negative result the SLN concept can be started.
PET Screening Investigations for Sentinel Node (Axillary) and Systemic Metastasis in Breast Cancer Patients Only positive results have any relevance for further diagnostic procedures and for further therapeutic efforts. This means that additional sentinel node labeling procedures involving blue stain and/or 99mTc labeling for detection of the sentinel node(s) can be avoided and thus also that in cases with positive parasternal nodes adjuvant therapeutic regimens should be performed. Wahl et al. (1991) investigated 12 patients with advanced breast cancer and also noted increased FDG uptake in axillary metastases. Nieweg et al. (1993) showed metastatic lymph node involvement in the axilla in 5 out of 11 patients studied, the smallest lymph node visualized with PET being 0.8 cm in diameter. In 18 patients, Adler et al. (1993) reported a sensitivity of 90% and a specificity of 100% for axillary PET imaging. Nine of 10 cases with positive results on axillary node dissection had positive PET scans. In a more recent study the authors investigated 50 patients with breast cancer prior to axillary lymph node dissection (Adler et al. 1997). The sensitivity and negative predictive value were both 95%, and the overall accuracy was 77%. The only false-negative PET scan was obtained in the largest patient, whose scan was of a low quality. However, SIR resulted in 11 false-positive PET findings with a specificity of 66%. Similar results have been reported by Crippa et al. (1998). Avril et al. (1996) studied 51 patients by PET and found an overall sensitivity and specificity in detection of axillary lymph node metastases of 79% and 96%, respectively. When only the patients with primary breast tumors larger than 2 cm (> stage pT1) were taken into account the sensitivity of axillary PET imaging increased to 94%, with a corresponding specificity of 100%. Lymph node metastases could not be identified in 4 out of 6 patients with small primary breast cancers (stage pT1), giving a sensitivity of only 33% in these patients. These results indicate that the detection of micrometastases and small tumor-infiltrated lymph nodes is currently limited by the spatial resolution of PET imaging. PET imaging did, however, provide additional information in 12 (29%) of 41 breast cancer patients, demonstrating
Can the ACR-BI-RADS Lexicon Influence the Choice of the Most Adequate Device for Removal of the Breast Lesion?
axillary involvement at level III (located medial to the border of the pectoralis minor muscle), periclavicular and retrosternal lymph node metastases, and bone and lung metastases. Moon et al. (1998) found whole-body PET imaging extremely accurate in patients with suspected recurrent or metastatic breast carcinoma. By patient, sensitivity and specificity were 93% and 79%, respectively, the corresponding positive and negative predictive values being 82% and 92%. By lesion, the sensitivity was 85% and the specificity 79%. With bone metastases there was a significantly higher proportion of false-negative lesions than with other nonosseous malignant sites. Falsepositive lesions were due to muscle uptake (n = 5), inflammation (n = 4), blood pool activity in the great vessels (n = 2), bowel uptake (n = 1) and unknown causes (n = 6). Lonneux et al. studied 39 women with suspected breast cancer recurrence (Lonneux et al. 2000). PET-FDG located 37 out of 39 sites in 31 out of 33 patients with recurrence, whereas conventional imaging identified sites of recurrence in only 6 out of 33 patients. PET missed 1 locoregional recurrence, and in 1 patient it failed to detect peritoneal carcinomatosis, which became clinically apparent 6 months after a negative PET scan. False-positive results corresponded to lung infection, degenerative bone disease, and reconstruction artifacts. In 75 patients with suspected recurrent or metastatic disease, FDG-PET correctly identified 16 patients with local recurrence, 28 with lymph node involvement, 15 with bone, 5 with lung, and 2 with liver metastases (Bender et al. 1997). CT/MRI identified 10 patients with local recurrences, 17 with lymph node involvement, 6 with bone, 5 with lung, and 1 with liver metastases. In addition, FDG-PET detected 6 local recurrences, 8 lymph node, and 7 bone metastases which were not visualized by CT/MRI. In conclusion, owing to the limited sensitivity of PET in the detection of small tumors, its use in the screening of asymptomatic women for breast cancer is not advisable. Furthermore, negative PET findings in patients presenting with palpable breast masses or abnormal mammography do not necessarily exclude breast cancer. This suggests that the number of invasive procedures performed may not be significantly reduced by the currently available metabolic imaging techniques. However, in patients with advanced breast cancer, FDG-PET,
because of its high positive predictive value, is particularly useful in determining the extent of disease. In this subgroup PET identifies locoregional lymph node metastases with great accuracy. Detection of micrometastases and small tumor-infiltrated lymph nodes is limited by the spatial resolution of PET imaging, which should be improved in the future. Whole-body PET imaging is very accurate in detecting patients with recurrent or metastatic breast carcinoma. PET imaging has been found to be very valuable for monitoring the effects of preoperative chemotherapy. Assessment and prediction of the response to therapy are possible sooner than with any other method. Therefore, even allowing for its limitations, PET imaging is still a valuable tool in the management of breast cancer patients.
Can the ACR-BI-RADS Lexicon Influence the Choice of the Most Adequate Device for Removal of the Breast Lesion? A. Schauer, V. Schauer
Partly by analogy to pathologists scaling of preinvasive and early invasive neoplastic breast lesions (atypical ductal hyperplasia, ductal carcinoma in situ and early invasive breast cancer), the American College of Radiology (ACR) has tried to develop a Breast Imaging Reporting and DATA System (BI-RADS) lexicon based on significant features as a basis for international comparative studies. This lexicon discriminates five categories of lesions: · Categories 1 and 2 raise no suspicion of malignancy · Category 3 probably benign, but malignancy cannot be definitely excluded · Category 4 suspect abnormality · Category 5 highly suggestive of malignancy (see Table 2) A few impressive case reports may demonstrate the value of the BI-RADS classification for better interdisciplinary communication, especially with respect to judge the risk and plan adequate further diagnostic and surgical treatment procedures.
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Chapter 21 Breast Cancer Table 2. Discordance between BI-RADS and histological result with regard to categories 4 and 5 and to device used for tissue sampling BI-RADS category
Frequency of cancer
Discordance between imaging and histopathology
Discordance between 11-G vacuum biopsy and other devices
Discordance rates not significant for masses
5
43.8%
4.8%
1.7% vs 6.8%
3.78% vs 2.7%
4
13.7%
2.6%
(P < 0.001)
P = 0.44
Case Histories J Case 1 This 63-year-old patient (Fig. 3 a±d) had no suspicious lesions on physical examination. Mammography revealed a very dense glandular body with multiple microcalcifications. These were partly singular and partly grouped, but mostly roundish with the ªteacupº phenomenon. Malignant densities were not detectable. The additional ultrasound investigation depicted several cysts. In conclusion, there were no regions suggestive of malignancy; rather investigations suggested fibrocystic disease. The lesions were classified as BI-RADS III and a further checkup in 3±6 months was advised. J Case 2 In a 50-year-old patient a microcalcification was found in the retromammillary region on left-sided digital mammography in a craniocaudal (cc) projection (Fig. 3 e, f). Regular mammograms showed a constant result over some years. J Case 3 A 70-year-old woman was admitted to hospital when the onset of neurological symptoms was noted. The initial diagnostic examinations confirmed bleeding within a brain metastasis from an unknown primary (CUP). During the search for the primary, mammographic investigation of the right breast showed a dense glandular body with no suspicious densities or microcalcifications (Fig. 4 a). Cutis and subcutis were not thickened. The lesion was classified as BI-RADS I. The left breast also showed very dense retromammillary tissue. In the lower inner quadrant there were several groups of microcalcifications ar-
ranged in a roughly Y-shaped configuration along course of the ducts (Fig. 4 b). They were classified as polymorphous lesions highly suggestive of DCIS and Bi-RADS IV. The histological diagnosis was focal DCIS (large cell, high grade) with stromal invasion. One year after breast-preserving surgery, the patient underwent mastectomy because she had an ªin-breast recurrenceº. J Case 4 This 61-year-old patient had calcifications classified as BI-RADS IV. Left-sided digital extended mammography showed retromammillary microcalcifications (Fig. 4 c, d). Histological examination led to a diagnosis of DCIS. J Case 5 A 54-year-old woman came into the out-patient clinic for screening. Inspection and palpation of the breasts did not disclose any suspicious lesions. Mammography revealed a roundish density in the left upper outer quadrant, with a mostly sharp shape except at the lower lateral side (Fig. 5 a). Little irregularity was seen. In the additional ultrasound investigation the lesion was unequivocally identified as a cyst. The classification was BIRADS II. On the right side the tissue was very dense. In the upper middle part there was a group of microand macrocalcifications, some of which were roundish and others rather long and thin (Fig. 5 b). The classification was BI-RADS IV. After needle marking of the right upper middle region and operation the histological examination led to a diagnosis of fibrocystic disease with microcalcifications.
Can the ACR-BI-RADS Lexicon Influence the Choice of the Most Adequate Device for Removal of the Breast Lesion? Fig. 3. a±d Mammography pictures recorded in a 63-year-old woman with a dense glandular body and multiple, mostly roundish microcalcifications suggestive of fibrocystic disease (BIRADS III). e, f Microcalcifications categorized as BI-RADS III in a 50-year-old patient, which gave a constant result on repeated mammographies over many years: e Microcalcification in the retromammillary region seen in left-sided mammography in a craniocaudal projection; f With zoom activated regional arrangement of monomorphous calcifications is shown more precisely (e, f see p. 186)
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Chapter 21 Breast Cancer Fig. 3 e, f (Legend see page 185)
Fig. 4. a, b Dense glandular tissue on the right side without any suspicious focal lesions (BI-RADS I) in a 70-year-old woman. In the lower interior quadrant of the left breast several polymorphous microcalcifications were seen, some of them in groups (BI-RADS IV). Histological investigation revealed high-grade ductal carcinoma in situ (DCIS) with mi-
croinvasion. c, d Calcifications categorized as BI-RADS IV in a 61-year-old patient. c Left-sided digital extended mammography showing microcalcifications in a central retromammillary region. d With zoom activated a more precise analysis of the segmentally arranged polymorphous calcifications is possible. Histological examination revealed DCIS
Can the ACR-BI-RADS Lexicon Influence the Choice of the Most Adequate Device for Removal of the Breast Lesion?
Fig. 4 c, d (Legend see page 186)
Fig. 5 a, b. Mammography of a 54-year-old woman with cystic density in the left upper exterior quadrant (BI-RADS II). In the upper middle part of the right side line-like micro-
calcifications are seen (BI-RADS IV). Histological investigation showed fibrocystic disease with microcalcifications
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In training programs tested in the Ukraine (Lehman et al. 2001) the initial mean baseline sensitivity, specificity and positive predictive values were 50%, 77%, and 43%, respectively. In conclusion, the authors stressed that the ACR-B1-RADS lexicon provides a systematic and efficient method of training radiologists to improve their interpretational skills in the evaluation of screening mammograms. Liberman et al. (2000), at Sloan±Kettering Cancer Center, tried to evaluate the significance of BIRADS in routine clinical work. The results of their studies are summarized in Table 2. The average imaging±histology discordance amounted to 3.1%. In discordant cases the authors recommend surgical excision because there is a high cancer risk (24%) in such cases. Wedegartner et al. (2001), using the ABBI system, had a cancer rate of approximately 22% in their series, while the positive predictive value (PPV) for BI-RADS-based indications for surgical excision in categories 4 and 5 was 31%. The authors conclude from their results that the use of BI-RADS should be mandatory in mammographic evaluation. This is an important point, not least with regard to the choice of the most suitable biopsy system for the individually adapted diagnostic procedure. Kim et al. (2001) analyzed 82 patients, 68 of whom had carcinoma. According to the BI-RADS lexicon, 61% of their lesions were classed as category 5, 35% as category 4 and 4% as category 3; this means that 93% of the cases with malignancies were classified as highly suggestive of malignancy. When Obenauer et al. (2001) evaluated vacuum biopsy specimens from 86 cases with BI-RADS category 3 lesions they found the spectrum of entities detailed in Table 3.
Table 3. Lesions described histologically and diagnosed in vacuum biopsies Fibrocystic disease
67 cases 78%
Papillomas
4 cases 4.7%
Fibroadenomas
4 cases 4.7%
Atypical ductal hyperplasia (ADH)
4 cases 4.7%
Ductal carcinoma in situ (DCIS)
3 cases 3.5% (one minimally invasive)
Sentinel Node Localization in the Different Node Groups The distribution of lymph node metastases in the different node groups and their frequencies relative to each other had already been intensively investigated by many clinical research groups many years before sentinel node research started. Partly with orientation on Veronesi's results (1993) and partly on the basis of our own results and those reported in the international literature, the rates of involvement in possible metastatic spread are summarized in Table 4. Figure 6 illustrates the various possible localizations of the SLN(s): the most frequent is within level I of the axillary node group, while a location among the lateral paraglandular nodes is rare; a further possibility is among the parasternal nodes. The position of the sentinel node(s) can be detected by the methods already described. The nodes are excised and investigated histologically and immunohistochemically in serial sections. Only parasternally localized sentinel nodes are generally not excised. However, when these are found to be the sentinels, this node group is irradiated postoperatively.
Table 4. Distribution of lymph node metastases in breast cancer cases (all pT stages) in the different basins
a
Axillary nodes levels I and II
Paraglandular nodes
Parasternal (mammaria interna) nodes (according to literature)
Mammaria interna nodes as basin according to labeling with 99mTc nanocolloid a
Interpectoral nodes
Two basins
75%
6±8%
20±28%
9%a
2%
7%
The frequency of labeling marks only the basin, and does not indicate metastatic involvement in comparison with the percentages in the other columns
Sentinel Node Localization in the Different Node Groups Fig. 6. Demonstration of the different possible localizations of the SLN(s). The most frequent is within level I (1) of the axillary node group. Occasionally they are among the lateral paraglandular nodes (2). They can also be in parasternal nodes (3)
Four Regions of Interest for Lymph Node Investigation Using Different Cartridges in MRI Evaluation To achieve the best possible investigation of the different node groups, especially in MRI imaging, separate cartridges are necessary. The fields for separate investigations be clearly delineated, as demonstrated in Fig. 7.
Confirmation of Breast Cancer Diagnosis Before Sentinel Node Labeling and Extirpation for Analysis Together with the Primary According to our present state of knowledge it is clear that before the sentinel node labeling procedure is started, the diagnosis of breast cancer for the primary should be confirmed. Otherwise, the complicated sentinel node detection procedures would have to be regarded critically in view of the stress they impose on the patient with the injection of blue dye stains and a radioactive substance. Because of these facts, and also because of the high personnel and pharmaceutical costs involved, these new procedures cannot be seen in the same light as operations on mammographically unclear lesions with the cancer detection rates ranging from 4 : 1 to 2 : 1 seen 10 or 15 years ago.
Therefore, the preoperative diagnostic programs using different radio-imaging systems and histoand/or cytopathological methods that do not harm the local structures must give a clear-cut diagnosis of malignant epithelial cancer of the breast. This means that the diagnosis can only be made by aspiration or needle biopsy in smears or very small biopsy cylinders (see also Chapter 16). The main point in this connection is that the cancers and the peritumoral structures should not be harmed. These statements are in keeping with the recommendation that if possible no attempt should be made to label sentinel nodes by peritumoral application of the labeling solution after surgical excision of the primary. In contrast subdermal application seems to be possible. In DCIS, it is difficult to make a decision in favor of sentinel lymph node examination. It depends on many factors. · DCIS cannot be detected with a high degree of certainty by mammography in the early stages. In contrast, in a retrospective analysis published by Viehweg et al. (2000), the majority (96%) of DCIS lesions showed contrast enhancement in MRI, with a 50% rate of so-called typical enhancement behavior. · Because there is no infiltrative cancer, it is difficult to obtain significant material by fine needle aspiration cytology preoperatively.
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Fig. 7. Demonstration of the four regions of interest for preoperative radiodiagnosis. The anatomical delineation of the different groups allows the development of specific cartridges for: (a) The most frequently involved axillary node
groups (levels I±III); (b) the paraglandular group; (c) the interpectoral group (the target group in rare cases of deep, prefascial localized cancers; (d) the parasternal nodes, involvement mostly in central or medical localized primaries
· As a rule, at least, it is not possible to exclude the presence of invasion.
± When in sentinel node-positive cases no invasion has been found in serial sections of the primary DCIS lesion, it is necessary to exclude multifocality or multicentricity. · When the histopathological diagnosis is DCIS (large cell) with high-grade malignancy, whatever the extension the SLN (s) should be excised and subjected to histopathological examination as described in Chapter 10. ± In discussions with the patient it must be made clear that such solutions are compromises and it is impossible ever be absolutely certain about phase-shifted multicentricity; recurrences can still occur later and develop into invasive cancers before being detected.
In these circumstances, it must be stated that the radio-imaging systems (mammography, MRI) and their results are the strongest indication available that we have to suppose DCIS is present. The question of whether or not SLN(s) should be excised in DCIS cases is more or less an individual therapeutic problem and must therefore be discussed with the patient (informed consent). A rough rule can be accepted as a guideline for discussion: · If histological examination of the primary lesions leads to the diagnosis of DCIS without any signs of invasion and the lesion is micropapillary and low grade, and if the process does not extend to more than 2.5 cm and the margins are free, lymph node excision can be avoided. ± However, a higher degree of safety can be achieved by removal and histological examination of the sentinel node(s). This has to be pointed out, because in rare cases lymphatic spread has been observed already to have taken place even in this category.
Sentinel Node Labeling in Microcarcinomas or DCIS Not Ascertained Preoperatively There are two main options: · In microcarcinomas or cases of less extensive DCIS one option would be to label the sentinel nodes before excision, by subdermal or peritumoral administration of the 99mTc-nanocolloid solution, and to excise the suspect lesion and the sentinel node in a single operative session.
Sentinel Node Localization in the Different Node Groups
· A second option would be to excise the focus that is suggestive of microcarcinoma or DCIS in order to confirm the diagnosis histologically and control the margins, and then to label the sentinel nodes by subdermal or subareolar injection using 99mTc-nanocolloid-solutions preparatory to their excision in a second operative session. This option seems to be correct for primary lesions with locations that are not too deep.
Cytological Examination of Nipple Secretion Can Confirm a Diagnosis of Ductal Cancer (Support for Prelabeling Cancer Diagnosis) It must be recommended that every mammillary secretion is cytologically evaluated. Even the appearance of the secretion can give information about its origin and quality. In the case of bleeding the most important differential diagnoses are papillary lesions, such as a papilloma, or papillary intraductal cancer or cancer that is already invasive. If cancer cells are detected further diagnostic procedures are indicated and must be instituted immediately without fail. In brownish yellow secretions cytopathologists often find vital or necrotic cancer cells as part of a ductal, especially comedocarcinoma or a papillary cancer. A clear or white secretion is not very rare and is associated with secretory stimulation, but cancer cannot be excluded (cytopathological examination of the smears).
Factors that Influence the Frequency of Lymphatic Metastasis and Block Lymphatic Drainage Breast cancer diagnosis and further developments in the SLN concept must be seen in relation to the pTNM system and the most important prognostic parameters, such as tumor size, degree of malignancy and lymph node status. The tumor size (pT) in well delineated cancers is determined by measurement of the native cancer tissue, the longest diameter being measured. In diffuse and growing cancers that are not well delineated, slices of the suspect areas are investigated histologically, which is an opportunity to measure the most widely extended tumor forma-
tions plus 10%, to allow for shrinkage processes caused by formalin fixation. Note that diffuse, often scirrhous, growing cancers or primarily multifocally developed lobular cancers with confluence of the disseminated foci must be emphatically delineated from so-called diffuse growing inflammatory cancers, because different therapeutic regimens are obligatory, and because · There is a high prevalence of hematogenous metastasis in inflammatory cancers. · Lymphatic metastasis cannot be definitely evaluated, because of the low significance and wide extension of the lesion, blockade of the subdermal lymphatics by cancer cells, and inflammation. Inflammatory cancers are rare, so that the problems associated with it have a secondary role in daily routine work. More importance in daily work attaches to the question of the implications of the pT values and the dependence of the search for sentinel node(s) on pT stage. Two questions are of interest with regard to the search for sentinel node(s): a) The increasing frequency of lymphatic metastases with rising pT value b) The increasing blockade rate with increasing pT value. Ad a) The frequency of regional lymph node metastasis increases from pT1a to pT3 from approx. 20% to approx. 70%. The rates related to the different stages are listed in Table 5. Ad b) The rate of blockade of lymphatic drainage and the pattern of the preferred new drainage pathways is largely unknown, but it must be concluded that when the drainage to the parasternal nodes is blocked, drainage to the subclavicular and interpectoral nodes increases.
Histopathological, Immunohistochemical, and Molecular Biological Examination of the Primaries ± Significance for the Sentinel Node Concept It is important and necessary for cancer subtyping to precede application of the sentinel node approach. E.R. Fisher (personal discussion) was one of the first authors to express very clearly that
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Chapter 21 Breast Cancer Table 5. Increasing rates of lymph node metastasis referred to the different pT-stages of breast cancers.a (SEER data from NCI [Survival in Epidemiology and End-Results program, 1989]) Stage
Diameter
Percentages of axillary node involvement
pT1a
< 0.5 cm
20.6%
pT1b
0.5±0.9 cm
20.6%
pT1c
1±1.9 cm
33.2%
pT2
2±2.9 cm
44.9%
3±3.9 cm
52.1%
4±4.9 cm
60%
> 5 cm
70.1%
pT value
pT3
ist at first view to delineate these cancers from adenosis. They are nearly always grade I cancers and not connected with unfavorable prognostic factors like c-erbB2 overexpression, expression of mutated p53, vimentin coexpression etc. In our studies (German Breast Cancer Study Group) of low-risk cancers the rate of tubular cancers was 12-fold that found in an unselected pT1N0M0 collection. Mucinous cancers are conspicuous by their mucus formation, which is sometimes difficult to assess in frozen sections but is easily detectable when stained with PAS reaction or Alcian Blue. From the aspect of nuclear grading they mostly give the impression of being grade I or II cancers, but biologically they behave mostly in the same way as grade I tumors (Fig. 9 a, b).
a
In an overview of the literature, Witt et al. (2002) stated that the frequency of axillary involvement in the pT1a stage given in the literature varies from zero to 28%
some subtypes of breast cancer have an excellent prognosis. In life-tables of a collective of 1500 patients, those with the following subtypes had a near-90% survival rate: · Tubular type of breast cancer (Fig. 8) · Mucinous subtype (Fig. 9 a, b) · Invasive (micro)papillary subtype (see Fig. 10) These subtypes are demonstrated in Figs. 8±10. Tubular cancers show far reaching isomorphism of the cancer cell nuclei, so that partly difficulties ex-
Cancers with Unfavorable or Incalculable Prognosis Large-cell high-grade types of breast cancer (often invasive ductal cancers, comedo type, with c-erb B2-(p185) overexpression (Fig. 11) and diffuse infiltrating scirrhous cancers (Fig. 12), some with intensively developed lymphangiosis carcinomatosa, show fast cancer progression with hematogenous metastasis or locoregional cancer infiltration (breast wall, pleura etc.), respectively. Therefore, this subtype is mostly not suitable for a SLN search, because · Subdermal or peritumoral labeling, as usual, is hardly possible because there is no peripheral delineation. Figs. 8, 9. Breast cancer types with excellent prognosis, in which the SLN search helps to avoid extended axillary revision (levels I and II) Fig. 8. Tubular cancer: in most cases grade I, very low mitotic activity, nearly regularly homogeneous hormone receptor equipment. In nearly all cases there is no axillary lymph node metastasis. Therefore, search for and investigation of SLN are highly valuable
Sentinel Node Localization in the Different Node Groups Fig. 9 a, b. Mucinous breast cancer. a Mostly a cancer of the elderly, this type is sharply delineated, so that on mammography it can be misinterpreted as a fibroadenoma. b Histopathology of mucinous cancer: Tubular or solid cancer cell formations swim in secreted mucus (Alcian blue stained) (AFIP picture). In most cases grade I±II with low mitotic activity and positive for steroid receptors; search for SLN therefore highly valuable
Fig. 10. Micropapillary low-grade breast cancer showing gracile intraductal papillary cancer cell proliferation with only low to moderate nuclear polymorphism and a low rate of mitosis. The invasive parts of the cancer show identical cellularity
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Chapter 21 Breast Cancer Fig. 11. Infiltrating large-cell breast cancer (grade III) with high degree of cancer cell dissociation. Simultaneous immunohistochemical double staining: (a) for Ki67 (MIB I): more than 50% of the cancer cells are in the proliferative compartment (brown-stained cancer cell nuclei) and (b) for p185 transmembrane protein [= oncoprotein of c-erbB2 (HER/ neu) (red-stained cancer cell membranes, arrows)
Fig. 12. Scirrhous structures in cancer (subtype of solid ductal, sometimes also lobular, cancers) can often hardly be delineated in the periphery of cancer growth. These cancers often infiltrate the subepidermal structures (peau d 'orange) and frequently metastasize early to the regional lymph nodes
· In extensive cancers mastectomy must generally be performed. · Because of breakout through the lymph vessels and nodes full axillary revision is generally indicated. Tumor Typing by Different Pathologists We have to realize that primaries with diameters of 1±2 cm have already undergone a relatively high number of spontaneous mutations based on genetic instabilities, leading to subclones with different phenotypes. However, as a rule these changes do not change the fundamental subtype, which is related not only to growth pattern but also to nuclear struc-
ture, cell size and other criteria. Accordingly, the classification of breast cancers according to the WHO (1982) seems to be absolutely practicable. It must be emphasized that the main type, namely the ductal invasive cancer with mostly solid growth pattern, also termed as type ªnot otherwise specifiedº (NOS), can generally easily be confirmed, even when parts of the tumor show adenoid structures, because these have nothing to do with a tubular cancer as a specific subentity of breast cancer, which is nearly always a grade I cancer (Fig. 8). In addition, grading of solid ductal cancers is also not influenced by the existence of adenoid (tubular) structures, because in multivariate analysis of the individual grading criteria: polymorph-
Sentinel Node Localization in the Different Node Groups Fig. 13. Invasive medullary cancer with large nuclei, prominent nucleoli, and pale nuclei. Note intensive lymphocyte infiltration of the cancer. In sentinel node labeling procedures no special restrictions are necessary. Subdermal labeling is possible, but so also is distinct peritumoral labeling with an optimal distance of 4±5 mm from the mostly sharp delineated cancer nodule
ism, mitotic activity, tubule formation, both polymorphism and mitosis rate, have been found to be of much higher significance than gland formation. Medullary cancer is a special entity with regard to: ± Radioimaging (mammography, MRI) ± Histopathology and ± Biological behavior. Medullary cancers are well delineated in the periphery and can therefore awake the impression of fibroadenomas on mammography and MRI. Histopathologically, they show a solid growth pattern almost without exception, and as a rule they develop in a prelobular site. Cytological examination reveals large nuclei with central large nucleoli; the mitotic activity is generally high. Therefore, most of these cancers are graded as grade-III tumors. Lymphocytic infiltration can have developed and may be intensive, but is also sometimes absent (Fig. 13). Biologically, in the first 5 years after surgery, in spite of the high mitotic activity medullary cancers have a similar or slightly better outcome than the main group of ductal invasive cancers (NOS). After 5 years, however, their survival rates are somewhat worse. These patients' lesions enhance strongly on MRI. See also subsection ªDuctal Carcinoma In Situº by V. Schauer and A. Schauer in this chapter.
Lobular Breast Cancers: Care Multifocality, Multicentricity, Bilaterality and Wide Variability in Biological Behavior in Relation to the Sentinel Node Concept Lobular cancers mostly account for 10±14% of all breast cancers in the different statistics published (Schauer 1981). They become apparent as destructive processes in the lobular fields of the pre-existing glandular structures (deletion). This deletion process with preserved innocent-seeming ducts in the tumor areas already gives a first hint indicating the right direction to go in to reach the correct diagnosis. An ªIndian fileº pattern of tumor growth is a second important feature, but solid and tubuloalveolar growth patterns are also possible. In this connection, it must be pointed out that the ªball-likeº growth pattern, especially, is quite helpful in the diagnosis, as well as the Indian file pattern. Because of the isomorphism of the cancer cells, which is sometimes far reaching, some tumors are classed as grade I cancers, but basically these cancers are known mostly to behave in a similar way to grade II cancers.
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Practical Viewpoints In practice, for optimal evaluation of the cancer's biology based on favorable features, some additional viewpoints must be included. We have to realize that with expansive local growth of the primary vascular and nutritional support decreases in the central parts, because of necroses and scar formation in these areas, while in the peripheral parts of the cancer, on the socalled growth front, the supply is much better as a rule. Therefore, the peripheral zone should be preferred for evaluations of the degree of malignancy (tumor grading). Furthermore, in the periphery the phenomenon of lymph vessel invasion can sometimes be more easily detected than in the central zones with densely packed tumor cell formations.
Tumor Grading, the Most Important Prognostic Factor in Simple Histological Examination Tumor grading is now mostly performed according to the system of Bloom and Richardson, sometimes locally modified. · The discussions on the use of the three- or four-grade system are now over, and in most pathology laboratories the three-grade system is used. · Furthermore, the discussion on hyper- and polychromasia of the cancer cell nuclei and their roles as grading features is no longer current, especially in multicenter studies, because
these features depend heavily on fixation, the thickness of the sections, and the different hematoxylin solutions used. The main features are gland formation, polymorphism and mitotic activity. (For comments on the grading factors see Schauer et al. 1998.) With reference to the significance of the individual factors it must be emphasized that polymorphism and mitotic activity (factors of the nuclear grade) are the most valuable and easily obtainable parameters. In most cases the rate of mitosis corresponds to the photometrically evaluated S-phase value. Because of staining artifacts and difficulties in the delineation of apoptotic figures, the rate of mitosis is not always easily counted. The S-phase value can be used to some degree as a control value and give further information on the speed of proliferation. The frequently discussed problem of inter-observer discrepancies, with consensus rates of only 70%, is the result of comparisons of results not obtained by ªexpertsº in tumor grading, that is to say by highly experienced pathologists. The low consensus values have mostly been discussed and published by gynecopathologists, most of whom have had only short periods of training in tumor pathology. Our own experience in this field indicates that young pathologists, and/or also co-operating biologists, have different levels of skill in reaching holistic judgments and that when welltrained and experienced pathologists do this work 90±95% agreement can be reached.
Fig. 14. C-erbB2-positive cancer (p185 positivity; Ab. 9G6; fac. p105 positivity in serum). Cross-section of a small duct with solid cancer cell proliferation totally filling the lumen. Demonstration of the p185 transmembrane protein using the antibody 9G6 for staining of the extracellular domain of the growth factor receptor
Sentinel Node Localization in the Different Node Groups
Oncogene Activities and Mutated Suppressor Genes Modify Biological Behavior Oncogene overexpression (e.g. c-erbB2) (p185) (Figs. 14±16) or expression of defective suppressor genes (p53) (Fig. 17) also play a part. Therefore, these features of tumor biology should already be evaluated at the earliest time point of cancer biology evaluation, as a rule in the primary. The intra- and extracellular domains of the cerb-B family members and corresponding growth factors (ligands) binding to the extracellular domain are demonstrated schematically in Fig. 18.
Whereas c-erbB1 and B2 have an unfavorable influence on tumor progression, c-erbB3 can be regarded as a more favorable factor. The German Breast Cancer Study Group first demonstrated that c-erbB2 overexpression led to fast hematogenous progression in breast cancer already in the pT1N0 stage. The 8-year overall survival of the patients (c-erbB2 negative and positive) was 85% (Fig. 19). With regard to these now internationally accepted results, it is necessary to exclude systemic spread in these early stages, even before the search for the SLN. Figure 18 documents the intra- and extracellular domains of the c-erbB family members and their extracellular binding growth factors.
Fig. 15. Invasive medullary breast cancer with strongly positive reaction of the extracellular domain of c-erbB2 oncoprotein (p185) using the antibody 9G6. Note also the large cancer cell nuclei with prominent nucleoli
Fig. 16. Large-cell high-grade breast cancer with strongly positive reaction of the growth factor receptor (p185) at the cancer cell membranes (red) and positive reaction for proliferation-associated nuclear protein using the antibody MIB I (brown staining of cancer cell nuclei; arrows)
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Chapter 21 Breast Cancer Fig. 17. p53 Positivity (positive reaction) with antibodies directed against the mutated (defective) suppressor gene (ªmutated wild typeº) in the cancer cell nuclei. Invasive solid cancer cell formations with positive reaction of the cancer cell nuclei (> 50%)
The ascertainment, especially of c-erbB2 overexpression (p185), in the tumor tissue of the primary must prompt conscientious investigations to exclude early hematogenous spread, using radioimaging and if necessary bone marrow and liver punctures, etc., before sentinel node investigations are discussed and started. The immunohistochemical reaction at the p185 transmembrane protein (extracellular domain) is demonstrated in Figs. 14±16. In summary in all breast cancers with unfavorable prognostic factors like high degree of malignancy, high S-phase, oncogene overexpression etc. hematogenous spread must be excluded before lymph node labeling. The higher incidence of locoregional and systemic recurrences in p185-positive cases is demonstrated in Fig. 20. The differences between the recurrence rates in c-erbB2 (p185) positive and negative cases in the pT1N0M0 collective can be clearly seen as soon as in the first 3 years of follow-up (Fig. 20). A second important change to a gene is, as already mentioned initially, the mutation of the tumor suppressor gene, p53 (Fig. 17), to a defective gene unable to induce apoptosis and, with that, to promote high proliferation activity. No significant data are available of the influences of molecular biological mechanisms affecting the increased spread (Fig. 21). A third biologically important factor is the markedly increased activity of the metalloproteases and cathepsin D, which promote tumor progression. This enzyme can even be detected by immunohistochemical investigation in the cytoplasm of the
cancer cells, but only biochemically measured high enzyme activities seem to be relevant. These evaluations can only be carried out when pathologists cooperate with biochemists or are themselves able to do biochemical work and possess adequate devices. In relation to high locally released proteolytic activities, opening of lymphatics promoting cancer cell invasion must be assumed. In these conditions changes of the lymphatic flow are also possible, but there are no evaluations relating to changes in lymphatic drainage. Does c-erbB2 (HER/neu) Overexpression Influence the Sentinel Node Concept? It has been known and statistically certified for some years and is now generally accepted that cerbB2 overexpression is at least one of the factors associated with fast hematogenous cancer progression. Therefore, it seems to be very important to obtain information about c-erbB2 (p185) positivity ± whether from biopsies or by FNAC evaluations ± at the earliest possible time point. J New Insights in Amplification Using the FISH Techniques At present, the idea that cancers which in addition to membrane positivity for p185 protein, basically show amplification of the c-erbB2 gene, also involve a high risk of lymphatic and hematogenous spread seems to be plausible. Professor Rçschoff (Chief of Pathology in Kassel, Germany) has put photographs
Sentinel Node Localization in the Different Node Groups
Fig. 18. Members of the c-erbB1±B4 [= epidermal growth factor receptor (EGFR)] family
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Chapter 21 Breast Cancer Fig. 19. Overall survival by treatment
Fig. 20. Comparison of cases overexpressing HER 2/neu showing positive immunohistochemical reaction for p185 oncoprotein with p185-negative cases, all in stage pT1N0M0 (patients in the German Breast Cancer studies) demonstrates statistically significantly higher recurrence and death rates in the p185positive group even in the few years immediately after the operation
documenting amplification of the c-erbB2 gene at our disposal. The first series of pictures demonstrates amplification of the c-erbB2 gene (Fig. 22 a±d). The amplification of the c-erbB2 gene activity can be seen still more clearly in a higher magnification [c-erbB2-(HER2/neu)-amplification red polygonal spots in relation of the centromeres (green)]. Figure 22 d is a higher magnification of Fig. 22 c. In the second case (Fig. 23 a±d), strong p185 positivity at the cancer cell membranes can only be seen at the intraductal proliferating cancer cells, whereas the invasive cancer cell formations are negative (Fig. 23 a). The intraductal cancer cells also show amplification of the c-erbB2 positivity (Fig. 23 c). These results, demonstrated by two cases, were recorded in cases with high c-erbB2 gene amplification during monitoring especially for systemic spread, but also for axillary metastasis and parasternal node involvement. Only looking for axillary sentinel lymph nodes could be dangerous in cases with c-erbB2 gene am-
plification, because organ metastasis can exist even at very early time points; CMF (cyclophosphamide, methotrexate, 5-fluorouracil) is then not helpful, but chemotherapy using anthracyclines may be effective.
Molecular Biological Techniques for Detection of Lymph Node Metastases The outstanding progress of recent years has been built on in the development of molecular biological techniques. In clinical research these methods can be used to recognize (for instance): · Gene alterations · Gene products with special characteristics, e.g., ± Cytokeratins (CK19mRNA evaluated by quantitative RT-PCR for breast cancer cells) and ± Mucins (MuC1) in epithelial cancer cells (breast, stomach etc.)
Sentinel Node Localization in the Different Node Groups Fig. 21. Function of the suppressor gene p53 (wild type) inducing G1 arrest or apoptosis in injured cell systems. Mutated p53 cannot eliminate malignantly transformed cells by apoptosis and allows unlimited cancer cell growth
± Enzyme activities, e.g., tyrosinase for detection of malignant melanoma cells ± Many other substances that are useful as cell markers. To get a feeling for the usefulness and significance of these methods in the framework of the histological and immunohistochemical methods described, it is necessary to have an insight into the techniques and biochemical processes on which these methods are based. The polymerase chain reaction (PCR) used works as follows:
· At specific DNA segments, which are responsible for cell-characteristic gene products, complementary synthetic oligonucleotides (primers) are bound. In Bostick's investigations, lymph nodes from patients without cancer expressed CEA, 9a 733.2, muc-1 and, at least in preliminary investigations, CK19. Therefore, positive results in the evaluation of these markers using RT-PCR would not have any value in diagnosis. · The primers allow the repeated duplication of the DNA segment in cyclic repetition, with subsequent separation of the DNA strands and repeated binding of the primer, leading to the synthesis of a large amount of this specific information potential. This process can be re-
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Chapter 21 Breast Cancer Fig. 22. a Invasive solid growing ductal breast cancer: moderate nuclear polymorphism and abundant developed cytoplasm. b Same case: with strong expression of c-erbB2-related p185 transmembrane protein (note the strong membrane-bound immunoprecipitate.) c Same case: amplification of the (HER/ neu) c-erbB2 gene (see delimited polygonal red spots, some large). d As in c, but at a higher magnification
garded as a very sensitive proof of the marker to be found. When a particular and strongly defined segment of the mRNA is the starting point for a specific piece of genetic information, this procedure is referred to as reverse transcriptase PCR (RT-PCR). In this reaction the mRNA extracted from the cells is transcribed to cDNA, and this cDNA is then multiplied by the PCR. As already pointed out, RT PCR is highly sensitive. It allows the detection of a single cancer cell within 106 lymphocytes and other cells related to
the lymph nodes. In practice, however, handling in the actual state is still doubtful (Bostick et al. 1998). False-negative and false-positive results are reported. This is depressing, because tissue used for molecular biological investigations is lost and neither molecular biological nor morphological based investigations can be repeated, for instance when a whole node has undergone the primary examination. Because under these circumstances not even the basic morphological evaluations can any longer be performed as routinely as was usual earlier, the
Sentinel Node Localization in the Different Node Groups
Fig. 22 c, d. (Legend see page 202)
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Chapter 21 Breast Cancer
Fig. 23. a Invasive ductal breast cancer with positive p185 reaction in the intraductal parts but negative reactions within the invasive cancer cell formations. b HE staining of the same cancer. Note the intraductal parts on the right and the invasive solid growing parts on the left of the picture.
c Intraductal part of cancer with amplification of the cerbB2 gene. Note large, polygonal, delimited red spots. d Invasive part of cancer without c-erbB2-gene amplification. Note the small red spots no bigger than the green spots, which mark the centromeres
Localization of the SLNs in Multifocal and Multicentric Breast Cancer
consequence is that N-staging is impossible, and with this less of the information that was the basis for adjuvant therapy was available. We therefore have to ask what the reasons for these unfavorable conditions are. False-negative results can be the result of inadequate sampling, but this can be improved by controlling the results, for instance by using imprint cytology. Technical faults can also be a cause, which must be linked mainly with the extraction of FNA. It is a well-known fact that the danger of contamination with exogenous RNA molecules is very high. In addition, false-negative results can also be triggered by wrong amplifications in contaminated extracts. False-positive results are at least partly correlated with wrong amplifications in PCR and lead to indications for and performance of more extensive, but unjustified, operative treatments. Altogether, the RT-PCR method is highly sensitive, but must be improved before it can be routinely used. With the aim of a high degree of security, specific indications for the use of RT-PCR are described and discussed in the different chapters dedicated to individual tumor entities.
Warning Signals for Our Strategy in SLN Investigation of Breast Cancer Patients Before the extensive procedures for the SLN investigations using the methods described are started, besides the well-known factors such as CEA and A125, investigations of some newly elaborated blood factors seem to be helpful in giving an overview of the status of the disease. It is now well known that the c-erbB2-related protein p185 is expressed in 20% of breast cancer cases, while mutated p53-coded protein is expressed in 15±20%. In cases with c-erbB2-positivity a p105 protein can be shed from the extracellular domain, obviously after splitting off as a result of metalloprotease activities. This protein can be detected in the serum of the patients by an ELISA technique. Among p53-positive cancer patients, 30±40% express antibodies directed to p53, which can be titered in the serum. It seems obvious that both in cases with p105positive sera and in cases with antibody formation in p53-positive cases directed to p53 protein, we
usually find not only incipient or advanced lymph node involvement but also, and much more frequently, hematogenous tumor seeding that has already taken place into the bone marrow and into the organs, especially the liver. These statements may also be of interest in the diagnosis and treatment of other cancer types (of the ovary, stomach, bladder, etc.). Therefore, cancers involving these special prognostic factors should be carefully differentiated, not only with reference to the question of the significance of sentinel node investigations or primary extended axillary revision, but also with reference to a general cytostatic concept also taking account of chemoresistance to CMF, the combination therapy used in the most cases.
Localization of the SLNs in Multifocal and Multicentric Breast Cancer V. Schauer Introduction Malignant tumors of the breast, sometimes occurring with synchronous or time-shifted multifocal, multicentric or bilateral foci, are the most common cause of death from tumor in women in the age group from 35±55 years (Silverberg and Lubera 1987). In the Western World 1 out of 10 women will suffer from breast malignancy, with the incidence increasing during the life time of each. In many countries screening programs for the early detection of breast cancer have developed, routinely using X-ray mammography in combination with a physical examination and ultrasound. In X-ray mammography, as is well known, characteristic microcalcifications can be depicted very sensitively (Feig 1988). Basically, some very characteristic subtypes of microcalcifications are the starting point for further diagnostic efforts. These are: · Microcalcifications in small groups, which are suggestive of ± Mastopathy ± Fibrocystic disease, sclerosing adenosis ± DCIS, lobular carcinoma in situ (LCIS) or invasive cancer · Longitudinal or ªY-likeº arrangement of calcifications, which is suggestive of ductal noninvasive or invasive cancer
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· Opaque (ªdust-likeº) densities, usually corresponding to comedo cancer.
Important Conditions for Detection of Small Cancer Foci in Multifocality and Multicentricity In unclear cases, or when the lesions cannot be accurately localized by X-ray mammography, MR mammography is a valuable diagnostic tool. With optimal technique applied by a welltrained radiologist with experience in handling and evaluation, more than 80% of cases in which X-ray mammography and ultrasound have not given clear results can be diagnosed by means of MRI. Although discussion is now developing about the value of X-ray mammography within so-called screening programs for early cancer detection, in view of its costs and the survival rates, it must be pointed out that as long ago as at the end of the 1980s, X-ray mammography was proved to extend survival at that time, as the only imaging method then available (Feig 1988). In the early phases of MR mammography, 16 years ago there was no agreement on the value of this method, because of the multitude of different measurement possibilities. The considerably worse spatial resolution than with X-ray mammography, the inability to detect microcalcifications, and the high costs and the need for injected contrast medium were seen as disadvantages. Since then, however, numerous publications have shown that MR mammography yields the highest sensitivity in the diagnosis of early and small breast cancers, and, particularly, that the multifocality and multicentricity of breast cancers cannot be adequately recognized except with this method (Kaiser and Mittelmaier 1992; Kaiser and Zeitler 1989; Allgayer et al. 1991; Fischer et al. 1993; Gilles et al. 1996; Heywang-Kæbrunner et al. 2001). The main problems remaining in the routine diagnosis with X-ray mammography are the socalled dense breast, especially in young patients (Page and Winfield 1986), the difficulty of examining breasts containing silicone implants (Cooney et al. 1994), the postoperative status with the development of scars (Rieber et al. 1997), and focal areas of breast density which cannot be classified with certainty.
It was hoped that MR mammography, especially contrast-enhanced MRI, would further improve diagnostic specificity in such cases. In particular, the amplitude and velocity of contrast enhancement in dynamic MRI seem to be valuable diagnostic criteria (Kaiser and Mittelmaier 1992; Rieber et al. 1997). This can be explained by the generation of early tumor angiogenesis, locally increased permeability enhanced by cytokines or locally produced mediators such as are found, for instance, in medullary cancers, which are probably reliable factors even in ªearlyº cancers 2±3 mm or more in size. Such tumors need an increased blood supply for nourishment and for removal of metabolic waste material before they can grow in an uncontrolled manner (Weidner et al. 1991). Unfortunately, contrast enhancement appears in a broad, overlapping manner in both malignant lesions and benign lesions such as fibroadenomas. Therefore, measurement of the dynamic contrast uptake of a lesion in the first minutes of the investigation is intended to help in differentiation between malignant and benign lesions. Many carcinomas and also the very rare carcinoid show either a very strong increase followed after more than 2 minutes by a constant or decreasing signal intensity, while other, benign and false-positive, findings are characterized by a progressive further signal increase extending over the entire timeframe of the dynamic evaluation. The early ªwashoutº effect seems to be the most reliable sign of malignancy in the MR mammography. This method permits higher specificity (Kaiser and Zeitler 1989) but results in a loss of sensitivity owing to tumors with marked but protracted enhancement patterns (Klengel et al. 1994). Under these aspects the diagnostic value, especially with reference to premalignant lesions, remains somewhat doubtful. On the other hand, very small cancer foci measuring only a few millimeters across, some of which are found in the stage of DCIS, can be localized by MR mammography. This is a very valuable fact, because 80% or more cases of early cancer that are not detected by X-ray mammography or ultrasound may be localized and confirmed in the histopathological evaluation.
Localization of the SLNs in Multifocal and Multicentric Breast Cancer
Practical Procedures and Devices Used in MRI The patient is positioned prone in the unit to minimize respiration artifacts. The breast examination is carried out using commercially available bilateral breast surface coils. The MRI is performed in a 1.5-T MR unit (Philips ACS NT) with a slice thickness of 2.5±3 mm in coronal and axial planes. A turbo-SE-T2 sequence is investigated and combined with a dynamic SE-T1 sequence (230 ´ 512 matrix, no gap, TR 600, TE 15, 400 cm field of view, acquisition time 6 min 35 s) before and after administration of the contrast solution. The contrast medium is injected in a dose of 0.4 mmol Gd-DTPA/kg body weight as a bolus given as fast as possible, with a subsequent bolus of 20 ml physiological saline solution to facilitate complete inflow of the contrast medium from the tubing into the cubital vein. Acquisition of data in the dynamic contrast medium series is begun immediately after the injection is started, starting after 1, 2, 3, 4, 5 and 6 min. Qualitative contrast medium uptake is evaluated using subtraction images produced by subtracting the individual images of the native sequence from the images acquired at the same respective slice positions for certain defined time intervals after contrast medium application. The subtracted images permit better visualization of the early contrast enhancement. Structures that appear focal after contrast medium administration, and areas corresponding to regions in which clinical examination has raised the suspicion of malignancy are noted.
SLN Search in Cases with Multifocal or Multicentric Breast Cancer The main aim of the systematic development of qualified breast cancer diagnosis is the reduction of mortality. This goes in parallel with early detection of noninvasive and early invasive breast cancers, that is cancers from which metastases have as a rule not yet developed. Furthermore, different imaging systems for labeling SLN (blue stain method, 99mTc labeling) or proof of metastatic spread, e.g., by PET help to detect metastatic involvement as early as possible. After histological and immunohistochemical verification of lymphatic spread the result is decisive for selection of further treatment strategies. The
pattern of lymphatic metastasis depends on the location of the primary. The cancers are most frequently located in the upper lateral quadrant of the breast. These tumors metastasize predominantly, and cancers of the lower lateral quadrant and the central parts and both medial quadrants partly, into the axillary nodes (in total 90%). However, centrally and medially located primaries in particular can also metastasize into the parasternal and infra- and supraclavicular lymph nodes (±28%). In cases of lymphangiosis carcinomatosa, cancer cells can be spread extensively, by lymphangiosis, to the pleura, the mediastinum and the contralateral breast. Since the field of view in X-ray mammography and that in ultrasound imaging are restricted, because of the anatomic morphology and the procedure of data acquisition, MR mammography and, increasingly, also PET are being used to cover a more extensive field of view containing axillary, parasternal, and infraclavicular lymph nodes. Exact knowledge about the quality and handling of the imaging (MRT, PET) and labeling (blue stain, 99mTc) techniques are important factors in the initial control of regional lymphatic spread, in general and most critically in cases with multifocal and/or multicentric cancer of the breast. A stronger, clear-cut definition of both entities, introduced by Fisher and Schauer to perfect interdisciplinary understanding in daily routine work and based on personal experiences and discussions in Pittsburgh 1984 is now generally accepted and used in the literature. Multifocality is defined as a cancerous lesion with satellite cancer foci ± short distances apart ± as a rule in the same quadrant of the breast; it is only in localization of these lesions near the quadrant lines that the lesions can reach the neighboring quadrant. In contrast, multicentric cancers are characterized by simultaneous development of multiple clearly separated neoplastic lesions in different quadrants. These definitions are meanwhile accepted not only by pathologists but also in radiodiagnosis (Rieber et al. 1997) and in surgical disciplines. The third possible type of simultaneous development of multiple cancerous lesions is bilateral cancer development in both breasts. Under the clearly defined categories of malignant lesions of the breast now current, multifocality is of special interest with respect to breast-con-
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serving surgery, because surgeons have the aim of avoiding total mastectomy if at all possible. In view of the requirements and intended surgical strategies it must be kept in mind that tubular and lobular cancers have a higher tendency to multifocality and multicentricity. Therefore, in such cases it is very important to be extremely careful in monitoring that the lesion has been completely excised. The question of multifocality and/or multicentricity can be answered most precisely by using MR mammography, which seems to be important for further classification, especially as it concerns the lymph node status. Demonstration of multifocal and/or multicentric disease is optimal when, in addition to plain X-ray mammography and ultrasound investigation, MR mammography is also performed after intravenous administration of contrast medium application and evaluated. In cases with confirmed multifocality, peritumoral injection of the 99mTc-contrast solution should be injected around the circumference of all foci in deeper locations and subdermally into areas corresponding to more superficially located foci. Whereas multifocal cancers usually drain to the same SLN (s) or the same basin, multicentric cancers can drain to separate basins (axillary and/or parasternal lymph nodes). This is why a separate series of injections around the circumference of each lesion is necessary to obtain the clear-cut results needed for further treatment (surgery, radiotherapy). A few cases are now reported to illustrate some specific situations that can be encountered in practical work.
Case Reports J Case 1 A 36-year-old woman had mastopathy of both breasts, seen as diffusely increased uptake of contrast solution on MR mammography (Fig. 24). In the lateral part of the left breast a highly suspicious lesion (BI-RADS V) surrounded by three satellite foci was revealed, signaling multifocal breast cancer. The main lesion extends as far as the border of the pectoralis muscle. In addition, there was strong contrast uptake in some axillary lymph nodes on the left. The diagnosis of cancer was confirmed by histological examination. J Case 2 MR mammography revealed a histologically confirmed carcinoma of the right breast in a 46-yearold woman patient (Fig. 25). This was a large tumor occupying almost the whole of both upper quadrants of the right breast. Ventral to the tumor was another solid region of early and strong contrast uptake, which was in keeping with the diagnosis of a satellite focus. In the left breast, another four areas of early local contrast enhancement were found in the inner quadrant and the lower outer quadrant, in keeping with the diagnosis of bilaterality and multicentricity. In the right axilla some lymph nodes up to 1.5 cm thick and with strong contrast uptake were observed. In addition, parasternally a right-sidedhighly suspect lymph node was observed next to the mammary artery. In this case, the detection of all putative sentinel lymph nodes was very impor-
Fig. 24. MR mammography of a 36year-old woman (case 1) with histologically confirmed cancer of the left breast, surrounded by three satellites (multifocality). Highly suspect lymph nodes were found in the axilla
Localization of the SLNs in Multifocal and Multicentric Breast Cancer Fig. 25. MR mammography of a 46year-old patient (case 2) with a huge, histologically confirmed, carcinoma in the upper quadrants of the right breast and highly suspect lymph nodes in the axilla and a satellite as a sign of multifocality. In addition, there are suspicious areas in the tissue of the left breast, which is consistent with a diagnosis of bilaterality and multicentricity
tant, since there were two different possible routes for lymphatic flow. J Case 3 The patient concerned was a 51-year-old woman with a multifocal, partly ductally invasive, partly
noninvasive (DCIS) cancer with extension of the DCIS foci into extensive parts of the breast (Fig. 26 a, b). No search for SLN(s) after labeling of the margin areas was indicated. The only information it could have yielded was whether the parasternal Fig. 26. a X-ray mammography in a 51year-old woman (case 3), showing multiple lateral densities, with microcalcifications in some. b Corresponding MRI, showing contrast medium-enhanced focal lesions of different sizes in both breasts. No precise histological data available for this case
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lymph nodes (mammaria interna group) were the target nodes (SLNs) or involved in a metastatic process (which would certainly be important for RT extension), and the labeling procedure is extremely difficult and problematic. J Case 4 This patient was 43 years old and had a multicentric breast cancer located in dense parenchyma of the breast, as seen on mammography (Fig. 27 a) and clearly demonstrated by MRI (Fig. 27 b). In cases of such extensive multicentricity the search for SLN is only of importance for confirmation or exclusion of drainage to parasternal basins and for decisions on adjuvant radiotherapy of the parasternal region. Routine axillary node revision seems to be the method of choice.
Fig. 26 b. (Legend see page 209)
J Case 5 Figure 28 a, b shows the mammography and the breast MRI of a 56-year-old patient with an ulcerating tumor of the right breast, growing through the thorax wall with infiltration of the pectoral and intercostal muscles. Mammographically, there are three roundish densities with contour irregu-
Localization of the SLNs in Multifocal and Multicentric Breast Cancer Fig. 28 a, b. Ulcerating tumor of the right breast in a 56-year-old woman (case 5). a Left: left-sided multicentric carcinoma with three roundish densities in gamma ray mammography (medial to lateral plane). Right: corresponding craniocaudal plane. b MRI of the ulcerated tumor on the right side, with invasion of the thoracic wall
3 Fig. 27 a, b. Multicentric carcinoma in the right breast of a 43-year-old woman (case 4). a X-ray-2a mammography (medial to lateral plane) of the multicentric carcinoma of the right breast. The cancer foci are indicated by arrows. b Corresponding MRI of the same multicentric carcinoma.
In the dynamic sequence the multiple foci show early strong enhancement. Peritumoral labeling of the medially located focus could be helpful to check whether drainage to the mammaria interna nodes is taking place
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larity and some irregular spicule-like extensions into the surrounding fat and glandular tissue in the left breast as morphologic criteria arousing the suspicion of malignancy. Corresponding to these findings, in the ultrasound that was performed in addition three irregular, partially lobulated focal lesions were seen, with a dominant dorsal echo and an absence of echo at their sides. In the MR mammography, the percentage increase in signal intensity during the first and second minutes after contrast medium administration is a sign of malignancy. In this specific case there were multiple focal lesions with strong contrast enhancement in the subtraction images 2±3 min after injection in the dynamic T1-sequence, which is consistent with the diagnosis of a multilocular carcinoma. Isolated contrast-enhanced structures in both breasts are interpreted as representing contralateral disease in addition to multifocality. The suspected diagnosis was confirmed histologically. The lesions were not
all detected with other diagnostic methods. Furthermore, in MR mammography multiple axillary and infraclavicular lymph nodes were visualized. In contrast to the excellent capability of detecting primaries in the MR mammography, the usage of this procedure alone does not make it possible to decide whether to perform SLN diagnosis. In such cases of extended multicentric tumor growth with bilateral involvement sentinel node search is without any value for further treatment strategies.
Fig. 29. Invasive bilateral ductal breast cancers in a 54-yearold woman (case 6): top right upper outer quadrant; middle left upper inner quadrant; bottom additional focus in left upper outer quadrant. In this specific case it might be help-
ful to use blue stain 99mTc for a bilateral SLN search, since the disease is unifocal on the right and multicentric on the left
J Case 6 This 54-year-old woman was found to have invasive bilateral ductal breast cancers (a) in the upper outer quadrant of the right breast, (b) in the inner upper quadrant of the left breast, and also to have (c) an additional cancer focus in the left-sided upper outer quadrant (Fig. 29).
Localization of the SLNs in Multifocal and Multicentric Breast Cancer
In this particular case it might be helpful to conduct a search for SLN(s) on both sides by labeling (blue stain 99mTc), because of the single focus seen on the right side and the multicentricity in the left breast. J Case 7 A multifocal breast cancer with lymph node metastases was detected in a 70-year-old woman on mammography (Fig. 30) (pN1bii according to histopathology). In such cases there is no point in searching for SLN(s).
J Case 8 A 57-year-old patient with cystosarcoma phyllodes and ductal invasive cancer was found to have a hypervascularized focus in the outer marginal area on the left (Fig. 31 a). The benign and malignant variants of cystosarcoma phyllodes are closely related to fibroadenomas, in which malignant degeneration is extremely rare. Both benign and malignant types cystosarcoma phyllodes often grow surprisingly fast. They can develop as soon as the second decade, but most develop in middle age. The most characteristic histopathologically and immunohistochemically evaluable features of both categories are demonstrated in Fig. 31 b±i. Despite the mostly sarcomatous growth pattern of malignant subtypes, we have to realize that these tumors quite frequently metastasize by the lymphogenic route before metastasis into the lungs occurs. Fig. 30. Multifocal breast cancer with lymph node metastases detected on mammography in a 70-year-old woman (case 7; histopathology: pN1bii)
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Fig. 31 a±d. (Legend see page 216)
Localization of the SLNs in Multifocal and Multicentric Breast Cancer
Fig. 31 e±g. (Legend see page 216)
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Fig. 31. a Cystosarcoma phyllodes and ductal invasive cancer revealed in a 57-year-old patient (case 8) by MRI mammography (MIP image): hypervascularized focus in outer marginal area on left ()) and small hypervascularized lesion further in the frontal direction (!). After MR-guided marking of this lesion a biopsy was taken: the histopathological diagnosis was ductal invasive breast cancer extending 5 mm (microcarcinoma). Other case: b Giant benign cystosarcoma phyllodes; no malignant areas found on histopathological examination. Satellite in basal position close to the pectoralis fascia. In the case of malignancy such extensive tumors can drain to axillary, parasternal and other regional lymph node groups. c, d Benign cystosarcoma phyllodes with elevated proliferative activity and segmental cellular hyperplasia at the glandular body (Ki67/MIB I staining). e Cystosarcoma phyllodes focal with epithelial (cytokeratin positive)
solid cell proliferation at one glandular structure. f Malignant cystosarcoma phyllodes, with a histological structure similar to that of malignant histiocytoma. Note high degree of cellular polymorphism. g Malignant cystosarcoma phyllodes: the epithelial parts of the tumor are stained with antibodies against cytokeratin 19. The anaplastic mesenchymal parts are cytokeratin negative. h Malignant cystosarcoma phyllodes with very high proliferative activity of the ductal epithelia (Ki67/MIB I reaction) and also high proliferative activity of the surrounding mesenchymal tumor components. i Malignant cystosarcoma phyllodes; mesenchymal parts with very high proliferation. More than 80% of the mesenchymal tumor cell nuclei are in the proliferative compartment, showing a strong reaction with the antibody Ki67 (MIB I)
Localization of the SLNs in Multifocal and Multicentric Breast Cancer
Fig. 32 a, b. MR mammography results recorded in a 37-yearold patient (case 9 a). a Fibroadenoma with hypervascularization in the right inner quadrant with a lobulated configuration; round hypodensive focus in T1-related native investigation. b Hyperintensity of the focus in the IR sequence, compatible with retention of large amount of water bound to mucopolysaccharides. Strong enhancement in the tumor area after administration of contrast medium. c Subtraction photography in same case. Histological diagnosis: myxoid fibroadenoma (figures kindly donated by Professor U. Fischer,
Gættingen). d Intracanalicular fibroadenoma with typical histopathological pattern. Epithelial and mesenchymal parts are proliferating simultaneously. The characteristic leaf-like pattern develops because the mesenchymal parts impress the gland-epithelium, as the top of a ªglove-fingerº can be impressed. Note highly vascularized mesenchymal structures (arrows). e Benign fibroadenoma with low to moderate proliferation in epithelial and mesenchymal parts (Ki67/ MIB I reaction). Picture documents young, strongly hormone-stimulated fibroadenoma in developmental phase
In such cases peritumoral labeling using blue dye using blue dye and/or 99mTc-nanocolloid helps to detect extra-axillary sentinel lymph nodes.
strong impression on ultrasound investigation of a fibroadenoma (case 9 a). The other example is that of a 48-year-old woman patient with a newly appeared focal lesion, which has a sharply defined, lobulated configuration that is in keeping with the histological diagnosis of a medullary carcinoma (Fig. 33). In both these cases there was a strong uptake of gadolinium in the first few minutes of the dynamic MRI, which makes the classification on the basis of the MRI uncertain. In the additional X-ray mammography and, especially, the ultrasound it was possible to differentiate between a fibroadenoma and a medullary carcinoma, on account of the characteristic morphological pattern.
J Cases 9 a and b Since there are malignancies with a more protracted or intermediate type of dynamic contrast enhancement (Klengel et al. 1994), the lack of fast Gd-DTPA uptake cannot exclude malignancy. One example that can be cited to underscore this statement is the differentiation between a benign fibroadenoma (Fig. 32 a±c) and a malignant medullary carcinoma such as is seen in Fig. 33. The 37year-old fibroadenoma patient showed progressive growth of a lobulated focus, which gave the very
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Chapter 21 Breast Cancer Fig. 32 d, e. (Legend see page 217)
Fig. 33. Roundish, partly lobulated and sharply delineated focus similar to fibroadenoma in a 48-year-old patient. Strong enhancement was seen in this case, but centrally the contrast medium was less enriched, which is compatible with focal fibrosis. Histopathological diagnosis was medullary breast cancer
Localization of the SLNs in Multifocal and Multicentric Breast Cancer
Progress and Goals in Local Disease During recent years it could be proved that the use of mammography and ultrasound in combination with MR mammography improves not only early detection of breast cancers (DCIS and small cancers), but also that of simultaneously detectable multifocal and multicentric cancers. With increasing experience we have also learned how to use sophisticated methods to exclude fibroadenomas from further cancer diagnostic principles and how to delineate fibroadenomas from, for instance, the medullary type of breast cancer, which is also round in shape and gives a bright signal. For the solution of this problem, detailed analysis of the maximum contrast signal increase of the carcinoma in the MRI might also be helpful in differentiation. The maximum contrast will be in the vital area of the tumor in the periphery, while in the center of the tumor necrotic or hyalinotic areas are usually found with a lower signal increase. By contrast, fibroadenomas show the maximum increase in the center of the mass. Moreover, in most cases they are surrounded by low-signal membranes or can exhibit septations within the lesion, which are usually not seen in carcinomas. These advances in practice and knowledge are also helping to reduce the rate of recurrences in the breast even in low-grade cases, at least some of which seem to be resistant to radiotherapy, possibly because of their very low proliferative activity.
Conclusions and Future Developments It is difficult to develop widely applicable treatment regimens owing the different possible cancer location in the breast, such as the multifocal and/ or multicentric localizations of the primary neoplastic lesions. Nonetheless, some basic rules can be established for further decision-making relating to the search for SLN. These are summarized in Table 6 for the main entities that may be encountered. Besides SLN detection with the blue-stain and imaging methods, which give no answers on the spot about cancer infiltration of the nodes (for an analysis of this problem see Chapter 5), one topic that has long been under discussion is the minimal
Table 6. Sentinel lymph node (SLN) search in cases with multifocality, multicentricity or bilaterality Types/locations
SLN search
a
Multifocality (foci close together) in the outer quadrants
Adequate
b
Multifocality in the inner quadrants or retromammillary (central)
Adequate for confirmation or exclusion of parasternal involvement
c
Multifocality with focal location near the thoracic wall
Of limited value: in special cases peritumoral labeling of deep located lesions can confirm or exclude interpectoral or subclavicular sentinel node localizations
d
Multicentricity
In most cases primarily axillary revision; SLN search helps to confirm or exclude parasternal (mammaria interna) involvement
e
Bilaterality
Adequate, especially in early cases
f
Bilaterality with multifocality respectively multicentricity
Decision making depending on the regimens above (a±d)
size of metastases that can be detected preoperatively, and in particular using the most sensitive imaging method for preoperative detection of metastatic lymph node involvement? CT, MRI, Sinerem (iron oxide) use and PET are all under discussion and have been evaluated in various comparative studies. Without discussing this problem in too much detail, it must be emphasized that none of these methods is able to reveal micrometastases. It seems that PET has some advantages over the other methods mentioned in the detection of metastatically involved lymph nodes. Therefore, complete axillary dissection and combined histological and immunohistochemical investigation of these nodes is the safest method of detecting early regional metastasis, at least at the moment. This principle also applies in cases of multifocal and multicentric or bilateral cancers. In view of these aspects, the precondition for optimal results in cancer detection and N-staging is close cooperation between physicians working in their own practices in the community and those in hos-
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pital departments of radiodiagnosis, nuclear medicine, and pathology. The principles of evaluation for parasternal lymph nodes after blue staining or after labeling by the 99mTc-nanocolloid nuclear medical method in multifocal and multicentric cancers remain unclear or at least incomplete, because surgical excision is generally avoided. The most promising methods currently available for the ascertainment of cancer infiltration are FNAC and PET, and in some circumstances also MRI and CT.
Ductal Carcinoma In Situ V. Schauer, A. Schauer
The incidence rate of DCIS has increased from 1± 3% to approximately 20% (Harris et al. 1992; Fisher et al. 1993; Stomper and Margolin 1994; Gilles et al. 1994, 1995, 1996), which is due to the international advances in mammography screening programs. This increase obliges us to reflect on the implications of this enormous progress, especially in view of the possibility of very early locoregional spread in cases with histologically undetected early stroma invasion. With special reference to the SLN concept, answers to the following questions must be found before optimal morphologically based decisions can be made: 1. What possible ways exist of detecting DCIS preoperatively (imaging analysis etc.)? 2. Does the rate of multifocality, multicentricity, or bilaterality forbid restricting treatment to local surgery? 3. Is DCIS by definition never invasive, or can invasiveness be definitely ruled out by histopathological examination? 4. If not, what is the rate of invasive cancers confirmed by lymphatic spread detected later? 5. What are the local and/or breast-related surgical consequences in noninvasive and early invasive DCIS cases (local excision only, with or without postoperative homogeneous radiation therapy or s.c. mastectomy in cases with more extensive disease or a higher degree of malignancy)? 6. When is SLN examination and/or axillary revision necessary to avoid later tumor progression?
Table 7. Localizations of different types of DCIS Subtypes of DCIS
Localization
Papillary cancer
? Central or middle part of the breast
Micropapillary low grade
? More peripheral
Comedo-type
? Mostly central
With reference to question 1, mammography is at present the most important imaging method, especially for the diagnosis of DCIS of comedo type (dust-like calcifications along the ductal systems) or noncomedo type (solid, cribriform micropapillary low-grade disease), which sometimes show focal ªchain-likeº microcalcifications in a ªstar-likeº arrangement, mostly along smaller ducts. It is well known that different subtypes of DCIS have prevalent localizations. These are summarized in the Table 7. In most cases DCIS is not palpable (palpable hyperdensity only in 10% of the lesions). Radiodiagnostically, unclear small foci causing only slight suspicion and characterized by stellate microcalcifications can be diagnostically evaluated by means of the vacuum-biopsy technique (Mammotome, Fischer, USA). For how it relates to the BI-RADS classification, see above. When malignancy can be neither confirmed nor excluded by mammography, the additional use of MR mammography may help to sharpen suspicion and to localize malignant lesions more precisely (Heywang-Kæbrunner et al. 1989; Kaiser and Zeitler 1989; Pierce et al. 1991; Gilles et al. 1994; Gribbestad et al. 1994; Heywang-Kæbrunner and Viehweg 1994; Orel et al. 1994; Turkat et al. 1994; Fobben et al. 1995; Kuhl et al. 1995; Weinreb and Newstead 1995; Buada et al. 1996; Fischer et al. 1996 b; Soderstrom et al. 1996). The criteria for MR mammographic verification of DCIS cases by MRI are: · Angiogenesis within the intraductal atypical epithelial proliferation (e.g., in papillary cancer types) or reactive periductal angiogenesis (see also Guidi et al. 1994). · Increased local vascular permeability in the terminal capillary system caused by the proliferating cancer cell formation (cytokine induced, e.g. in medullary cancer, by factors increasing vascular permeability released from necrotic cancer cells of comedo-type cancer) (see Table 8).
Ductal Carcinoma In Situ Table 8. Summary of MR imaging findings for histopathological characteristics analyzed in 36 patients with DCIS Histopathological characteristics
Dynamic MR findings Positive
Negative
Architectural patterns comedo carcinoma
22
2
Noncomedo carcinoma
12
0
8
0
Intermediate
10
0
High
16
2
Present
11
1
Absent
23
1
Absent
7
0
Weak
10
0
Moderate
9
2
Intense
8
0
Absent
16
0
Weak
5
2
Moderate
6
0
Intense
7
0
13
2
7
0
14
0
Nuclear grade Low
Microinvasion
Necrosis
Stromal inflammation
Tumor angiogenesis Weak Moderate Intense
Gilles et al. (1995) investigated some important factors for MR imaging in DCIS cases and found stroma inflammation and tumor-induced neoangiogenesis were relevant.
Strong Enhancement of Benign and Malignant Lesions of the Breast in MRI Important permeability-increasing mechanisms in breast lesions are summarized in Fig. 34. Besides this concentrated overview some pictures should fill in any gaps in readers' knowledge and refresh their memories to help in daily diagnostic routine (see Fig. 35). Fibroadenomas are the only benign lesions of the breast, as already mentioned (Fig. 35 a), that show female cycle-dependent strong enhancement on MRI investigation. Most of the patients affected are young. When fibroadenomas persist for longer periods sclerosing fibrosis and reduction of the vascularization develop. A fibroadenoma with strong enhancement is shown in Fig. 35 b. Papillary lesions (benign papillomas and papillary cancers) develop intraductally, in most cases centrally in the parenchyma of the breast. They must be differentiated from micropapillary small lesions, which develop in the periphery of the ductal system. Bleeding from the nipple (Fig. 36) is a sign that a larger, mostly more centrally localized papillary lesion is present (Fig. 37). The exact location of such a lesion can be detected by galactography. Radiologists report that medullary breast cancers (Fig. 38) show characteristic spherical, sharply delineated enhancement similar to that of fibroadenomas. However, the reason for this quality has never been explained. It can be speculated, as already mentioned (see scheme in Fig. 34), that the local increase in vascular proliferation and permeability is mediated by cytokines released from the dense populations of lymphocytes and histiocytes. Comedocarcinomas, mixed types with a partly cribriform growth pattern (Figs. 39, 40), develop predominantly in larger ducts. This tumor type also shows strong enhancement on MRI in parts, though the cancer cell proliferations within the ducts show no vascularity. The enhancement is obviously induced by increase of permeability of the periductal vascular network by tumor necrosis factor (TNF) or similar substances liberated in the necrotic areas (see scheme in Fig. 34). In rare cases, comedo-type cancer can be part of Paget's disease, meaning intraepithelial cancer
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Fig. 34. Enhancing factors making it possible to demonstrate benign and malignant breast neoplasms in MRT investigations
Ductal Carcinoma In Situ
Fig. 35. a Intracanalicular fibroadenoma of the breast with typical leaf-like structure in a 16-year-old woman. b Same patient: immunochemical staining for factor VIII-associated endothelial protein. Note the highly developed capillary system of the myxoid stroma parts (red stained). c Extracanali-
cular fibroadenoma with balanced growth of epithelial and fibrous tissue structures. d Extracanalicular fibroadenoma (same case): staining for Factor VIII-associated protein at the endothelia (red stained) of the strongly developed capillary system
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Chapter 21 Breast Cancer Fig. 36. Papillary lesions (papillomas and papillary cancers) are often discovered through bleeding from the nipple after defect formation by the ªpapillary fingersº
Fig. 37. Benign papilloma with vascularization of the papillary proliferations. Larger papillomas are precursor lesions signaling later development of invasive papillary cancers
infiltration of the areola. For a description and the histological substrate see Fig. 41a, b. In such cases mastectomy is indicated. A preoperative search for sentinel node(s) with subareolar injection of the 99m Tc labeling solution could help by revealing any sentinel nodes in the mammaria interna chain, which would be useful since in positive cases postoperative RT of this region could then be considered, but on the other hand such decisions must be very carefully made with all factors critically weighed up. The thesis that increased vascular permeability caused by TNF, stromal inflammation, and angiogenesis is the most important factor in cancer detection by MRI and that the same factors also have an important role in DCIS is underlined by our own observations and by the listed findings of
Gilles et al. (1995). In investigations of 36 DCIS cases, necrosis (caused by TNF) was absent in only 7 cases, while stromal inflammation was detectable in 50% of the 36 cases and tumor angiogenesis, the most important factor, because of increased permeability of newly formed capillaries, was found in 34 of the 36 cases. The results of the investigations conducted by Gilles et al. (1995) are summarized in Table 8. It seems clear that in quite a high percentage of cases the different factors can be superimposed on each other to positive effect and can perhaps even potentiate each other. As in invasive breast cancers also in the early stages, namely DCIS, multifocality and multicentricity are important features that must be considered in MRI investigations.
Ductal Carcinoma In Situ Fig. 38. a Medullary breast cancer with large prominent nucleoli of the cancer cell nuclei, contrasting with low-density karyoplasm (thin section, H&E staining). b Another case of medullary breast cancer with highly polymorphous cancer cell formations in the central and left part of the figure and a dense lymphocytic infiltration of the stroma on the right. c Same case as in b: medullary breast cancer cell formations on the left of the figure and dense lymphocytic infiltration on the right. Staining for factor VIII associated protein at the new developed capillary system. Note intensive capillarisation (red stained capillaries), especially within the lymphocytic infiltrate
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Chapter 21 Breast Cancer Fig. 39 a, b. Comedo cancer, which mostly develops in central or middle parts of the breast in larger ducts. a Overview: some ducts with sharply delineated necroses, in some with cribriform growth pattern. b Single duct containing comedo cancer; necrosis seen in the center of intraductal cancer cell proliferation
Fig. 40. Mainly cribriform growth pattern, with necrotic cancer cell detritus in the glandular lumina
Ductal Carcinoma In Situ Fig. 41 a, b. Paget's disease of the breast (= intraepidermal cancer of the areola). a Differential diagnosis: eczema of the areola. Characteristics: local in situ state, but in > 80% of cases there is already deeply invasive ductal cancer; as a, this condition is an indication for mastectomy. Labeling for SLN(s) is not indicated, because it is difficult to localize and, especially, to delineate the primary within the breast. The possibility of axillary and/or parasternal lymph node metastasis must be taken into account. b Histological picture in Paget's disease. Note the pale and loosely spread intraepithelial cancer cells
Table 9. Results of MR-mammographic DCIS-imaging by different Radiology Research Groups Authors
No. of cases
Tesoro-Tess (1995) Gilles et al. (1996)
34
Orel et al. (1997)
Sensitivity
Specificity
Accuracy
83%
93%
87%
95%
51%
72%
Greenstein et al. (1997)a
13
77%
Westerhof et al. (1998)
33
45%
67%
56%
a
Greenstein et al. report that there was ductal enhancement in 6 of the 10 cases investigated, regional enhancement in 3 of them, and a peripheral enhancing mass in 1 case
In MR mammographic DCIS imaging diagnosis different results have been obtained by radiology research groups, who so far have been working with different protocols and in small numbers of cases. The main results are presented in Table 9.
Experienced radiologists report that in their series of cases investigated following MR images that had primarily suggested DCIS approximately 30% already had an invasive character with at least early stromal invasion (Heywang et al. 1989; Kaiser
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and Zeitler 1989; Harms et al. 1993; Gilles et al. 1994; Heywang 1994; Piccoli et al. 1995; Stomper et al. 1995). This statement is based on the experiences of pathologists, who find under serial sectioning of the tumor cell population breaking through the basement membrane. There is absolutely no doubt that in these cases a search for and investigation of the SLN(s) must be started. In connection with question 2 above (p. 220), we should point out that multifocality, multicentricity, or bilaterality of lesions arousing suspicion on mammography and/or MR mammography always requires evaluation of all singular suspicious foci, which must be performed on an individual basis: · When questions 3 and 4 are considered, it must be clear that DCIS is ªin situ cancerº and by definition primarily not invasive. However, in cases with larger extension (> 2.5 cm) the pathologist cannot check every duct in the whole continuous longitudinal extension for minimal stromal invasion. Therefore, the rates with later lymphatic spread into axillary nodes cannot be calculated with the value zero. The rates of lymphatic spread to the sentinel node(s) reported in the literature range between 2% and 6%. Because of the reality of phase-shifted multifocality, later new development of preinvasive or invasive cancer, node involvement in the axilla or spread to the parasternal nodes must always be considered in the follow-up of these patients. In response to questions 5 and 6, there are no strict guidelines for surgical treatment of small or extended DCIS lesions or DCIS with early stromal invasion. The treatment of small low-grade foci (see the Van Nuys classification) can be limited to local excision without further adjuvant treatment (RT, ChT). In extended lesions > 2.5 cm or in multifocal lesions complete subcutaneous mastectomy, or in high-grade cases with the danger of involvement of the large ducts or milk sinuses complete mastectomy is also indicated. Because only a limited percentage of DCIS cases can be strongly assumed on mammography or MRI, when suspicion is low intraoperative histological diagnosis of DCIS has an important role. In cases with confirmed DCIS intraoperative SLN-labeling using blue dye and/or 99mTc nanocolloid should be routinely performed with the purpose of avoiding
· Overlooked occult LN metastasis and · Complete axillary revision in cases with negative SLN (Pendas et al. 2000). Concerning Lymph Node Staging Whenever a decision for s.c. mastectomy or total mastectomy is made, a sentinel node investigation must be performed at the very least. This is urgently necessary, to avoid undetected dangerous tumor progression in the axillary nodes. The alternative would be complete axillary revision. Overall, with respect to the possibility of early stromal invasion, DCIS must be seen as a serious lesion, because in cases with a high degree of malignancy the early development of periductal neoangiogenesis before cancer invasion develops offers excellent conditions for early hematogenous metastasis if stromal invasion develops (Weidner et al. 1991, 1992).
Gamma Probe Handling in the Operation Room and Sterilization Procedures A. Schauer
The devices used must be sterilized as usual for instruments used in the operating room. Some points deserve special mention because the handling is more specialized and the devices are more cost intensive than the usual surgical instrumentarium. Sometimes it is better for the devices to be cleaned and sterilized in the operating suite by the users than to send them to the central sterilization unit. This can easily be understood, because inadequate handling or transport can destroy the instruments. The following procedures for sterilization are possible: · Autoclave sterilization · Sterilization after packing in a glove or tube, with the cable also totally covered. The control devices kept where the surgeon can see them do not need to be made sterile; these should be placed on a separate trolley. However, it is always necessary that once the sterile and nonsterile parts are connected it is imperative to ensure that the probe cannot fall and be destroyed. When the sterile probe is used, it may become contaminated with the tracer. Therefore, initial cleaning with isopropyl alcohol, followed by wiping
Gamma Probe Handling in the Operation Room and Sterilization Procedures
with a damp cloth after it has been dipped in a radioactive decontamination solution (e.g. Decon90 or Radiac wash) is indicated. The radiation should then be measured to exclude background radiation activity. When this cannot be excluded, an enzymatic detergent should be used to dissolve all organic material and remove it from the devices. In the operating room the following rules are to be recommended. · The surgical staff and the nursing personnel must be informed in the strongest possible terms about changes to be made to inadequate handling practices and about safety programs that must be observed to avoid contamination in an adequate manner. · All contaminated material related to the primary operation and sentinel node preparation and excision should be stored in safe conditions for at least 3±4 days before sterilization and use in further operations. Experience suggests that procedures followed in recent years have been sufficient for good clinical and laboratory practice. They can be divided into procedures concerning the practical handling and procedures concerned with sophisticated and scientifically based knowledge. Because practical experience accumulates rapidly, the following points must be discussed and organized: · Because success rates are dependent on the technique used and the skill of the medical investigator, a proper learning period at centers with sufficient experience seems to be very important. · The dye techniques and gamma probe techniques in combination reduce the time period for learning. Both methods can be used for both malignant melanoma and breast cancer operations and also for other cancer treatment programs.
Radiation Protection in Pathology Laboratories J Practical Advice General remarks on good practice in pathology have already appeared in the general section of the book (see Chapter 2).
When histopathology laboratories are included in interdisciplinary cooperative programs investigating SLNs special precautions must be developed. This is absolutely necessary, because not only the SLNs must be examined, but also the primaries, and in the case of positive nodes also the nodes excised from the basins. This means that pathologists must be careful to ensure protection during the ªacute investigationº of the primary, which is mostly performed by preparation and staining of frozen sections, and also during the later investigation of the sentinel node(s) and if necessary other nodes from the basin using the paraffin technique and subsequent H&E and immunohistochemical staining. Taking all procedures together some fundamental rules must be emphasized: · All investigations should be performed in the same room, including storage of the different tissue parts. · When pathologists and their technicians are working on the fresh unfixed native tissue, they should use eye, nose, and mouth protection, as surgeons generally do. · Especially the acute phases of the work-up of the primary and the preparation of the sentinel node(s) should be performed when the material arrives from the operating room in a protected condition, i.e., in sealed vessels with radiationprotected walls, with no interruptions or disturbances and in the shortest possible time period, to keep radioactive exposure as short as possible. To be on the safe side, dose rate readings should be used, when these techniques are among the routine investigations carried out in the laboratory. Should any of the pathologists or technicians on the staff be pregnant they should not work in this field; if they really cannot be substituted for by colleagues, they should be maximally protected. Experts in radio-measurement have stated that when the 99mTc-tracer is used, after preparation of the sentinel lymph node(s) practically no measurable exposure can be detected. The instruments and devices should not be used for any other purposes and should be optimally cleaned after use. For all working procedures it is important to know that only the acute investigations necessary for actual decision-making should be performed immediately.
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All biopsy material used for histological examination after embedding in paraffin should be fixed in formalin for 48 h before the embedding procedure starts. After this time interval a decrease of the radioactive (radiation) energy is only 250 Sv from the initial value, and after 1 week the tissue contains less than 1 Bq and can then be treated as nonradioactive. The surgeons must be informed about the delay of 2 days necessitated by the pathologists' wait for the decay of radioactivity. It is also important for this information to be given to the patient, because she has to know: · That there is nothing sinister or mysterious behind the delay before she hears the histologybased result. · That exact work-up of the SLN (histology and immunohistochemistry in serial sections) also takes time but is essential for an informed decision for or against axillary revision at levels I and II. Detection of Metastatic SLN Involvement by Routine H&E Staining Immunohistochemistry and RT-PCR The discussion on how to make sure that the regional lymph nodes investigated are free of tumor has already been in progress for a long time (Berry et al. 1988). This matter is highly significant, because in many cases therapeutic regimens depend on the answer to this question to a large extent (e.g., extent of operative intervention, chemotherapy, radiation therapy). It should be clear even to persons who are not experienced in pathohistological techniques and microscopic work that for the detection of even small tumor cell foci 50±100 lm in diameter the investigation of a node needs a very high number of serial sections. When a lymph node 5 mm thick (this would be a small one) is sectioned the number of sections necessary is about 50 at least. Based on this number of serial sections for investigation in one node, the number increases massively to approximately 600 when the mean number of 12 nodes examined in axillary node staging has to be analyzed. If such investigations were carried out routinely pathology departments would not be able to cope with such extensive investigations in terms of either cost or manpower. The current, obviously nearly unchangeable, situation is deeply depressing, because we know from
many studies that the prognosis in cases with metastatic lymph node involvement is poorer, as it is also even in cases with only micrometastatic involvement of one or some more nodes. With respect to this technique- and manpowerdependent nearly solved medical problem, it must be stated that no clear-cut requirements have been published by the responsible organizations and ministries or the societies of pathology (national and international) and the national and international sections of the IAP (International Academy of Pathology); nor have any of these bodies issued guidance on how to calculate the costs of the lymph node staging procedures that would be really useful. Therefore, we can be sure that the highly costintensive N-staging investigations are routinely performed in a similar way to most other investigations, i.e., they will be ªcost neutralº with respect to ªmaterial and manpower inputº. This signifies that the SLNs are investigated in too few steps. But we can be sure that when sentinel node investigations are performed with reduced accuracy of evaluations and no axillary revision follows the recurrence rates will increase and with this, the cure and survival rates will fall. It follows from this that such handling with markedly inferior conditions would be seen as negligent from the viewpoint of pathology, but also from that of the insurance companies that are responsible for financing medical diagnosis and treatment. The use of immunohistochemistry for detection of tumor cell clusters or even single cancer cells can be classed as an outstanding step forward and a new advantage. Cytokeratin staining of breast cancer cells in primaries and metastases was first performed systematically by the German Breast Cancer Research Group (Altmannsberger et al. 1981; Schauer et al. 1984). Using the highly sensitive APAAP technique developed by Mason and Stein for staining cytoplasmic cytokeratin-intermediary filaments of the cancer cells, even single cancer cells can be detected with certainty from the conspicuous impressive red staining of the cytoplasmic structures (Figs. 42, 43). This method would not be necessary in addition to H&E staining in cases with large-cell, solid or adenoid growing cancer cell formations, because the tumor cells or their clusters can easily be seen on normal routine staining. However, in cases with small cell subclones and in less well-differentiated small-cell cancers, cytokeratin staining is very helpful in cancer cell detection.
Gamma Probe Handling in the Operation Room and Sterilization Procedures Fig. 42. Detection of single cancer cells in lymph nodes using antibodies directed to the intermediary filaments (cytokeratins) of the epithelial breast cancer cells. Early lymph node metastases from breast cancer. Note single cells and small cancer cell clusters in the marginal sinuses stained with antibodies directed to cytokeratins (CK8, CK18)
Fig. 43. Detection of loosely spread breast cancer cells that are not completely reliably detectable by histology but can definitely be demonstrated by immunohistochemical staining. Loosely spread cancer cells from breast cancer, stained with antibodies directed to cytokeratins. In HE stainings such cells cannot be differentiated with certainty from cell types characteristic of the macrophage system (MPS)
Such small-cell types of breast cancer most often belong to the lobular subtype. The cancer cells sometimes cannot be differentiated from so-called sinus histiocytes or cell populations of the reticuloendothelial system. Use of the immunohistochemical staining described also involves pitfalls and complete familiarity with the technique is essential if exclusions of malignancy concluded from it are to be valid. It is possible that cellular cytoplasmic, cytokeratin-containing particles of cancer cells destroyed by necrosis or apoptosis are included in macrophages after take-up. After staining for cytokeratins by immunohistochemical techniques these phagocytic cells belonging to the MPS may impress as epithelial metastatic cancer cells. A second possible pitfall can result from a cross-reaction of anti-cytokeratin antibodies with
cytoplasmic structures of immature plasma cells (plasmoblasts). However, such possibilities of ªmimicry of epithelial cancer cellsº rarely have a role and can be ruled out by the experience of pathologists or in unusually difficult cases by immunohistochemical control investigations using antibodies against macrophages (CD68, MAK 387) or cells of the different plasma cell subtypes by using anti-IgG, IgA, IgD for instance in serial sections. At the same time, positive or negative results of the search for cancer cells in SLNs is not yet the ªsignal boxº for axillary revision in levels I and II in many hospitals, because it is not yet fully confirmed and certified by multicenter follow-upstudies that sentinel node excision alone is sufficient to exclude axillary node involvement in all
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negative cases. This means that in many clinics axillary revision is routinely performed in most cases, at least during learning phases. The question now before us is: must all axillary nodes be excised (the average number in the first German Breast Cancer Study was 12±14) for investigation by H&E staining and, in alternate serial sections, also by immunohistochemical staining with antibodies directed against cytokeratin-positive cancer cells. This question basically has to be considered in the same way as the one about certainty in cancer cell detection in sentinel node investigations. And the answer is similar: it would be highly appreciated if this were done. With respect to our laboratory work, we have done such extensive investigations in critical cancer cases (e.g., cases with small-cell, strongly dissociating cancers), but not routinely in all cases. In conclusion, the aim of many hospitals with highly developed breast cancer treatment units is to investigate the SLN(s) intensively by performing alternate H&E staining and immunohistochemical staining for cytokeratin-positive cancer cells and to avoid more intensive axillary revision. But as long as we have only the old data for the percentage of skip metastases, in the range of 3%, axillary revision at levels I and II, as performed in recent decades, is inevitable in unclear cases from certain aspects. At the moment this decision must be seen under the aspect that even just one remaining tumor-infiltrated lymph node (skip metastasis or false-negative sentinel) can multiply to three or more metastases with breakout through the capsule and consequent inoperability. Nonetheless, there are counterarguments, which give some hope! The rates of early detection of cancers have increased, becoming very high, since detection rates have been supported by new, highly specialized radiological imaging systems (mammography, MRI). Therefore, it may be that the true rate of skip metastases has gone down to 1%, or at most to less than 2%. The question of whether this statement is correct has not yet been fully checked, but studies are now in progress. At the moment, it can only be assumed that small incipient cancers have lower rates of lymphatic stops and therefore lower rates of passing on to other node groups than the sentinel node. The value of immunohistochemical analysis of the SLNs for detection of very early metastasis is highly significant; using this method in any node-
positive cases detected, axillary revision is subsequently performed. This strategy excludes the progression of skip metastases within the axillary node chain, thus also excluding the axillary inoperability that otherwise follows. It is thus easily understood that many pathology laboratories include the use of immunohistochemically supported node staging in their routine-programs. Investigations in many laboratories ± using different antibodies and staining techniques for cancer cell detection in putative metastatic lymph nodes ± were aimed at the detection of early cancer metastasis with as high a degree of certainty as possible, combined with routine H&E staining procedures (Sloane et al. 1980; Altmannsberger et al. 1981; Schauer et al. 1984; Wells et al. 1984; Bussolati et al. 1986; Raymond and Leong 1989; Sedmak et al. 1989; Byrne et al. 1987, 1992; Spring et al. 1990; Chen et al. 1991; Galea et al. 1991; Elson et al. 1993). Technical Procedures for Histopathological Lymph Node Investigation There is no doubt that the false-negative rate increases with an incorrect or inadequate histopathological examination. Therefore, it is necessary for pathologists to follow a strict schedule for their lymph node investigations. In our department, since 1976, when we first began to perform ªintraoperative staging,º it has been usual to divide smaller lymph nodes into two halves and bigger ones more than 5 mm thick into three or more slices, with the middle slice(s) not more than 3 mm thick. Afterwards we do the same using the paraffin technique (Schauer et al. 1981). To keep false-negative rates as low as possible, many authors (Czerniecki et al. 1999; Turner et al. 1997, 1999; Schreiber et al. 1999) agree that serial sections are necessary and that combined investigations with H&E staining and immunohistochemical examinations with antibodies directed to cytokeratins give maximal safety. For confirmation or exclusion of micrometastases the combined investigation results in a benefit of approximately 9±10% (Turner et al. 1997, 1999; Czerniecki et al. 1999; Schreiber et al. 1999). From the standpoint of pathologists, it must be recommended that investigation of the sentinel nodes by H&E and immunohistochemical stainings must be very stringently performed, with at least 12 serial sections of every
Gamma Probe Handling in the Operation Room and Sterilization Procedures
sentinel node (absolute minimum) and preferably 20 of each half of the node(s) and, if the nodes are larger, 20 sections of the middle slice also, that is to say a total of 40 sections of each small and 60 sections of each larger lymph node. This means more work in departments of pathology; however, it is reasonable in view of the cost-intensive treatment that a recurrence would incur. The risk of undetected sentinel node involvement in Turner's investigations (Turner et al. 1997, 1999) amounted to < 0.1%. Dowlatshahi et al. (1997) screened the literature by conducting a search of the entire body of MEDLINE data available in the late 1990s in order to evaluate the significance of micrometastases measuring 0.2±2 mm. They found that the detection rate with conventional investigation procedures was inadequate. Serial sectioning plus immunohistochemistry increased the detection rate by 9±30%. Altogether, a definite survival disadvantage has been noted for patients with such occult metastases that have not been detected by commonly performed histological examinations. These results demand critical investigation in the evaluation of sentinel node significance. In Meyer's serial sectioning scheme (Meyer 1998) three sections at intervals of 250 lm were stained (2 with HE and 1 with immunohistochemical staining). This method allows metastases 0.5 mm in diameter to be found with a theoretical probability of 1, and metastases 0.1 mm in diameter with a probability of 0.46. He also recommends immunohistochemical staining, especially for lobular cancers, because in this type single tumor cells cannot always be distinguished from sinus histiocytes or reticulum cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) investigations are in progress in various laboratories, but no results that could be applied in real practical usage are available so far (see also Chapter 4). In cell lines of breast carcinomas, mammaglobin and carcinoembryonic antigen have been found in 100% and 71%, respectively. These markers will be used in a ªmultimarker panelº in a multicenter study program. Marchetti et al. (2001) investigated seven mRNA markers, namely: CEA, CK19, Cmet, mammaglobin, MUC-1, beta-1 ? Gal Nac-T and p97, mammaglobin mRNA and CEA mRNA being the only ones that were not expressed in normal nodes. The authors analyzed the results of 248 consecutive patients with breast cancer; 89 had histologically documented lymph node metastasis.
· Mammaglobin mRNA was expressed in 97% of the patients with positive nodes, whereas CEA mRNA was expressed in 79%. · In the group with histologically negative lymph nodes 46 (29%) and 32 (20%) were found to be positive for mammaglobin and CEA expression, respectively, indicating at least the possibility that metastases not detected in routine histological examination of one lymph node section could be present. This preliminary evaluation did not involve any comparisons with the results of serial sectioning of the nodes and cytokeratin stainings. Apart from this, no control investigations were carried out that could have confirmed that mRNA of both parameters, mammaglobin and CEA, was related to vital cancer cells in all cases and not related to material from apoptotic cells picked up by macrophages (this problem has already been discussed in Chapter 4).
Intraoperative Imprint Cytology of SLN(s) FNAC, imprint cytology and core biopsy are the basic techniques used in cytopathological evaluations. Aspiration cytology is steadily used for evaluation of many palpable and/or radiologically suspicious lesions, often with the use of ultrasoundguided puncture (see Chapter 16). The last possibility mentioned is often used for evaluation of unclear mammographic or MRT related lesions of the breast, such as low-grade-suspicious lesions or nodules, or fibrocystic disease, to confirm or exclude malignancy. Furthermore, suspicious lesions encountered during the follow-up of surgically treated breast cancer patients can be evaluated with help of FNAC. In contrast, lymph node puncture using aspiration cytology is only used when systemic disease is suspected (e.g. lymphoma), and as a rule not for confirmation or exclusion of a primary axillary metastatic process from breast cancer. However, when the SLN is excised, imprint cytology of the slices with intraoperative evaluation seems to be useful in cases with suspicious node(s), because in positive cases axilla revision with node extirpation at levels I and II can be per-
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formed immediately, thus avoiding a two-step operation. Imprint cytology is a reliable method, as verified by our previous intraoperative combined program of breast cancer staging by histology and imprint cytology. Such results are only possible, however, when pathologists and cytologists are highly trained and have long-term experience. Our previous investigations, in which we compared results of imprint cytology and of histological examinations of 10±20 axillary lymph nodes for N-staging of breast cancer patients, showed that the methods compared differed by only 2%. Such precise results are only possible when pathologists and cytopathologists are already highly experienced and the interobserver differences have virtually no role, however. It must be emphasized that this method ± when carefully performed ± does not destroy the lymph node substructures and no tissues are lost from the nodes. These features mean that the proposed serial sectioning of the paraffin-embedded node-material is not influenced or limited. Some investigators take additional material from the SLN by blind puncture to get additional aspirate for further smears for H&E staining and immunohistochemical cytokeratin staining. This can only be done with fine needles (23 G) to avoid destroying too much of the node structures. However, these intentions involve very careful handling, and it must be clear that this method can give only limited results. Only positive results can be valued. Therefore, this method is no substitute for the systematic and precise analysis of SLN(s) by serial sectioning and combined HE and immunohistochemical stainings of paraffin-embedded nodes. In both the above strategies [imprint cytology and lymph node puncture at the surgical prepared node(s)], the newly developed ultrarapid immunohistochemical methods (performance within 20± 30 min) can be used intraoperatively (see Nåhrig's contribution, Chap. 17). Immunohistochemically stained smears using the APAAP technique can be evaluated very quickly, and the immunohistochemical staining for cytokeratins as cancer cell markers makes it possible to find single intensively red-stained cancer cells very easily.
Table 10. Important factors in cancer cell detection when SLNs of breast cancer patients are investigated Cell types
Marker
1. Reticuloendothelial cells (dendritic reticulum cells)
S100-Protein
2. Histiocytes
CD68/MAK 387
3. Plasmoblastic cells
IgG, IgA, IgD, IgM
4. Neoplastic cells of breast cancer (large cell high grade, small cell)
pan-cytokeratinantibodies cytokeratins 8,18 AE1/AE3
Specific breast cancer subtypes:
growth pattern and secretion products
Medullary cancer
Large nuclei and large nucleoli
Tubular cancer
Tubular, tubuloalveolar pattern
Mucinous cancer
Mucus-formation: PAS, Alcian blue positive
There is no doubt that SLNs with macroscopically visible cancer infiltration at the cut surface can be evaluated already intraoperatively by frozen section techniques. Nonetheless, intraoperative evaluation of all sentinel nodes by the use of frozen section techniques, as proposed recently by Veronesi et al. (2001), seems not to be devoid of risk (as already detailed in the general section), because too much lymph node tissue remains uninvestigated when frozen sectioning and consecutive paraffin embedding techniques are used. As already pointed out, cancer cell detection in lymph nodes can be difficult, especially in cases with high degrees of ªcancer cell dissociationº. Therefore, besides cytokeratin stainings of cancer cells, help can be sought from other strategies: · Delineation of ªcancer cell like cell elementsª · Exclusion of false-positive immunohistochemical stainings (pitfalls) (see Table 10) In more highly differentiated cancer cases, specific cellularity, growth pattern and proof of special differentiation products can also be helpful. The most important factors are summarized in Table 10.
Gamma Probe Handling in the Operation Room and Sterilization Procedures
Practical Conclusions Based on the Experiences in Clinical Management, Nuclear Medical and Pathohistological Investigations International experience indicates that the use of sentinel node detection strategies needs knowledge in different fields (tumor biology, topographic anatomy, nuclear medical and radiodiagnostic knowledge, etc.). With reference to this background of necessary experience we also understand that special ªtricksº (e.g., pushing aside the breast from the axilla for better detection of the sentinel node(s) with the gamma probe) can be helpful and that on the other hand pitfalls are possible. An overview of some of these important factors that influence our handling techniques is given below, illustrated by reference to specific situations and documentation of the consequences.
tion of the primaries. This opinion is supported by historical investigations: Dabelow (1957) and other anatomists found extensive parts of the breast parenchyma in deep parts in directly prefascial sites. Above these parts, sometimes extensive fatty tissue has developed, and the fibrous septa are arranged horizontal to the pectoral muscle. It can be concluded from these anatomical structures that the lymphatic stream also runs at least partly horizontally (e.g., to the mammaria interna nodes, or in deeper locations to the interpectoral nodes, or upwards to subclavicular nodes, and not exclusively to the surface structures of the breast). Dabelow's original picture and labeling-proposals in it are documented in Fig. 44.
Injection of 99mTc Colloid Must Be Adapted to Localization of the Primary Lesion(s) (see also Chapter 9) The tendency, based on scientific facts and on the experience of recent years, is to use subdermal injection, especially in more superficially located primaries, because the lymphatic flow passes from the breast parenchyma to the subdermal lymphatics. On the other hand, when primaries are in deeper localizations, peritumoral administration is more significant in finding the true lymphatic drainage not only to the axillary but also to the mammaria interna, subclavicular, and interpectoral nodes. This problem is also discussed in the general section, as are the advantages and disadvantages of subdermal and peritumoral administration of the labeling solutions (see Chapter 9). One point is critical: after subdermal injection an advantage is that labeling of the axillary sentinel node(s) sets in very quickly, but, as briefly mentioned above, at least in more deeply localized primaries the labeling can be incorrect. In these cases peritumoral injection of the labeling solutions results in much more correct indication of the SLNs. The statement that in most cases the lymphatic drainage proceeds from the deeper parts of the breast parenchyma to the surface structures is obviously not compatible with deeper localiza-
Fig. 44. Breast with demonstration of ductal and lobular parenchyma according to Dabelow (1957). Note: In superficially located cancers (red) the lymphatic drainage reaches the surface structures; therefore, subdermal injection of the 99m Tc labeling solution is optimal. In the case of cancers located deep in the parenchyma (green) drainage in different directions must be reckoned with. Therefore, peritumoral application of the 99mTc-nanocolloid solution is more realistic and obviously more valuable for staging
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Handling in Cases with Nonpalpable Cancer This category of cancers subsumes all in depth localized diffuse developed and growing cancers, not palpable as a more or less delineated node. The cancers develop often multifocal from the lobular parenchyma, but in more seldom cases also from ducts, especially in the state of early stromal invasion these cancers are less delineated and hardly palpable. An example of such a multifocal diffuse invasive nonpalpable cancer is demonstrated in Fig. 45.
Handling and Consequences in Cases with Primaries in the Lateral Quadrants The high degree of variability in breast cancer location in the lateral quadrants is well known. Cancers can be located extremely far laterally in the axillary tail and even in the lower level of the axilla. These in some cases extreme lateral positions result in radiation interference between the labeled primary and the labeled axillary sentinel node.
The problem can be solved by increasing the distance between the two labeled regions. To do this the breast needs to be moved in the medial and caudal directions (Fig. 46). Implications for improvement of the SLN search are listed briefly below: · The breast should be moved in a caudal-medial direction to increase the distance between the primaries in the lateral quadrants and the axillary SLN. This improves the possibility of exact SLN localization by the use of the gamma probe (reduction of radiation overlap of primaries and SLN). · A collimator should be used to avoid scattering. · The gamma probe should be used after SLN excision to check completeness of the resection.
Management in Cancers with Tendency to Multifocality or Multicentricity The rates of multifocal and multicentric breast cancers are at least partly type related. Lobular cancers are multifocal or multicentric in 10±15% Fig. 45. Diffuse nonpalpable cancer: after labeling by peritumoral injection (blue dye and/or 99mTc-nanocolloid) an axillary lymph node is labeled as the sentinel node. Primary localized by imaging (mammography, MRI, ultrasound); peritumoral (subdermal) ultrasound-guided injection of 99mTc-nanocolloid/blue dye
Gamma Probe Handling in the Operation Room and Sterilization Procedures Fig. 46. Two possible localizations of cancer, in the upper and lower lateral quadrants, with drainage to a sentinel node in the axilla (level I)
of cases, while some are bilateral. These can develop simultaneously or at different times. In tubular cancers the rate of multifocality or multicentricity is approximately 8%. Ductal invasive cancers (NOS) are multifocal or multicentric in *13% of cases, while some are time shifted and in some such cases bilateral disease develops (7±10%). In order to obtain an overview of the percentage of clinical nonmetastasized breast cancer cases in which the sentinel node search must be discussed (reflections on metastasis to different basins) and in special cases to breast-preserving surgery newer data on the rates of multicentricity would be of interest. Recently Vlastos et al. (2000) investigated a collective of 284 breast cancer cases (pT1±2N0M0), 60 of whom had multicentric disease, in order to com-
pare the outcome of those with multicentric disease with that of patients with unifocal cancers in the same collective (N0±1, difference in 8 years of follow-up). The frequencies of 2, 3, 4 or more lesions occurring in the same patient are listed in Table 11. These facts are of interest with regard to labeling procedures when simultaneous multifocality and/or multicentricity has developed. Because the tumor growth can start at different time-points, it may be that one of the foci is blocking lymphatics, with the consequence that a second cancer focus might divert the lymphatic drainage to a different basin (e.g., in the mammaria interna group). However, it is also possible that the different foci drain to different basins (Fig. 47). It is concluded as a result of the increasing simultaneous detection of SLNs in axillary and mammary
Table 11. Multicentricity in pT1±2N0±1M0 breast cancer cases (Vlastos et al. 2000) Total number of cases (N) pT1±2N0± 1M0 284
Rate of multicentric cancers n
%
60
21
Two cancers
Three cancers
n
%
n
%
30
10.5
13
4.6
Four and more cancers n
%
17
5.9
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Chapter 21 Breast Cancer Fig. 47. Simultaneous development of multifocal and multicentric cancer [I local multifocality, II multicentricity (two cancers, both primaries, in different quadrants)]
interna lymph node groups that in most cases of multifocality or multicentricity mastectomy is necessary. In cases with EIC as well as extended multifocality safety also dictates mastectomy. Axillary sentinel nodes must be removed, and internal mammary node(s) can be punctured or excised when labeling of the sentinels indicates possible involvement of these nodes. Axilla revision may be required, depending on individual labeling and on the histopathological results. In our own studies (Schauer et al. 1998; Rauschecker et al. 1998) on 1036 patients (733 treated with breast-conserving surgery) the local recurrence rate after 8 years' follow-up was 8.8%, despite postoperative radiotherapy of the conserved breast. In most cases the cancer had obviously developed de novo in a phase-shifted manner over the course of multifocal or multicentric carcinogenesis. In these cases axillary revision was performed as a primary procedure. To the best of our knowledge the literature includes no investigations concerning: a) Altered flow after previous radiotherapy b) Significance of sentinel node search under these altered conditions when a new cancer develops.
One point seems to be especially important. When the recurrence in the breast is confirmed as a second primary (e.g., by FNAC or core biopsy), peritumoral labeling, if adapted to blocked lymphatics by fibrosis or sclerosis, can at least indicate lymphatic drainage to the mammaria interna, subclavian, or interpectoral nodes. When such aberrant drainage can be demonstrated important steps in the evaluation of these nodes are possible. If cancer metastasis is confirmed in these nodes consideration of adjuvant therapeutic effort is indicated (e.g., local radiotherapy), which is only possible in fields which were not in the primary-radiotherapy areas located, or systemic cytostatic therapy. Worldwide, Kurtz and his colleagues Amalric and Spitalier (1983) have reflected most intensively on the treatment options for late breast cancer recurrences (second primaries in the irradiated breast) or contralateral second primary cancers. They investigated 276 patients followed for 10± 21 years after lumpectomy and radiotherapy and obtained the results shown in Table 12. In Kurtz's investigations all the late recurrences were operable, and they did not appear to be associated with decreased survival. Kurtz stated (importantly for
Gamma Probe Handling in the Operation Room and Sterilization Procedures Table 12. Late recurrences of breast cancer (ipsi- and contralateral) (Kurtz et al. 1983) Number of cases with follow-up
Recurrences in breast
Contralateral recurrences
Early recurrences with 5 years
Late recurrences after 10 years
Late recurrences T1/T2
276
15.6%
7.2%
63%
5/43
53%/25%
reflections about the sentinel node search in cases of recurrence) that he did not see it as an indication for mastectomy of the ipsilateral breast when a second primary developed or when a second primary developed in the contralateral breast.
The following figure gives an impressive impression of the lymphatic drainage system and is basic to our understanding of the different possibilities of drainage in centrally localized breast cancers (Fig. 48).
Management in Cases with Centrally Localized Primaries
Pitfalls Attributable to ªMimicryº of Sentinel Node(s) in Wrong Positions
Centrally localized primaries frequently metastasize to axillary lymph nodes, but they can also drain to nodes of the mammaria interna group and to the interpectoral or infraclavicular basins. Therefore, especially in cases with a central localization of the primary, these basins must be meticulously evaluated by labeling procedures and the gamma probe.
Normal lymph drainage can be blocked by scars. The drainage to the mammaria interna lymph nodes can be potentiated when scars in the lateral parts of the glandular body of the breast block the flow to the axillary nodes. The lymphatic drainage via the retromammillary lymph circle may then be strongly increased, and with it drainage of cancer cells to the nodes of the mammaria interna chain.
Fig. 48. The different basins or node groups into which centrally localized cancers can drain
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Chapter 21 Breast Cancer Fig. 49. Centrally located cancer directly above the areola. A scar in the upper lateral quadrant is hampering or strongly reducing lymphatic flow to the axillary node group. Therefore, the main flow is draining to node(s) of the mammaria interna group. Exact timing is necessary to find out that when flow is reduced the axillary basin can also be involved
This possibility of diversion is documented in Fig. 49.
Pitfalls in Labeling of Deep-seated Primaries Deep in the breast parenchyma, primaries, some with prefascial localizations, can drain to different lymphatic basins depending on their localization (Fig. 50). Subdermal (superficial) or subareolar administration of the labeling fluid, mainly draining to the axillary nodes, can lead to severe misinterpretations. It means that axillary nodes would be labeled, whereas the true lymphatic flow from the primary goes to other nodes or node groups. This corresponds to ªmimicry of a sentinel node in wrong positionª. In summary: · Drainage to axillary nodes is possible in deep located primaries, but not obligatory [Fig. 50, (1)] · Other target nodes, depending on the localization of the primaries, can be: mammaria interna-related lymph nodes [Fig. 50, (2)], subclavicular
nodes [Fig. 50, (3)], and interpectoral nodes [Fig. 50, (4)]. Their positions are documented in Fig. 50. Figure 51 documents that after superficial (subdermal) administration of the labeling fluid drainage is mostly to the lower axillary nodes (level I) but the cancer can drain directly through the layers of the pectoralis muscle to the interpectoral nodes or upward to the subclavicular and parasternal nodes (see Fig. 51, red arrows).
Orientation of Labeling Procedure on the Wrong Substrate After incorrect injection of the labeling solution around a tumor-like scar formation or nodular formations of sclerosing adenosis etc., instead of the precise peritumoral injection described in the general section, examination of the lymphatic drainage can give a misleading result with drainage to the wrong basins (parasternal nodes, etc.) (see Fig. 49). The axillary node(s) may be not or only weakly labeled.
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Fig. 50. Different directions of lymphatic drainage from the different parts of the glandular body of the breast (left). The lymph nodes and their groups are named on the left.
On the right the different possible localizations of primaries are shown (red dots). It can easily be recognized that the lymphatic stream passes to different node groups
Figure 52 demonstrates the ªperitumoralº labeling around a noncancerous lesion draining to the parasternal nodes, whereas the axillary node (which is the true sentinel node) is only weakly labeled, because of minimal drainage from the marginal areas of the incorrect injection sites.
Experiences in Sentinel Node Labeling with 99mTc-Nanocolloids The main factors in detection of the sentinel node(s) are · Dosage of radioactivity (99mTc-nanocolloid) · Quantity of radioactive fluid, · Distance of injection site from the primary and injection modality (subdermal, peritumoral) · Exact timing. Fig. 51. Inadequate, subdermal injection of the labeling solution with drainage to the axillary nodes (1) and actual drainage of the cancer to interpectoral (2) or parasternal nodes (3) (brown labeling solution, red cancer)
Some examples may demonstrate the detection of sentinel nodes in breast cancer cases. In the first case (Fig. 53) dependence on the timing is demonstrated. In the acute phase 10 min after the injection unspecific scintigraphic imaging is detectable
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Chapter 21 Breast Cancer Fig. 52. Markedly incorrect labeling of a parasternal lymph node, mimicking a sentinel node from the main stream after labeling of a noncancerous lesion (1). Scar or sclerosing adenosis (green). Labeling solution around scar or adenosis, not around cancer. Only weak labeling of the axillary node (which may not be measurable by the gamma probe) because of diverted drainage (2)
(Fig. 53 a), while after 2 h strong labeling of at least one axillary node and of one small parasternal node is observed (Fig. 53 b). The lymphoscintigraphic results obtained in a 30-year-old woman with a centrally located leftsided breast cancer are shown in Fig. 54 a. The 99m Tc-nanocolloid solution was administered by peritumoral injection, and 20 min later labeling of a small parasternal node and stronger labeling of an axillary node were visible. Three hours later, the labeling of the parasternal node had vanished and only the axillary node labeling was still visible. This dynamic development indicates that evaluation of scintigrams in very early phases after administration of the tracer solution (20 min) may give misleading results and may also have undesir3 Fig. 53 a, b. Labeling of SLN(s) in a breast cancer patient (82 years old) with a primary located centrally and laterally. a Note acute labeling of the axillary nodes; parasternal nodes and infraclavicular nodes are also weakly labeled, however (10 min). b After 2 h one axillary node is very strongly labeled, but there is also a parasternal node showing strong but distinct labeling. (This result can be important for adjuvant therapy and decision making)
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Fig. 55. Bifocal breast cancer in the upper lateral quadrant of the left breast in a 48-year-old woman. Strong enhancement at the site of injection of the labeled contrast solution. 99m Tc of one parasternal lymph node was visible after 30 min, and weak labeling of two additional nodes in the region of the upper part of the mammaria interna chain. In the later phase (1.5 h after injection of contrast solution) an infraclavicular node is also weakly labeled
Fig. 54 a, b. Labeling of the axillary SLN in a 30-year-old woman with a centrally located primary. a 20 min after peritumoral injection of the 99mTc-nanocolloid solution, both a small parasternal node and an axillary node are marked. b 3 h after the injection only the axillary node shows strong labeling. The weakly labeled loop (primary to parasternal and with a horizontal course to the axillary node) has disappeared
able consequences (e.g., postoperative radiation of the parasternal field). A further case demonstrates that ± as is well known ± even cancers of the upper lateral quadrant can have their sentinel lymph node(s) among the parasternal nodes. Case Report This 48-year-old woman underwent radioimaging, which revealed two cancer nodules in the upper lateral quadrant (0.9 and 0.6 cm in diameter). 99m Tc-Nanocolloid, 200 MBq, was injected subdermally and peritumorally. Labeling of one parasternal lymph node was observed 30 min after injection of the labeling solution in four portions of
50 MBq each. In photographs taken 1.5 h after the injections two parasternal sentinel nodes and one node craniodorsal to the primary (i.e., in an infraclavicular site) were labeled (Fig. 55). The localizations of the parasternal nodes were marked on the skin above them. The final conclusion reached in the postoperative histopathological examination was bifocal ductal invasive cancer, stage pT1b, pN0 (0/18) pMX, grade II, clinically M0. In view of the risk of parasternal lymph node metastasis, adjuvant chemotherapy with cyclophosphamide (600 mg/kg) and doxorubicin (60 mg/kg) has been administered.
Differential Diagnosis of Very Sharply Delineated Breast Cancers All imaging systems (mammography, MRI, ultrasound) can show up round, sharply delineated nodes within the breast parenchyma. These round nodes often correspond to specific subtypes of breast cancer; but for diagnosis of a fibroadenoma large foci of sclerosing adenosis (with and without microcalcifications) must be delineated. The histological criteria of these cancer subtypes and the MRI findings of fibroadenomas are listed in Table 13.
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Chapter 21 Breast Cancer Table 13. Important histological and radiodiagnostic delineation criteria of cancer subtypes and fibroadenomas Malignant lesions
Specific characteristics (histology/radiology)
Mucinous cancer
Mostly grade I or (II) PAS, Alcian blue, positive mucus
Medullary cancer
Mostly grade III (II) lymphocyte infiltration, high rate of mitosis
Benign lesions Intra- and extracanalicular fibroadenomas
ªYoungº ? strong signal in MRT ªOlder typesº ? less intensive signal in MRT, because of fibrosis
Nodes of sclerosing adenosis
No strong signal in MRT, because of reduced vascularization
Can two-step axillary revision, i.e., I Work up of the sentinel II Extended axillary revision in sentinel node-positive cases really be avoided? The discussion of diagnosis in SLN(s) by examinations of frozen sections (at six levels of the node) and consecutive paraffin embedding and sectioning must again be considered critical, because material loss can be very great in a method involving two procedures. In the case of a lymph node with a maximal thickness of 5±6 mm, for instance, 2 mm can already be lost through the initial freezing and paraffin-cutting procedures, when the technician has to cut the frozen and paraffin blocks and initially discard inappropriate sections with the aim of getting all parts of all tissues represented in the sections. Recommendations for us of a method involving two cutting procedures in the same material is at odds with the decision made by IAP, that smaller primaries (< 1 cm) should not be investigated in frozen sections, because it is much easier to make a secure diagnosis in a primary 4±5 mm in size than to be certain of the negativity of single cancer cells or small clusters in a lymph node when the loss rate is doubled by two-step cutting procedures. Therefore, with regard to the implications of a false-negative result, a two-step operation procedure should be considered seriously. When the SLN is investigated in paraffin exclusively in serial sections, a second operation with axillary revision (levels I and II) is indicated only in positive cases, and the loss of
node tissue that has not been histologically examined can be kept very small. Only in cases with intraoperative positive imprint cytology from SLN axilla-revision can be immediately performed. Accuracy of SLN Biopsy in Patients with Large Primaries Up to a few years ago the question implied by this heading was not discussed at all, because in cases with large primaries the routine treatment was mastectomy with axillary revision (levels I and II). In early pT2 cases the SLN concept can be applied in the same manner as in pT1 cases. However, in more advanced pT2 and in pT3 cases, especially when these have developed in small breasts, peritumoral 99mTc-sulfur colloid labeling is difficult and breast-conserving surgery becomes progressively more difficult and ultimately impossible. Now, however, with the developing tendency to perform preoperative down-staging by means of chemotherapy (CMF or anthracycline-containing regimens in c-erbB2- and/or p53-positive cases) the chance that breast-conserving surgery will become possible increases (McCready et al. 1988; Bonadonna et al. 1990; Schwartz et al. 1994; Botti et al. 1995; Fisher et al. 1997, 1998; Kling et al. 1997; Cunningham et al. 1998; Kuerer et al. 1998). In this context, it must be emphasized that it is of critical importance to perform axillary lymph node staging before chemotherapy is started, for the following reasons: · Because lymphatic spread after axillary revision before down staging ± especially in cases with chemoresistant primaries ± would be directed to other basins (interpectoral, infraclavicular or parasternal) · Because noninvasive imaging techniques fail to detect incipient metastasis in the axillary lymph nodes. Furthermore, no systematic investigations have been carried out in order to find out whether the rate of simultaneously developing axillary and parasternal lymph node metastases (we call it ªdouble basin sentinel node implicationº) increases in proportion to the size (pT-value) of the primary. To avoid extended axilla revision before chemotherapy-induced down-staging of the primary the team working in the Mayo Clinic and the Philadelphia University Hospital has recently tried to eval-
Gamma Probe Handling in the Operation Room and Sterilization Procedures
uate the accuracy of SLN biopsy in a collective of 103 patients with large primaries (> 2 but < 5 cm *pT1±2). The detection and localization of SLN(s) could be confirmed in 99% of these cases. The overall rate of lymph node metastasis was 59% [95% exact confidence interval (95% CI), 49±68%], or 61 of 104 cases. The SLN false-negative rate was 2% (95% exact CI, < 1±11.5%) (2 patients). In 56 tumor cases with primaries > 3 cm 1 false-negative result [2% (95% exact CI, < 1±15%)] was identified, and the rate of lymph node metastasis was 62.5% (95% exact CI, 48.5±75%) (35 of 56 tumors). Among 30 SLN-positive patients with tumors > 3 cm in size who underwent complete axillary lymph node dissection, 3 of 8 patients [37.5% (95 exact CI, 8.5±75.5%)] with micrometastasis (< 2 mm) to the sentinel lymph node had positive non-SLN, compared with 21 of 22 patients [95.5% (95% exact CI 77±100%)] with macrometastases (> 2 mm) to the SLN (P = 0.002). An overview of Bedrosian's data is given in Table 14 (Bedrosian et al. 2000), which documents the sentinel node detection rate, the rate of falsenegative sentinel nodes, the average number of axillary lymph nodes investigated, and the rates of metastatically involved nodes in the presence of pT2-cancers (divided into > 2 cm and > 3 cm). The comparison of a collective (n = 87) with 2% false negative sentinel nodes with a collective of cancers with diameters > 3 cm (n = 56) with approximately the same overall rate of metastases (59% vs 62%) and a 37% rate of micrometastases showed the same rate of false-negative nodes (2%) in the second collective. The results of this group are summarized in Table 15. These results can only give a clue that might help in individual decision-making in cases with larger primaries. The most critical points, which must be very carefully calculated and discussed, are: · Unfavorable relation of the size of the breast to tumor size plus necessary tumor free margins. · Resistance of the cancer to the cytostatics usually used (e.g., c-erbB2-, p53-, or vimentin-positive cancers resistant to CMF). In CMF-resistant cases, when a non-anthracyclinecontaining combination is used, if there are no locoregional and hematogenous metastases at the time of primary diagnosis the cancers can spread
Table 14. Overview regarding accuracy in the Pennsylvania project (CI confidence interval) No. of patients
a b c
Total no. of patients
103
Total no. of breast carcinomas > 2 cm; including double cancers
104
SLN identified (%)
103 (99)
95% Exact CI (%)
95±100 a
Average no. of SLN (range)
2.1 (1±6)
Average no. of lymph nodes (range)
19.6 (2±61)b
Overall rate of incidence of axillary lymph node metastasis (%)
61 (59)
SLN identified
60
SLN with metastatic disease
58
False-negative SLN (%)
2 (3)c
Tumors > 3 cm
56
Overall rate of incidence of axillary lymph node metastasis (%)
35 (62.5)
SLN identified (%)
55 (98)
SLN with metastatic disease
33
False-negative SLN (%)
1 (3)c
49±68
< 1±11.5
48.5±75
< 1±15
Includes all patients with SLN identified Includes only the 87 patients who underwent completion axillary lymph node dissection One patient with no identified SLN but with involvement of axillary lymph nodes
during chemotherapy and can have fatal consequences, whereas immediate surgical treatment with axillary revision could have prevented metastasis with its possible fatal outcome. Therefore, if down-staging is intended, it is essential that informed consent taking full account of the points discussed is obtained from the patient (sine qua non). The authors conclude from their results that SLN biopsy is an appropriate method for the Nstaging even in cases with larger primaries and that it is highly accurate (for pT1 cases see Albertini et al. 1996; Giuliano et al. 1997; Veronesi et al. 1997; Krag et al. 1997).
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Chapter 21 Breast Cancer Table 15. Micro- and macrometastases and false-negative SLN rate in the Pennsylvania-pilot project on larger primaries (N = 87)
a
No. of cases
Overall rate with lymph node metastases
False-negative rate of SLN
No. of cases with pT > 3 cma
Overall rate lymph node metastases
Micrometastasis rate
False-negative rate SLN
87
59%
2%
56
62%
37%
2%
pT > 3 cm 33/34 cases sentinel positive and 1 (= 3%) negative
It must be emphasized that the use of immunohistochemical staining for cytokeratins (8, 18, or AE 1/3, MoAb 1: 250 Boehringer Mannheim) to detect single cancer cells or cell clusters within the nodes, as already reported by Turner et al. (1997) and Czerniecki et al. (1999), has improved the staging-result by 10±15%. Down-staging in cases with clinically positive (this finding must be critically tested) axilla together with pathohistologically negative axillary lymph nodes has ranged from 6±32% (Schwartz et al. 1994; Fisher et al. 1997; Kling et al. 1997; Kuerer et al. 1998). Finally, it must be made clear ± again ± that the down-staging procedure has the disadvantage that it is also tried in chemoresistant cases or cases with resistance to specific regimens (e.g., CMF resistance in c-erbB2-positive and p53-positive cases). This may lead to the dilemma that down-staging cannot be achieved in the primary and cancer destruction in the axillary nodes is not attained, with resultant tumor progression and cancer infiltration of further axillary nodes (McCready et al. 1988; Botti et al. 1995), so that the likelihood of local tumor clearance is lowered.
Significance of Pathohistological Analysis of SLN and Non-SLN for Occult Metastasis: Conclusions Drawn from Recent Results of the US Multicenter Study The obvious international aim, which depends on cooperation between surgeons, gynecologists, and pathologists (Attiyeh et al. 1977; Black et al. 1980; Apostolikas et al. 1988), is now to concentrate on SLN evaluation, with investigation of one or of a few axillary nodes using HE and immunohistochemical analysis in serial sections and to omit the very extensive axillary node analysis in SLN-nega-
tive cases (Bussolati et al. 1986; Krag et al. 1993; Giuliano et al. 1994; Albertini et al. 1996). If occult metastasis is considered more likely to be present in SLN, this search will shift a proportion of women currently considered lymph node negative into the group of lymph node-positive patients, with the consequence of adjuvant chemotherapy for these patients (Weaver et al. 2000). Chemotherapy regimens are discussed in Chapter 33 at the end of this book. It has been suggested that occult disease that is not histologically confirmed may be a predictor for the approximately 25% of lymph node-negative patients who develop recurrences (Weaver et al. 2000). But the data obtained in different investigations, which could give an idea of the significance of occult disease, are contradictory and discussion on this point has sometimes been controversial (Fisher et al. 1978; Bussolati et al. 1986; Friedman et al. 1988; International Breast Cancer Study Group 1990; Chen et al. 1991; Galea et al. 1991; Neville et al. 1991; Byrne et al. 1992; de Mascarel et al. 1992; Clayton and Hopkins 1993; Elson et al. 1993; Hainsworth et al. 1993; Nasser et al. 1993; MacGuckin et al. 1996). In a multicenter study supported by the US National Cancer Institute, original pathology material from 431 patients was investigated (Weaver et al. 2000). Metastases were found in 15.9% of the SLN and 4.2% of the non-SLN [odds ratio (OR) 5.3; P = 0.001; 95% CI 3.5±5.4]. Occult metastases were identified in 4.09% of SLN and 0.35% of nonSLN (OR 12.3; P < 0.001; 95% CI 5.6±28.6). The overall case conversion rate was 10.3%. All occult metastases identified were < 1 mm. The likelihood (OR) of metastases in non-SLN was 13.4 times as high for SLN-positive than for SLN-negative patients (P < 0.01; 95% CI 6.7±28.1). The additional metastasis detection rate was 2.6% in a second review. It increased by a further 8.9% when deeper serial sections in HE and immunohistochemical stainings for cytokeratins were evaluated.
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When the detection rates of the second review and the consecutive serial sectioning (HE and immunohistochemistry) are taken together, the resulting rate of combined occult metastases amounted to 11.5%. This rate is at the lower end in the range of 9±33% reported in the literature (Dowlatshahi et al. 1997). In 162 SLN biopsies investigated by Guiliano et al. (1995) with immunohistochemical stainings, 11 lymph node-positive patients (6.8%) were detected; in the investigations of Cox et al. (1998) the corresponding proportion was 10%. When immunohistochemical support is used in detection of occult metastasis (antibodies directed to cytokeratins 8, 18, AE 1/3 etc.), in view of the enormous investment of staff time needed for sectioning staining, evaluation (technicians and medical staff), it seems unlikely that false-negative results can be totally eliminated either in laboratories with top-class equipment or in normal routine laboratories. Improvements in techniques for serial sectioning and staining, improvements in antibody production and development of automatic scanning machines may be helpful in lowering falsenegative rates in the SLN material investigated. This is also suggested by Krag et al. (1998). Let it be emphasized from the start that if no additional technicians can be employed to manage these extensive investigations in pathology laboratories, there is no hope of reducing the rate of false-negative nodes to near zero, especially in pathology laboratories with low staffing levels, meaning unavoidable disaster for patients.
Benefits of the SLN Investigation Pro Sentinel node investigation No axillary revision necessary in 70±80% of cases No costs for axillary revision Side effects of axillary revision avoided Extra-axillary paraglandular nodes detected and excised
Contra Axillary revision: Higher degree of safety in levels I and II, though not in the paraglandular region Skip metastases not left behind
The possibility that the parasternal and/or internal mammary lymph nodes could be affected by primary cancer spread and, in a low proportion of cases, also be an additional or secondary sentinel node localization has long been recognized as a difficult and specialized problem. The resultant discussion has always been carried on at many different levels and in concealment, for various reasons: · One reason is that it is rare for the parasternal lymph nodes to be the only target of the metastatic process and thus the sentinel node group. Simultaneous involvement of the axillary and parasternal lymph nodes is encountered more frequently. In such cases there is no way of clarifying whether the axillary or the parasternal lymph nodes were involved in the metastatic process primarily or whether the double metastatic involvement of both lymph node groups has developed in a phase-shifted manner, with one affected and then the other, and the overall status is one that has resulted relatively late in the course. · The parasternal lymph node chain cannot be reached so easily as the axillary nodes for surgery. · Surgical excision of the parasternal node chain, which has been evaluated in some breast cancer centers, has not been successful in terms of improving survival rates. · Radiotherapy to the parasternal lymph node chain is difficult, and at the same time it is doubtful whether it is always acceptable, because the heart and the central anterior part of the lungs are located within the radiation field. Based on discussions about all these difficulties, some of which are unchangeable, opinions differ on the question of taking biopsy specimens from these nodes. Many authors follow the policy of not obtaining biopsy specimens from these nodes, while others advocate routine excision when these nodes seem to be the sentinels. At present it is really difficult to find an answer to this question ourselves, because · Techniques for obtaining consistent results in labeling the parasternal sentinel node group are not yet adequate. ± Improvements and standardization seem to be essential for extensive clinical, and per-
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Chapter 21 Breast Cancer
haps also multicenter, studies that would allow the development of a new basis for the assessment of this problem. · As a consequence, in cases diagnosed as positive, the biopsy seems to be problematic on the one hand, and needle biopsy is insufficient to get an overview of the whole node, or node chain, to confirm or exclude micrometastasis and to make a reliable statement on the matter possible.
Significance of False-negative Results of SLN Investigations There is no doubt that the fear of false-negative results is implicit in all critical papers discussing the sentinel node concept in breast cancer treatment. One of the main points is that in false-negative cases important additional treatment is not performed (Hohenberger et al. 1998). Accordingly, radiologists, surgeons and pathologists have to work with the extreme precision and cooperate more closely with each other than ever before. This means that when sentinel node(s) cannot be detected [positive rate between 93%, 97± 98% (Crossin et al. 1998; Jones et al. 1996)] and 98.7% (Veronesi et al. 1997, 1999) axillary resection must a priori be performed as usual. Veronesi et al. (1999) recommend a randomized study to determine whether axillary dissection can be avoided in patients with uninvolved SLNs. Such studies are of interest, but they have very far-reaching implications with respect to several parameters, including different extent of metastatic spread into different basins according to localization of the primary, different tumor types, stage differences in sentinel detection (pTs), types with and without lymphangiosis carcinomatosa, different values of false-negative rates in a multicenter study, etc. How best to avoid axillary resection in cases of DCIS is a constant subject of discussion. With tumors up to 2.5 cm in size involvement of the axillary nodes is very rare, but in the case of more extensive lesions the frequency of undetected invasion and axillary involvement increases. In these cases SLN detection and histopathological and immunohistochemical examination in serial sections seems to be quite helpful in further decision making in avoiding total axillary revision. Accurate and authoritative statements supported by prospective studies are still lacking (Cox et al. 1998 a, b).
Most surgeons do not excise suspicious parasternal nodes for histological examination (Cox et al. 1998 a, b; Roumen et al. 1997). In the statement issued by the Robert Ræssle Clinic, Berlin (Hohenberger) it is suggested that for the avoidance of axillary resection at least two requirements must be fulfilled: · In the experience of the surgeon the failure rate for sentinel node evaluation must be below 5%. · The patient must have been informed about the risk of undetected tumor-involved lymph nodes of the axilla (Hohenberger et al. 1998).
Is It Necessary to Have Alternatives to the Actual Concept Using Extensive and Cost-intensive Histopathological and Molecular Biological Methods? This question cannot be answered yet, because at the moment the SLN concept (sentinel node evaluation, and no axillary revision in negative cases) is still not completely clear. But, if a decision has once been made in favor of trying to detect the SLN, followed by excision and histopathological evaluation of a high standard to exclude the necessity for surgical axillary revision in SLN-negative cases, there is no alternative concept with the same aim of avoiding total axillary revision. Even now, since the introduction of breast-conserving surgery we have seen a second revolution in avoidance of total axillary revision when the concept proves to be practicable in most clinics and can be accepted with clearly defined conditions. The time has therefore come when the question must be answered: progress for all, with special support to fulfill all criteria, or what we do not want, a two-class system of medicine.
Treatment of Breast Cancer Cases Is Dependent on Whether the Sentinel Lymph Node Status Is Positive or Negative Whether adjuvant chemo- and/or radiotherapy is needed on the basis of the SLN node status depends essentially on two main points: · Will an adjuvant chemo- and/or radiotherapy have a real benefit in sentinel node-negative or -positive cases?
Gamma Probe Handling in the Operation Room and Sterilization Procedures
· What are the consequences when the SLN(s) is/ are located within the parasternal lymph node chain? In agreement with the International Consensus Meeting held in 1998 in St. Gallen, Switzerland, in cases with negative SLN(s) and signs that the primary is a low-risk lesion (see Chapter 33, Table 11), as a rule no adjuvant chemotherapy is recommended. In cases with moderate risk (1±3 positive lymph nodes) or cases with breast preserving surgery, negative nodes and unfavorable prognostic factors, CMF-respectively anthracyclin therapy improved the 5- and 10 year survival-rates only for a few percents. With respect to these facts, chemotherapy and/ or antihormone therapy must be recommended. In c-erbB2- or p53-positive cases anthracycline-containing regimens should be used in preference to the cyclophosphamide-methotrexate-5-fluouracil (CMF) regimen. In high-risk cases, chemotherapy regimens should be selected and administered according to the international recommendations (CMF-anthracycline-containing combinations; see tables at the end of the book). When the SLN(s) are positive, an axillary revision should be performed, as the number of positive lymph nodes influences the therapy decided on. Because all (approx. 12±15) lymph nodes must be examined histologically, a second operation for axillary revision (levels I and II) is unavoidable. Adjuvant radiotherapy of the axilla is recommended in all cases with > 3 positive lymph nodes, and women with 1±3 positive lymph nodes would probably also benefit. In cases with parasternally located SLN(s) detected by scintigraphic images experience has not yet shown how cancer infiltration can be confirmed or excluded without the use of invasive methods. Because surgical parasternal lymph node excision programs in the framework of ªultraradical surgeryº have not been successful, no further reflections have been discussed. If it is assumed that histological examination of the parasternal lymph nodes cannot be performed, the risk of a metastatic spread via lymphatics remains high. One option would be FNAC guided by imaging devices. In the case of a positive lymph node we recommend radiation of this area in addition to the current standard therapy.
If a histological diagnosis is not possible, additional parasternal radiation therapy should be considered with due consideration for adverse factors (primary tumor > 1 cm, axillary lymph nodes positive, G3 cancer, hormone receptor negative, cerbB2 and/or p53 positive) chemotherapy should be performed. In c-erbB2-positive cases (p105 protein in serum probes of the patients can be controlled), rather than the CMF regimen anthracycline-containing regimens should be used. The newest and the routinely used staging-related therapy regimens are summarized in the last chapter of the book. Legal and Ethical Aspects The following points must be critically considered: · Peritumoral injections, particularly of high amounts of solutions which increase positive results in the SLN detection, may distend veins by increasing pressure and tumor cells may be disseminated via the bloodstream. This depends mainly on the amount of fluid injected. This could be avoided, in breast cancer patients for instance by subdermal injection. However, if the labeling substance is injected too far away from the primary tumor results can be incorrect. · False-negative results in terms of sentinel node represent a major clinical problem. This can happen in the case of skip metastasis or direct lymphogenic metastasis into the axilla, bypassing the sentinel node or passing through the sentinel node without an outgrowth of metastasis. If lymph node dissection is not performed after a negative result of sentinel node examination legal problems can arise: · If the surgical protocol is not included in the so-called informed consent, it is possible for the patient to bring an action against the doctor concerned if an axillary recurrence develops later. · In most papers the risk of subsequent axillary involvement after exclusive SLN excision is reported to be relatively low and only compared with the negative aspects of lymph node revision, such as pain, loss of sensibility in circumscribed areas, bleeding and infection in the operation site and edema of the arm (Maunsell et al. 1993; Liljegren and Holinberg 1997; Suenemann and Willich 1997). Bad as these complica-
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tions are, they cannot be compared with the possibility of the main complication after avoidance of axillary revision, namely the possibility of axillary inoperable tumor recurrence. This is very important, and a dangerous situation. The extensive studies of Fisher (1978) and many others demonstrate that subsequent involvement of axillary nodes with micro- or macrometastases (critical point more than four involved nodes) definitely reduces the 5-year survival rates. When more than four lymph nodes are involved the survival rate is 15% at most. Since in cases with unfavorable prognostic factors, such as grade III, cerbB2 and/or p53 positivity, disease can spread from even one undetected axillary node to four regional lymph nodes within a few weeks, with the current performances it would be irresponsible simply to accept that axillary revision for complete axillary staging can be dispensed with when surgical revision of the axilla is possible. It is the intention of this article to help in the avoidance of complications, and, especially of hostility against doctors bearing responsibility for their patients. In some ways the situation is similar to that following the introduction of breastconserving surgery when many groups had little experience. According to this situation, the rate of locoregional relapses rose in patients treated by groups who did not work exactly according to the protocol. Today it seems clear that when there is correct cooperation between surgeons and pathologists, ªin-breast recurrencesº must be seen as analogous to primaries with metastatic potential. It must be stressed that the work-up with detection of the sentinel node(s) is still being researched in many clinics and not generally performed as a routine procedure.
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Chapter 21 Breast Cancer McCready DR, Hortobagyi GN, Kau SW, Smith TL, Buzdar AU, Balch CM (1988) The prognostic significance of lymph node metastasis after preoperative chemotherapy for locally advanced breast cancer. Arch Surg 124:21±25 Meyer JS (1998) Sentinel lymph node biopsy: strategies for pathologic examination of the specimen. J Surg Oncol 69:212±218 Moon DH, Maddahi J, Silverman DH, Glaspy JA, Phelps ME, Hoh CK (1998) Accuracy of whole-body fluorine18-FDG PET for the detection of recurrent or metastatic breast carcinoma. J Nucl Med 39:431±435 Moore MP, Kinne DW (1996) Is axillary lymph node dissection necessary in the routine management of breast cancer? Yes. Important Adv Oncol 2:45 Mumtaz H, Hall-Craggs MA, Davidson T, Walmsley K, Thurell W, Kissin MW, Taylor I (1997) Staging of symptomatic primary breast cancer with MR imaging. Am J Roentgenol 169:417±424 Nasser IA, Lee A, Bosari S, Saganich R, Heathley G, Silverman ML (1993) Occult axillary lymph node metastases in ªnode-negativeº breast carcinoma. Hum Pathol 24(9): 950±957 Nathanson SD, Anaya P, Karvelis KC, Eck L, Havstad S (1997) Sentinel lymph node uptake of two different technetium-labeled radiocolloids. Ann Surg Oncol 4:104 Nieweg OE, Kim EE, Wong WH, Broussard WF, Singletary SE, Hortobagyi GN, Tilbury RS (1993) Positron emission tomography with fluorine-18-deoxyglucose in the detection and staging of breast cancer. Cancer 71:3920±3925 Neville AM, Price K, Gelber RD, Goldhirsch A (1991) Axillary node micrometastases and breast cancer. Lancet 337(8749):1110 Obenauer S, Fischer U, Baum F, Dannert S, Fçzesi L, Grabbe E (2001) Stereotactic vacuum care biopsy of clustered microcalcifications classified as BI-RADS3. RæFo Fortschr Geb Ræntgenstr Neuen Bildgeb Verfahr 173:696±701 Offodile R, Hoh C, Barsky SH, Nelson SD, Elashoff R, Eilber FR, Economou JS, Nguyen M (1998) Minimally invasive breast carcinoma staging using lymphatic mapping with radiolabeled dextran. Cancer 82:1704 O'Hea BJ, Hill AD, El-Shirbiny AM, Yeh SD, Rosen PP, Coit DG, Borgen PE, Cody-HS III (1998) Sentinel lymph node biopsy in breast cancer: initial experience at Memorial. J Am Coll Surg 186:423±427 Ollila DW, Brennan MB, Giuliano AE (1998) Therapeutic effect of sentinel lymphadenectomy in T1 breast cancer. Arch Surg 133:647±651 Orel S, Schnall M, Livolsi V, Troupin R (1994) Suspicious breast lesions: MR-Imaging with radiologic-pathologic correlation. Radiology 190:485±493 Page DL, Winfield AC (1986) The dense mammogram. Am J Roentgenol 147:487±489 Pendas S, Danway E, Giuliano R, Ku N, Cox CE, Reintgen DS (2000) Sentinel node biopsy in ductal carcinoma in situ patients. Ann Surg Oncol 7(1):15±20 Picoli CW, Matteucci T, Outwater EK, Siegelman ES, Mitchell DG (1995) Breast cancer diagnosis with MR-imaging: effect of clinical and mammographic findings on recommendations for biopsy. Radiology 197:(P)372
Pierce W, Harms S, Flamig D, Griffey R, Evans W, Hagans J (1991) Three dimensional gadolinium-enhanced MRimaging of the breast. Pulse sequence with fat suppression and magnetization transfer contrast. Radiology 181:757±763 Pijpers R, Meijer S, Hoekstra OS, Collet GJ, Comans EF, Boom RP, Diest PJ van, Teule GJ (1997) Impact of lymphoscintigraphy on sentinel node identification with technetium 99m-colloidal albumin in breast cancer. J Nucl Med 38:366±368 Rauschecker HF, Sauerbrei W, Gatzemeier W, Sauer R, Schauer A, Schmoor C, Schumacher M (1998) Eight-year results of a prospective non randomized study on therapy of small breast cancer. The German Breast Cancer Study Group (GBSG). Eur J Cancer 34:315±323 Raymond WA, Leong A-Y (1989) Immunoperoxidase staining in the detection of lymph node metastases in stage I breast cancer. Pathology 21:11±15 Reuhl T, Haensch W, Markwardt J, Schlag PM (1998) Die Sentinel Lymphknoten-Detektion bei Patienten mit Mammacarcinom (Sentinel lymph node detection in patients with breast carcinoma). Zentralbl Chir 123 [Suppl]5:72±74 Rieber A, Merkle E, Bæhm W, Brambs H-J, Tomczak R (1997 a) MRI of histologically confirmed mammary carcinoma: clinical relevance of diagnostic procedures for detection of multifocal or contralateral secondary carcinoma. J Comput Assist Tomogr 21(5):773±779 Rieber A, Merkle E, Zeitler H, Gærich J, Kreienberg R, Brambs H-J, Tomczak R (1997 b) Value of MR mammography in the detection and exclusion of recurrent breast carcinoma. J Comput Assist Tomogr 21(5):780±784 Roumen RM, Valkenburg JG, Genskens LM (1997) Lymphoscintigraphy and feasibility of sentinel node biopsy in 83 patients with primary breast cancer. Eur J Surg Oncol 23:495 Sandrucci S, Mussa A (1998) Sentinel lymph node biopsy and axillary staging of T1±T2N0 breast cancer: a multicenter study. Semin Surg Oncol 15:278±283 Schauer A (1981) Pathologische Anatomie des Mammacarcinoms. In: Siewert A, Schauer A, Nagel G, Frischkorn R (eds) Mammacarcinom. Chirurgie der Gegenwart. Urban & Schwarzenberg, Munich, pp 6±39 Schauer A, Marx D, Schauer M, Binder C, Kuhn W, Meden H (1998) Breast-preserving surgery: decision making. Anticancer Res 18:2107±2138 Schauer A, Osborn M, Weber K, Altmannsberger M (1984) Antibodies to different intermediate filaments as histogenetic tumor markers. Acta Histochem Suppl 29:129±136 Schauer A, Korabiowska M, Kellner S, Schumacher M, Sauer R, Bojar H, Rauschecker H (1998 a) Grading system for breast cancer. Anticancer Research 18(3C):2139±2144 Schauer A, Marx D, Schauer M, Binder C, Kuhn W, Meden H (1998 b) Breast preserving surgery decision making. Anticancer Res 18(3C):2107±2137 Schelfhout VR, Coene ED, Delaey B, Waeytens AA, De Rycke L, Dele M, De Potter CR (2002) The role of heregulin-alpha as a motility factor and amphiregulin as a growth factor in wound healing. J Pathol 198(4):523±533
References Schreiber RH, Pendas S, Ku NN, Reintgen DS, Shons AR, Berman C, Boulware D, Cox CE (1999) Microstaging of breast cancer patients using cytokeratin staining of the sentinel lymph node (see comments). Ann Surg Oncol 6:95±101 Schwartz GF, Birchansky CA, Komarnieky LT, Mansfield CM, Cantor RI, Biermann WA, Fellin FM, McFarlane J (1994) Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast. Cancer 73:362±369 Sedmak DD, Meineke T, Knechtges DS (1989) Detection of metastatic breast carcinoma with monoclonal antibodies to cytokeratins. Arch Pathol Lab Med 113:786±789 Silverberg E, Lubera J (1987) Cancer statistics. CA Cancer J Clin 37:2±19 Silverstein MJ, Gierson ED, Waisman JR, Senofsky GM, Colburn WJ, Gomagani P (1994) Axillary lymph node dissection for T1a breast carcinoma. Cancer 73:664±667 Singer E, Landgraf R, Horan T, Slamon D, Eisenberg D (2001) Identification of a heregulin binding site in HER3 extracellular domain. J Biol Chem 23, 276(47):44266± 44274 (Epub 2001) Sloane JP, Ormerod M, Imrie SF, Coonbes RC (1980) The use of antisera to epithelial membrane antigen in detecting micrometastasis in histological sections. Br J Cancer 42(3):392±398 Smith IC, Ogston KN, Whitford P, Smith FW, Sharp P, Norton M, Miller ID, Ah-See AK, Heys SD, Jibril JA, Eremin O (1998) Staging of the axilla in breast cancer: accurate in vivo assessment using positron emission tomography with 2-(fluorine-18)-fluor-2-deoxy-D-glucose. Ann Surg 228:220±227 Soderstrom CE, Harms SE, Copit DS, Evans WP, Savino DA, Krakos PA, Farell RS, Feamig DP (1996) Three dimensional RODEO breast MR-imaging of lesions containing ductal carcinoma in situ. Radiology 201:427±431 Springall RJ, Rytina E, Millis RR (1990) Incidence and significance of micrometastases in axillary lymph nodes detected by immunohistochemical techniques. J Pathol 160:174A Statman R, Giuliano AE (1996) The role of the sentinel lymph node in the management of patients with breast cancer. Adv Surg 30:209±221 Stomper P, Margolin F (1994) Ductal carcinoma in situ: the mammographer's perspective. Am J Roentgenol 162:585± 591 Stomper PC, Hermans S, Klippenstein DL, Winston JS, Edge SB, Arredondo MA, Mazurchuk RV, Blumenson LE (1995) Suspect breast lesions: findings at dynamic gadolinium enhanced MR-imaging correlated with mammographic and pathologic features. Radiology 197:387±395 Tesoro-Tess JD, Amusoro A, Rovini D, Balzarini L, Ceglia E, Civelli E, Trecate G, Savio T, Musumeci R (1995) Microcalcifications in clinically normal breasts: the value of high field surface coil Gd-DTPA-enhanced MRI. Eur Radiol 5:417±422 Turkat T, Klein B, Polan R, Richman R (1994) Dynamic MR-mammography: a technique for potentially reducing the biopsy rate for benign breast disease. J Magn Reson Imaging 4:563±568 Turner RR, Ollila DW, Krasne DL, Giuliano AE (1997) Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 226:271±276, 276±278
Turner RR, Ollila DW, Stern S, Giuliano EA (1999) Optimal histopathologic examination of the sentinel lymph node for breast carcinoma staging. Am J Surg Pathol 23:263± 267 Veronesi U, Cascinelli N, Bufalino R, Morabito A, Greco M, Galluzzo D, Delle Donne V, De Lellis R, Piotti P, Sacchini V, Conti R, Clemente C (1983) Risk of internal mammary lymph node metastases and its relevance on prognosis of breast cancer patients. Ann Surg 198:681 Veronesi U, Cascinelli N, Greco M, Bufalino R, Clemente C, Galluzzo D, Donne V delle, Lellis R de, Sacchini V (1985) Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg 202:702 Veronesi U, Paganelli G, Galimberti V, Viale G, Zurrida S, Bedoni M (1997) Sentinel node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 349:1864±1867 Veronesi U, Paganelli G, Viale G, Galimberti V, Luini A, Zurrida S, Robertson C, Saccini V, Veronesi P, Orvieto E, De Cicco C, Intra M, Tosi G, Scarpa D (1999) Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 17(91):368±373 Veronesi U, Zurrida S, Mazzarol G, Viale G (2001) Extensive frozen section examination of axillary sentinel nodes to determine selective axillary dissection. World J Surg 25(6):806±808 Viehweg P, Lampe D, Buchmann J, Heywang-Kæbrunner SH (2000) In situ and minimally invasive breast cancer: morphologic and kinetic features on contrast-enhanced MR imaging. MAGMA 11(3):129±137 Vlastos G, Rubio IT, Mirza NQ, Newman LA, Aurora R, Alderfer J, Buzdar AU, Singletary SE (2000) Impact of multicentricity on clinical outcome in patients with T1-2 N0-1 M0 breast cancer. Ann Surg Oncol 7:581±587 Wahl RL, Cody RL, Hutchins GD, Mudgett EE (1991) Primary and metastatic breast carcinoma: initial clinical evaluation with PET with the radiolabeled glucose analogue 2-[F-18]fluoro-2-deoxy-D-glucose. Radiology 179:765±770 Weaver DL, Krag DN, Ashikaga T, Harlow SP, O'Connell M (2000) Pathologic analysis of sentinel and nonsentinel lymph nodes in breast carcinoma. Cancer 88:1099±1107 Wedegartner U, Otto U, Buitrago-Tellez C, Bremerich J, Oertli D, Torhorst J, Bongartz G (2001) Percutaneous stereotactic biopsy of non-palpable breast lesions using the Advanced Breast Biopsy Instrumentation (ABBI) system: critical evaluation of indication strategies. Ræfo Fortschr Geb Ræntgenstr Neuen Bildgeb Verfahr 173:224±228 Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med 324:1±8 Weidner N, Semple J, Welch W, Folkman J (1992) Tumor angiogenesis: a new significant and independent prognostic indicator in early stage breast carcinoma. J Natl Cancer Inst 84:1875±1887 Weinreb JC, Newstead G (1995) MR-imaging of the breast. Radiology 196:593±610 Wells CA, Heryet A, Brochier J, Gatter KC, Mason DY (1984) The immunohistochemical detection of axillary micrometastases in breast cancer. Br J Cancer 50(2):193±197
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Witt A, Obwegeser R, Auerbach I, Tempfer C, Yavuz D, Kubista E (2002) Axillary lymph node dissection in pT1 breast cancer: a retrospective analysis of 315 patients and review of the literature. Wien Klin Wochenschr 114(10/11):387±390
Chapter 22
Thyroid Cancer
Is the Sentinel Lymph Node Concept Practicable and Acceptable in the Diagnosis and Treatment of Thyroid Cancer? In thyroid cancer, extensive neck dissection has long been discontinued; rather so-called berry picking of nodes for intraoperative examination by imprint cytology or in frozen sections and paraffin embedding of the residual material with consecutive serial sectioning is practiced. Sentinel nodes cannot be defined accurately in relation to the intrathyroidal localization of a primary. This is understandable: · Because the intrathyroidal network of lymphatics can be severely altered by regressive changes in goiters. · Because no ªspecific basinsº can be definitely related to particular parts of the thyroid gland. The lymph nodes primarily involved in regional metastatic processes are mainly localized in the cervical chain of paratracheal nodes along the course of the large cervical blood vessels and the upper mediastinal nodes (see Figs. 25, 26). In addition, the involvement of the nodes depends to some degree on the intra- and, in rare cases, extrathyroidal localization of the primary tumor. For instance, Kelemen and his colleagues (1998) injected 0.1±0.8 ml of 1% isosulfan blue dye directly into suspicious thyroid masses and found that the blue dye passed along the lymphatics to the sentinel node within seconds. All sentinel nodes located in the paratracheal area were stained blue, while in two cases the jugular nodes were also stained. The authors suggested on the basis of their preliminary results that sentinel node biopsy could be helpful in further decision making. Papillary thyroid cancer often presents with enlarged extrathyroidal lymph nodes. The primary ascer-
22
tainment of this tumor type (papillary structure and psammoma bodies) is confirmed in surgical biopsy specimens of the excised node by histological examination. Because more than 90% of papillary carcinomas express sodium iodine symporter, positive nodes, but not micrometastases, can also be detected by iodine-131 scintigraphy. Before the labeling of regional lymph nodes by blue stain and/or 99mTc application the question arises as to whether FDG-PET can help by yielding more information: · On the nature and extension of the primary, and perhaps also on multifocality and/or bilaterality · On regional lymph node involvement These question are discussed in the next section by Avril et al.
Is FDG-PET Helpful in T- and N-staging of Thyroid Cancer? N. Avril, W. Weber, M. Schwaiger
No systematic single-center or multicenter studies are available in which the results of searching specifically for sentinel lymph nodes (SLNs) that were already tumor-infiltrated with FDG-PET search have been compared with those yielded by different preoperative N-staging methods. A limiting factor for more extensive study programs that must be taken account of is the existence of different cancer subtypes and a scale of different degrees of differentiation. All this means that a large number of cases are required for comparison, as is intensive cooperation between endocrinologists, surgeons, nuclear medicine specialists, and pathologists. Generally, the experience reported from the published investigations has led to the conclusion that thyroid cancers with persisting functional dif-
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ferentiation for hormone synthesis and iodine uptake appear to have low glucose metabolism, whereas undifferentiated tumors are often characterized by high glucose utilization (Feine et al. 1996). Recently a multicenter study has been conducted to evaluate the clinical value of FDG-PET in differentiated thyroid carcinoma and to compare the results with those of both 131I whole-body scintigraphy and 99mtechnetium 2-methoxyisobutylisonitrile (MIBI) or thallium-201 scintigraphy (Grçnwald et al. 1999). In each case clinical evaluation included histology, cytology, thyroglobulin level, ultrasonography, computed tomography and subsequent clinical progression. FDG-PET was performed in 222 patients: 134 with papillary tumors, 80 with follicular tumors, and 8 with mixed-cell type tumors. The sensitivity was 75% for the whole patient group and 85% for the 166 patients with negative 131 I whole-body scintigraphy. Specificity was 90% in the whole patient group. The sensitivity and specificity of 131I whole-body scintigraphy were 50% and 99%, respectively. When FDG-PET and 131 I whole-body scintigraphy were combined, tumor tissue was missed in only 7% of patients. The sensitivity and specificity of MIBI/Tl were 53% and 92%, respectively. The conclusion that can be drawn from these results is that FDG-PET indirectly helps to provide support for the SLN concept, because preoperatively confirmed regional lymph node involvement makes the search for SLN(s) unnecessary and all further operative and adjuvant regimens can be planned on the basis of the N-positive stage. In contrast to the lack of studies on the detection of cancer-infiltrated SLNs, investigations designed to detect recurrences with node metastasis have been quite successful. Alnafisi et al. (2000) studied 11 asymptomatic patients with a history of papillary thyroid cancer who had undergone total thyroidectomy, therapy with 131I, and negative findings on 131I whole-body scintigraphy but persisting elevations of thyroglobulin. All these patients had FDG uptake in the neck region or upper mediastinum. Sonographically guided biopsy confirmed malignancy in 6 patients, was nondiagnostic in 2 patients, and gave normal findings in 1 patient. In 2 patients, the sonographic results were normal and no biopsy was attempted. FDG imaging redirected the treatment of 7 patients, resulting in surgery
and/or external-beam radiotherapy. Surgical histopathology confirmed thyroid tumor in all 4 surgically treated patients.
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histoand Cytopathologists Working Together A. Schauer
Because thyroid cancer, in contrast to many other tumor types, is increasing slightly in frequency and the survival rates have not yet been optimized, this tumor needs continuous special attention. Therefore, in thyroid cancer too, early detection, regional node staging, and exact surgical treatment with the aim of R0 resection are all of great importance. The scintigraphically ªcoldº node is the indicator for further investigations in order to confirm or to rule out thyroid cancer disease. The rate of such nodes in which malignancy is ascertained by pathologists ranges from approximately 2% to 20%.
FNAC, the Most Frequently Used Initial Diagnostic Method for Ascertainment of Cancer Diagnosis in the Primary As in the strategies applied in breast cancer diagnosis before sentinel node evaluation, a morphologically based diagnosis is also highly valuable for decisions on thyroid cancer treatment in cases raising the suspicion of thyroid cancer. In Germany some university hospital departments of surgery have a main emphasis on thyroid cancer diagnosis and treatment as well as abdominal surgery. One of these departments is that in the charge of Ræher and his colleagues. Even in the 1980s he compared the detection rates of thyroid cancers before and after introduction of cytodiagnosis for diagnostic clearance of thyroid lesions. Together with Wahl, he compared the cancer detection rates among his patients in the timespan 1966±1971, before cytodiagnosis was used, in the early phases of cytodiagnosis (1974±1976), and after systematic technical and cytodiagnostic training had started. Their results allow the conclusion that when the doctors concerned were more experienced the cancer detection rate was twice as
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together Table 1. Thyroid cancer detection rates before and after use of cytodiagnosis for the evaluation of suspicious thyroid lesions. (From Ræher and Wahl 1981) No. of surgical treated cases
evaluations using FNAC and help in making decisions on surgery-based evaluations together with histopathologists.
Rate of malignant tumors
Before use of cytodiagnosis 1966±1971
837
5.1%
After introduction of cytodiagnosis 1974±1976
280
6.4%
1977±1979
177
11.3%
Table 2. Relevant factors which can in combination signal increased risk for thyroid cancer development Increased risk (geographical factor)
In endemic-areas
Sex
< > , (relative frequency)
Age
< 20 years > 60 years
Number of nodes
Solitary node > multiple nodes
Recurrent goiter
2±4 times
Previous radiation of the neck region
30±40%
high as before routine use of cytodiagnosis in FNACs. The results of these evaluations are listed in Table 1. Whereas in different sites the fine-needle aspiration cytology (FNAC) is partly substituted by other methods (operation according to CT and MRT, core biopsy, vacuum biopsy, etc.), FNAC has retained the diagnostic ªdomainº in undiagnosed lesions of the thyroid. In view of excellent experience in recent decades, the prominence of FNAC for diagnosis can easily be understood, because in many cases surgical intervention can be avoided. Additional criteria, which can at least help in making decisions on whether FNAC should be applied and possibly, in special cases, also whether an operation is indicated are listed in Table 2. It is necessary that all relevant criteria are assessed in an integrative way and not as single points, to avoid unnecessary surgical interventions. As is well known, the radioiodine scintigraphy criteria can support diagnostic
Syringe Quality and Handling of the FNAC Puncture For minimally invasive, diagnostic investigations the Cameco device with changeable syringe (Fig. 1) has an important role and is frequently used. As already mentioned in Chapter 17, this method allows fan-shaped guidance of the fine needle and thus collection of cell material from a circumscribed area. These procedures are demonstrated and schematically described in Fig. 2. In diagnostic programs with FNAC as the initial diagnostic instrument, it must be borne in mind that suspicious cold nodes may be located intrathyroidally. In this case these nodes may not be detected by scintigraphic investigations (see Fig. 3). In such cases the result of palpation is at odds with the scintigraphic picture.
Fig. 1. Cameco syringe: one-way syringe within a pistol-like casing, mostly used for fine-needle aspiration cytology (FNAC)
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Fig. 2. Schematic illustrating performance of FNAC in five steps. I Puncture of the node or the suspicious area. II Aspiration, with development of pressure lower than atmo-
spheric pressure. III Guidance of needle through a fan shape in the course of aspiration. IV Development of pressure equilibrium. V Retraction of the needle
pT Classification (Fig. 4) The postoperative histopathological pT classification (Fig. 4) must include the following subpoints:
Fig. 3. There are cold nodes in three positions. a Intrathyroidal suspicious cold node. b Mainly extrathyroidal cold node, not detectable in anterior-posterior scintigraphy; in view from side seen as subcapsular small defect. c Extrathyroidal cold node not detectable in anterior-posterior and side views. On palpation arouses suspicion as sentinel lymph node (SLN)
In addition, if there is a cold node within the thyroid near to the palpable, partly or totally extrathyroidal, node, the last-mentioned node (position c in Fig. 3) may give the impression that it is a sentinel node, justifying the suspicion of cancer infiltration.
pT1: Solitary tumor nodule with 1 cm or less maximal extension, without perforation of the thyroid gland capsule ± With tumor capsule ± Without tumor capsule or with invasion or perforation of the tumor capsule ± Without invasion of blood vessels and/or lymph vessels ± With invasion into blood vessels and/or lymph vessels pT2: Solitary tumor with more than 1 cm diameter without invasion of the thyroid-gland capsule ± With tumor capsule ± Without tumor capsule or with tumor capsule invasion or perforation ± Without invasion in blood vessels and/or lymph vessels ± With invasion into blood vessels and/or lymph vessels
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together
Fig. 4. Comparison of clinical classification (TNM) with postoperative classification according to the pTNM system. The scheme is in accordance with drawings that appear in the TNM Atlas (Spiessl and Scheibe 1982)
pT3: Multiple tumors (uni- or bilateral) and/or isthmic tumor without transgression of the thyroid gland capsule ± With tumor capsule ± Without tumor capsule or with invasion or perforation of the tumor capsule ± Without invasion into blood vessels and/or lymph vessels ± With invasion into blood vessels and/or lymph vessels pT4: Tumor with extension through the capsule of the gland
In cases with massive tumor growth (pT4), the SLN concept does not have an important role, because during operation tumor-free margins and regional lymph nodes removed by local en bloc resection must be histologically controlled intraoperatively with the aim of widening the operation field if this is indicated by the histological results. As in many other tumor types, with increasing tumor mass (pT1 < 1 cm diameter, pT2>1 cm diameter or multifocality) the risk of metastatic spread also increases.
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Pitfalls of Atypically Located Nodes Nonetheless Connected with the Organ
Difficulties in and Limitations of Preoperative Thyroid Cancer Diagnosis Before the Search for SLN(s)
In physical and nuclear medical evaluation, it is well known that superficially located benign or malignant lesions can break out of the organ. The different node positions and the pitfalls in diagnosis are summarized in Fig. 3. Regional lymphatic spread of thyroid cancers depends on two main factors: a) Tumor type b) Local extension of the primary (pT)
· Confirmation of thyroid cancers without causing bleeding and harm to the organ before the search for sentinel node(s) starts is only possible by means of FNAC. · In addition, sentinel node labeling is only of interest in cases with differentiated cancers, which means not in cancer cases with diffuse extrathyroidal invasive growth (anaplastic cancer subtypes). In such cases preoperatively initiated sentinel node search programs would have no value. The main subtypes of nondifferentiated thyroid cancers are summarized in Fig. 5 a±c.
In relation to these statements it is obvious that the involvement of the regional SLN(s) must preferentially also be seen under these aspects. With reference to point a, it should be remarked that, whereas follicular thyroid cancer mostly develops hematogenous spread into the lungs and bone marrow even in cases with a highly differentiated follicular pattern, papillary cancer, at least initially, mostly spreads into regional lymph nodes, at least in the early stages of the metastatic process. Cases in which papillary thyroid cancer is found primarily in regional (sentinel) lymph nodes are not rare, and they are important evidence for early and preferential lymphatic spread. The relatively low percentage of undifferentiated thyroid cancers (polymorphous or small cell anaplastic) shows initial local fast growth and early breakthrough so that they pass through the capsule, with subsequent regional tumor infiltration and lymph node involvement.
Fig. 5 a±c. Main types of low-differentiation thyroid cancers and their differential diagnosis by histo- and cytopathology. a Spindle-cell-shaped cancer (pseudosarcoma) with epithelial character confirmed by use of cytokeratin antibodies. b Polymorphous nuclear cancer. c Small-cell anaplastic can-
Figure 6 (a and b) demonstrates a polymorphous cellular type of thyroid cancer (histology) and Fig. 7 (a±c), the small-cell anaplastic carcinoma subtype. (Fig. 7 a shows the cytology after Giemsa staining; Fig. 7 b, the histological evidence of vimentin expression; and Fig. 7 c, an anaplastic cancer with angiomatoid pattern and fibrosis.) Papillary thyroid cancers can mostly be diagnosed with certainty (papillary growth pattern, psammoma bodies), because real papillary proliferations are practically always malignant, only in the course of thyrostatic therapy real papillary proliferations can develop focally. Besides the clear-cut papillary proliferations which can also be verified in cytological smears, psammoma bodies are highly characteristic for this tumor subtype (Fig. 8). According to Hedinger and Sobin (1974), different subtypes of papillary thyroid cancers, some with favorable (Fig. 9 a±c) and some with more unfavorable prognosis (Fig, 10 a±d), can be distinguished.
cer. Conditions that must be checked for in the differential diagnosis of each of these subentities are a fibrosarcoma and malignant fibrous histiocytoma; b malignant polymorphous cellular histiocytoma and endocrine metastasis of a polymorphous cellular lung cancer; c non-Hodgkin lymphomas
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together Fig. 6. a Polymorphous nuclear anaplastic thyroid cancer; note the high degree of nuclear polymorphism. SLN labeling is possible only in very early stages. b Polymorphous cellular thyroid cancer. Note the large, in some cases multinucleated, cancer cells. Differential diagnosis: metastasis from polymorphous nuclear lung cancer. SLN search is useful only in early stages; when capsular breakthrough has already occurred it is of no value
These subtypes have been schematically demonstrated by Schauer (1984) (Fig. 9 a±c and 10 a±d). It is well known that papillary thyroid cancers can develop even in childhood or youth. In all age groups, cervical lymph node metastases can be the first substrate detected, and the primary cannot be precisely localized until after this. Figure 11a shows a cervical lymph node metastasis from a papillary thyroid cancer, which was not diagnosed until this metastasis was found. Fig. 11 b demonstrates papillary oncocytic cancer, 11 c Lindsay-tumor (see also Fig. 9 c). In aspiration cytology follicular cancers often cannot be diagnosed with certainty, because it is frequently impossible to differentiate between follicular adenomas and cancers. In such cases, the only diagnosis possible is ªfollicular proliferation.º Even after
pathohistological examination of highly differentiated follicular cancers showing strong thyroglobulin synthesis (Fig. 12 a±c), a diagnosis of highly differentiated follicular cancer can only be safely made after detection of vascular invasions (Fig. 13 a±d) or cancer-related perforation of the capsule of the suspicious node (Fig. 13 e). In moderately differentiated cancers with clear-cut invasive cancer growth, expression of thyroglobulin (Fig. 14) and higher proliferative activity (Fig. 15), histopathological verification of malignancy is not problematic. In conclusion, how useful sentinel node labeling is cannot be evaluated until after the histological diagnosis has been made in material from the nodal lesion, and in difficult cases in serial sections. All these facts lead to the conclusion that in cases in which a more precise cytological diagno-
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Chapter 22 Thyroid Cancer Fig. 7. a Small-cell anaplastic thyroid cancer with cell picture reminiscent of lymphoma cells. Caveat: This is a diagnostic pitfall! Rule out lymphoma by using common leukocyte antigen antibodies (CLA): for B-cell lymphomas use 4KB5, and for T-cell lymphomas use CD43, UCHL1. Confirm epithelial origin by using pan-cytokeratin antibodies. b Small cell anaplastic thyroid cancer with double-expression of cytokeratins and vimentin. Staining with antibodies directed to vimentin in the figure. SLN labeling only possible in very early stages. c Small cell anaplastic thyroid cancer with angiomatoid pattern and interstitial fibrosis
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together
a
b
Fig. 8. Typical picture of a papillary thyroid cancer with typical psammoma bodies. a Typical papillary growth pattern, three calified psammoma bodies at the top.
b Papillary thyroid cancer with follicular growth pattern and ground glass nuclei. Note multiple psammoma bodies, partyl with tree stemlike layering
Fig. 9 a±c. Subtypes of papillary thyroid cancers with different prognosis. Highly differentiated cancer subtypes with favorable prognosis. a Subtype with typical papillary growth pattern and ground-glass nuclei of the cancer cells, there can be psammoma bodies in the interstitium. b Highly dif-
ferentiated papillary thyroid cancer with normal chromatin distribution of the cancer cell nuclei; no ground-glass nuclei can be seen. c Highly differentiated follicular structured thyroid cancer (Lindsay tumor) with typical ground-glass nuclei
sis than ªfollicular proliferationº is not possible, the SLN labeling procedures would be carried out in an unclear situation as far as the diagnosis of the lesion under scrutiny is concerned. A similarly critical situation pertains with the diagnosis of oncocytomas or oncocytic carcinomas (Hçrthle cell adenoma or carcinoma) by FNAC. In this connection it must be added that oncocytes in fine-needle aspirates are not always the substrate of an oncocytic tumor, because oncocytic transformations also occur in regressively altered thyroid tissue. In our own series, in follow-up studies of 33 patients with oncocytic tumors, 2 had a malignant course culminating in death. In a separate case, intraoperatively we found a follicular, highly differentiated lesion not definitely
meeting the criteria of malignancy and in addition a metastasis in a contralateral node. Lastly, in the thyroidectomy preparation a small nodule of a oncocytic cancer, which had not been primarily detected during the preoperative scintigraphic investigations, was found. This case demands meticulous care in view of the frequent multifocality of thyroid cancers and the frequent simultaneous occurrence of different subtypes. In Fig. 16 a typically reddish brown colored oncocytic cancer nodule is shown, while Fig. 17 a, b shows highly to moderately differentiated oncocytic cancer. Figure 18 demonstrates lymph vessel invasion by a malignant oncocytoma and Fig. 19, regional lymph node metastases.
265
Chapter 22 Thyroid Cancer
Fig. 10 a±d. Subtypes of papillary thyroid cancers with different prognosis. Low-differentiation papillary cancers, some with a worse prognosis. a Papillary and solid growth pattern with sclerosis, higher degree of polymorphism, hyperchromasia and mitotic activity; b papillary and solid
growth pattern without sclerosis; c some areas with groundglass nuclei, squamous cell metaplasia (:), and vascular invasions ( ) (arrows); d some follicles with ground glass nuclei (:), marked atypia, squamous cell metaplasia, and high rate of vascular invasions ( ) (arrows)
Direct perforation of the vascular wall, endothelial adhesion, and cancer cell necrosis are important criteria of vascular invasion and, with that, of malignancy of the lesion. Johnson et al. (1999) investigated 11 patients with Hçrthle cell neoplasms, using isosulfan blue dye for sentinel node marking. One of the cases was considered malignant. No positive sentinels were found in any of these cases. The authors concluded that the addition of sentinel node sampling to the operative strategies might yield further valuable prognostic information. It is easier to diagnose a medullary thyroid cancer (MTC), because neuroendocrine granules can be suspected even in Giemsa stainings of the smears and be confirmed in immunohistochemical stainings using antibodies directed to chromogranin A or calcitonin. In Fig. 20 a, b a medullary cancer with a positive reaction for calcitonin is illustrated. Figure 20 a demonstrates the typical perifollicular growth pattern and Fig. 20 b, multifocal development from the parafollicular cell populations. In Fig 20 c the characteristic chromogranin staining is shown and in
Fig. 20 d, the characteristic calcitonin staining. In Fig. 20 e blood vessel invasion can be seen, indicating possible hematogenous metastasis. Figure 21 demonstrates interposed neuroendocrine amyloid masses in addition to a positive calcitonin reaction. In Fig. 22 a spindle-cell differentiated medullary cancer is shown. This growth pattern makes it necessary to exclude cancers with similar cellularity (e.g., metastasis of lung cancer or melanoma). In conclusion, with a view to the main types of neoplastic thyroid lesions subtyping is possible by FNAC and/or histopathology in most cases; however confirmation of malignancy is only possible when clear-cut cytological criteria of malignancy are found, whereas the discrimination of premalignant or low-grade malignant lesions from benign lesions is difficult or even impossible on FNAC, and sometimes even on histopathological examination involving for vascular invasions and/or perforation of the capsule by invasive cell formations in serial sections. None of this really restricts decisions for pre- and intraoperative sentinel node labeling.
)
)
266
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together Fig. 11. a Papillary thyroid cancer: only a few ground glass nuclei are seen (arrows). b Papillary thyroid cancer, oncocytic type. Note moderate polymorphism of the cancer cell nuclei. SLN-labeling helps to detect lymphatic spread. c Papillary thyroid cancer, follicular type. Typical ground glass nuclei, especially on the left side of the figure (Lindsay tumor). SLN-labeling helps in detection of local lymphatic spread (compare with Fig. 9 c)
267
268
Chapter 22 Thyroid Cancer Fig. 12 a Highly differentiated thyroid cancer. Note isomorphism of cancer cell nuclei. It is not rare for hematogenous metastasis to precede regional lymphatic spread. b Highly differentiated follicular thyroid cancer; far-reaching nuclear isomorphism. Hardly any mitotic activity is detectable. Development of 99mTc-nanocolloid labeling can be helpful in regional SLN detection and regional surgical cancer clearance. c Follicular type of thyroid cancer: immunohistochemical reaction with antibodies directed to thyroglobulin. Note the strong staining of the cancer cells (red)
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together
Fig. 13. a Highly differentiated follicular thyroid cancer. Lymph vessels are seen in the upper part and a small vein with cancer cell invasion in the lower part of the figure. Perforation of the capsule by the highly differentiated follicular cancer is seen at the upper right. b Low-differentiation follicular thyroid cancer. Note cancer cell invasion into a small vein in the upper part of the picture and lymph vessel invasion in the lower right. Capsule has been perforated by a solid cancer cell group. c Blood vessel (capillary) invasion by a moderately differentiated thyroid cancer. Note endothelial proliferation with growth over the cancer cell cluster (arrows). d Invasive, moderately differentiated thyroid cancer of follicular type with clear cell differentiation and cancer growth within a larger vein (left). e Moderately differentiated thyroid cancer with capsular perforation (arrows) and cancer growth in the regional soft tissue. Parts of the primary are seen (left). Cancer infiltration into the regional soft tissue (right)
269
270
Chapter 22 Thyroid Cancer Fig. 14. Moderately differentiated follicular thyroid cancer with solid growth pattern. Expression of thyroglobulin documented by immunohistochemical reaction. Hematogenous spread is prevalent, with locoregional spread in some cases. However, SLN labeling is helpful in regional cancer clearance
Fig. 15. Invasive moderately differentiated follicular thyroid cancer. Immunohistochemical staining for Ki67 (with the antibody MIB I). Approximately 50% of the cancer cells are in the proliferative compartment
Fig. 16. Typical sharply delineated reddish brown node in the presence of an oncocytic tumor
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together Fig. 17. a Oncocytic thyroid cancer (Hçrthle cell carcinoma), in parts with follicular differentiation. Hematogenous and lymphatic spread are possible. b Oncocytic (Hçrthle) cell cancer, with moderate differentiation. Note the strongly eosinophilic, abundant granular cytoplasm
Fig. 18. Oncocytic thyroid cancer: lymph vessel invasion
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Chapter 22 Thyroid Cancer Fig. 19. Lymph node metastasis from an invasive oncocytic thyroid cancer, with a moderate degree of nuclear polymorphism and eosinophilic granular cytoplasm. Hematogenous and lymphatic spread are possible, SLN labeling can be helpful in locoregional cancer clearance
Fig. 20. a Medullary thyroid cancer: growth around the pre-existent follicular structures of the thyroid gland. Immunohistochemical staining for calcitonin. b Medullary thyroid cancer: multifocal cancer development, perifollicular to thyroid follicular structures, filled with thyroglobulin. Immunohistochemical staining for calcitonin. c Invasive medullary thyroid cancer: immunohistochemical staining for chromogranin. d Same invasive medullary thyroid cancer: immunohistochemical staining for calcitonin. Local lymphatic and also hematogenous spread are possible. e Invasive medullary thyroid cancer with blood vessel invasion: immunohistochemical staining for chromogranin. Note intravasal erythrocytes besides cancer cell populations at bottom right
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together Fig. 20 c±e
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Chapter 22 Thyroid Cancer Fig. 21. Medullary thyroid cancer: immunohistochemical staining for calcitonin. Note the interstitial homogeneous, brownish masses corresponding to neuroendocrine amyloid
Fig. 22. Undifferentiated, spindle-cellular medullary thyroid cancer. Spindle cell sarcoma and malignant fibrous histiocytoma must both be excluded.
Choice of the Most Efficient Labeling Strategy Peritumoral injection in thyroid gland must be seen as an absolutely different entity than at other tumor sites. Whereas in breast cancers and melanomas the labeling solutions are injected into soft tissue structures from where they can be resorbed by the highly developed lymphatic network, in the thyroid gland the solution has to be injected into a highly capillarized endocrine parenchyma. This means that lymphatic resorption is low relative to the fast vascular resorption (endocrine organ). This can easily be understood, because resorption here follows principles similar to those of hormone
resorption, so that the labeling solutions pass directly into the blood stream. Therefore, some special points must be taken in account: · The volume of the injected solution should be as small as humanly possible. · Direct intraoperative labeling using blue dye solution has benefits over preoperative labeling procedures. · If 99mTc-colloid solutions are used the dosage should be as low as possible because of the high hematogenous uptake.
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together Fig. 23. Lymph node groups that can be the SLNs in thyroid cancer. Group A: paratracheal nodes; group B: paravasal nodes; group C: nodes of the upper mediastinum
Main Basins of Lymphatic Drainage from Thyroid Cancers
New Approaches to the Search for Sentinel Node(s) in Thyroid Cancer
Most papillary cancers show early lymphatic spread. The most important basins (Fig. 23) are: · The paratracheal node group · The cervical groups both sides · The upper mediastinal nodes
Catarci et al. (2001) compared the three different strategies used in sentinel node detection. They ascertained the following identification rates: · Preoperative lymphoscintigraphy: 66% · Vital dye (Blue Patent V, 2.5%): 50% · Probe scanning (optimal dosage 22 MBq): 83%
These nodes can also be subgrouped according to their localizations at different levels. A comparison between the various specifically named node groups that can be involved (Fig. 23) and their coordination to the different levels is demonstrated in Fig. 24 a, b and Table 3. Figure 25 reflects the surgical operation site, from which as a rule early lymphatic spread (N1a and N1b positions can be reached (see also Fig. 26).
The identification rate increased to 100% when all three methods were used. On the basis of the data obtained the group is now recommending a controlled trial. The results of preliminary studies based on limited numbers of patients are listed in Tables (Tables 4±7). Some of the groups taking part preferred intraoperative labeling, using blue dye solution, while others used labeling with 99mTc-nanocolloid. 99m Tc-nanocolloid labeling may achieve increasing clinical significance
275
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Chapter 22 Thyroid Cancer
Fig. 24 a, b. Comparison of a cervical lymph node groups 1±8 (Hermanek et al. 1993) with b level-related grouping (I±VI) (Robbins et al. 1991)
Table 3. Lymph node groups 1±8 with corresponding levels and names according to Robbins et al. (1991) and the TNM Atlas Level (Robbins et al. 1991)
Lymph node group number
TNM Atlas (1992) a
Robbins et al. (1991)
I
1
Submental nodes
Submental group
2
Submandibular nodes
Submandibular group
II
3
Cranial jugular nodes
Upper jugular group
III
4
Medial jugular nodes
Middle jugular group
IV
5
Caudal jugular nodes
Lower jugular group
V
6
Dorsal cervical nodes along the accessory nerve
Posterior triangle group
7
Supraclavicular nodes
8
Prelaryngeal and paratracheal nodes
VI a
Anterior compartment group
TNM Supplement (1993)
· Because radioiodine scintigraphy does not allow detection of regional lymph node metastasis owing to by the high uptake of radioiodine by the pre-existing thyroid parenchyma.
· Because iodine-131 can only mark lymph node metastasis after total thyroidectomy (see Fig. 27). · Because radioiodine labeling can only detect lymph nodes that are already metastatic, and not cancer-free SLNs.
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together
Fig. 25. Middle field, in which the majority of SLNs corresponding to thyroid cancer are located, as delineated by Robbins et al. (1991). The field is fully consistent with the nominated lymph node group subsumed at N1a and N1b in the classification system published by the German Society of Otolaryngology (Bootz 2000). The published N-classification of thyroid cancers is illustrated in Fig. 26
It might be, therefore, that labeling of sentinel nodes with 99mTc-nanocolloid allows a most selective lymphadenectomy intraoperatively, with a higher degree of certainty of locoregional cancer clearance. Rettenbacher et al. (2000) recently published impressive preliminary results obtained with 99m Tc. His strategy can be briefly summarized as follows: · Injection of 0.5 ml containing 37 MBq 99mTcnanocolloid divided into four aliquots into the primary. · Dynamic images (high-resolution collimator, 1 frame per 15 s, 64 ´ 64 matrix, GE Elscint, model SP6) obtained up to 10 min after tracer administration, followed by static anterior and lateral oblique images (256 ´ 256 matrix up to 1 h after tracer administration. · Identification of the SLN with the handheld gamma probe (c-Trak, Care Wise, Morgan Hill, Calif., USA). · Marking of SLN detected on the skin with water-resistant colored pen. · After total or subtotal thyroidectomy, removal of the SLNs, supported and controlled with the gamma probe. The results obtained by the Salzburg group are summarized in Table 6. I am grateful to Dr. Rettenbacher for the well-documented case reported in his original publication (Fig. 28). Work on finding optimal strategies is apparently still in progress, but practically all groups are al-
Fig. 26. N-Classification of thyroid cancer. N1a Metastases in ipsilateral cervical nodes; N1b metastases in bilaterally, medially, contralaterally or mediastinally located nodes
277
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Fig. 28. Lymphoscintigraphy of a 35-year-old patient with an invasive papillary thyroid cancer 1.8 cm in diameter. 99mTcnanocolloid, 30 MBq, was injected into the primary, the injection area being covered by a lead shield. Two SLN are localized in the medial jugular compartment (thick arrow), and one SLN can be seen in the lower jugular region (thin arrow). (Lymph scintigrams have been kindly donated by Dr. L. Rettenbacher and Prof. Dr. G. Galvan, Department of Nuclear Medicine and Endocrinology, State Hospital, Salzburg, Austria)
Fig. 27. Follicular thyroid cancer: pT3N1M0. Status after total thyroidectomy and central neck dissection. Postoperative radioiodine ablative therapy. In a later iodine-131 control scintigraphy a supraclavicular lymph node metastasis was detected. (These pictures were kindly put at our disposal by Priv. Doz. Dr Meller, Department of Nuclear Medicine, University Hospital, Gættingen)
ready in favor of applying the sentinel node concept in thyroid cancer too. It seems that this concept can take the place of more or less uncon-
trolled lymphadenectomy (berry picking) practiced in many clinics up to now. Tables 4±7 show new approaches in sentinel node labeling using blue dye or 99mTc-nanocolloid solutions. Pelizzo et al. (2001) investigated 29 cases with papillary thyroid cancers in an attempt at screening. For SLN marking the authors injected patent blue V dye solution into the thyroid nodule. Thyroidectomy and lymph node removal at levels III, IV, VI, and VII (see Fig. 24 a) followed. The thyroid nodule and sentinel and nonsentinel nodes were investigated in frozen sections and the remaining specimens, in paraffin sections. The results obtained in these investigations are given below (Table 8). In investigations carried out by Haigh and Giuliano (2000) the identification rate in a papillary thyroid cancer series was high. In 15 of 16 cases SLNs could be detected and exactly localized. In 9
Table 4. Results of sentinel node labeling in thyroid lesions by Kelemen et al. (1998) Pharmaceutical used
No. of patients
Size of nodules
Malignant lesion(s)
Benign lesion(s)
Cases in which SLN detected (n)
Cases in which SLN not detected (n)
SLN positive in malignant cases (n=%)
Location of SLN Paratracheal
Jugular
Isosulfan blue dye mean vol. 0.5 ml
17
0.4± 4.0 cm
12
5
15/17
2/17
5/12 = 42%
13
2
Properties of Primaries in the Thyroid Gland and Staging by Surgeons and Histo- and Cytopathologists Working Together Table 5. Results of sentinel node labeling by Dixon et al. (2000) No. of patients
Pharmaceutical used
Drainage verified (n)
SLN detection rate
Drainage through: central lateral to mediastinal nodes
Central SLN
Truly positive SLN in papillary cancers
Negative SLN in papillary cancers
40
Isosulfan blue dye
31
26
11
6
4/12
2/12
SLN detected in benign lesions: 14/18
Table 6. Results of sentinel node labeling in thyroid lesions by Rettenbacher et al. 2000 Pharmaceutical used
No. of patients
Site and timing of injection
Imaging strategy
Malignancies
Benign lesions
Identification of SLNs
SLN failure
Nos. of SLN
False negatives
99m
9
Intratumoral 1 h before operation
Dynamic up to 10' planar and oblique up to 1h
6
1 Oncocytoma
All 4 papillary cancers
Both (2) follicular cancers
5´1
0
4 Papillary
2 other
TcNanocolloid, 37 MBq
1´3
2 Follicular
1´4
Table 7. Strategies of investigation a (Sahin et al. 2001)
a
No. of patients
Pharmaceutical used
Palpable solitary node
Diagnosis by
Injection modality
Volume
1st hour
90±120 min after injection
13
99m
Tc nanocolloid
13 pat
FNAC
3 Days before operation 15 MBq (0.4 mCi) 99m Tc
0.2 ml
Dynamic images 60 frames ´ 1 min
Static anterior and lateral images
No. of patients
Early frames
Lymph node detection
Dynamic acquisition
Malignant lesions
Positive nodes
13
Intratumoral accumulation
10/15
7/10
5/13
1
Results
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Chapter 22 Thyroid Cancer
Table 8. Significance of sentinel node labeling in papillary thyroid cancer cases Rate of SLNs detected intraoperatively
SLNs with neoplastic involvement
Non-sentinel nodes infiltrated by cancer
SLN not involved and other nodes also free
22/29 = 75%
4/22 = 18.2%
2 cases
18/18
Table 9. Results of SLN search during thyroidectomy (Haigh and Giuliano 2000) Pathology
N
SN identified
SN metastases
Benign
21
17/21 (81%)
±
Follicular adenoma
7
6
±
Hçrthle cell adenoma
3
2
±
Colloid nodule/ multinodular goiter
7
5
±
Hashimoto thyroiditis
4
4
±
Malignant
17
16/17 (94%)
9/16 (56%)
Papillary
16
15
9
Follicular
1
1
0
cases metastasis was found in the SLNs. The number of follicular cancers in their series was too small to allow firm conclusions (Table 9).
Value of the SLN Concept in Thyroid Cancer Treatment In the course of the last three decades there has been significant progress in locoregional clearance of thyroid cancers: · It was very important to leave the uni- or bilateral neck dissection strategy behind and to look for a less injurious method, especially in view of the subsequent local neural lesions. · This had been attempted with the so-called berry-picking strategy, meaning removal of palpable enlarged lymph nodes; this method has only low-grade specificity and is also inadequate in terms of topographical-anatomical continuity between the lymphatic network and the intrathyroid primary. Therefore, this method could only be seen as a strategy that might be
successful, and then only more or less by chance. · After experience of these unsatisfactory surgical strategies, followed by the incalculable local cancer clearance, the introduction of the sentinel node concept seemed to be helpful and to offer hope of developing significant advances: ± by providing better surgical guidance with respect to local cancer clearance. ± by including lymph node basins not reliably detected by the berry picking strategy. In contrast to earlier methods, extirpation of regional labeled lymph node(s) corresponding to the direct lymphatic basin of the primary after peritumoral injection with patent blue stain or isosulfan blue dye-solution and/or 99mTc nanocolloid solution, gives rise to the hope that more selective lymphatic tumor clearance can be achieved. This procedure, with or without the use of 99mTc as a labeling substance, could be adopted as the classic method in place of iodine labeling, which is still the most frequently used but can only be evaluated in cases in which regional lymphatic spread has already occurred. It must be pointed out that not only the follicular thyroid cancers show a positive reaction on 131/125Iscintigraphy, but also the papillary cancers, which synthesize thyroglobulin in more than 90% of cases. Whereas this method is suitable for detection of metastases, 99mTc-labeled nanocolloids are the best markers to detect the regional tumor-free SLNs for excision and histopathological and immunohistochemical investigation. That both methods, iodine-131 scintigraphy and the dye method (using blue stains), combined with the labeled nanocolloid method are appropriate for the improvement of local surgical tumor clearance results from the fact that in the case of positive scintigraphic results using iodine as marker Npositivity must be stated a priori and the operative strategy must be adapted to this. However, it must be emphasized that micrometastases and metastases from cancers that have already lost the biological capability of using iodine for thyroglobulin
References
synthesis cannot be detected. In addition, it is also not possible to localize the sentinel nodes for intensive investigations using serial-section and immunohistochemical techniques to exclude very early development of micrometastasis. In spite of the intensively developed network of the cervical lymphatics and their node stations, which is also responsible also for contralateral metastases, three main fields of lymph node localization can be defined. These are mentioned above with more detail: · The paratracheal (retrothyroidal) lymph nodes above and below the isthmus of the thyroid gland · The cervical lymph nodes along the carotid arteries and the jugular veins at both sides · The upper mediastinal nodes These three fields of node localization must all be borne in mind both in scintigraphic evaluations and in any investigations in all steps of the intraoperative search for the nodes (Figs. 23, 26).
Dependence of Therapy Regimens on (Sentinel) Lymph Node Status in Thyroid Cancer Subtypes In cases with papillary or follicular thyroid cancer classed as pT1aN0M0 no further adjuvant treatment is given, whereas in thyroid cancer classed as pT1a and higher pTsN1M0 and M+ a radioiodine treatment regimen is applied in institutes of nuclear medicine (see also Chapter 33). In papillary cancers with the highest rate of regional lymphatic spread, the adjuvant therapy problem is looked at in a different way. A large proportion of papillary thyroid cancers are seen clinically by reactions to radioiodine and, in addition, in reactions to antibodies directed to thyroglobulin, which are positive in more than 90% of cases. Therefore, radioiodine therapy is performed in more highly differentiated cases with cancer-infiltrated regional (sentinel) lymph nodes. In undifferentiated invasive thyroid cancers the sentinel node concept does not play any significant part, because of the diffuse regional cancer invasion. With reference to regional lymph node involvement in oncocytoma, the metastatic process can be seen as similar to that in follicular cancers. However, because oncocytomas do not incorporate
radioactive iodine at any significant rate, adjuvant radioiodine therapy cannot be considered. In both node-negative and node-positive cases a ªwait and seeº strategy is emerging more and more as the method of choice. It must be made clear that in approximately 5± 10% of cases cancer of the thyroid develops as a multifocal cancer. Accordingly, it can happen that a lymphogenous metastasis develops not from the main nodule but from a small focus that has not been detected preoperatively. This also applies to metastases to nodes on the opposite side to the main nodule. In very rare cases follicular or papillary thyroid cancers can develop together with a metastasizing malignant oncocytoma (Hçrthle cell cancer).
References Alnafisi NS, Driedger AA, Coates G, Moote DJ, Raphael SJ (2000) FDG PET of recurrent or metastatic 131I-negative papillary thyroid carcinoma. J Nucl Med 41:1010±1015 Bootz F (ed) (2000) Oncology of head and neck region (German Society of Otolaryngology consensus report by order of the Presidium), HNO 48:104±118 Catarci M, Zaraca F, Angeloni R, Mancini B, Fillippo MG de, Massa R, Carboni M, Pasquini G (2001) Preoperative lymphoscintigraphy and sentinel lymph node biopsy in papillary thyroid cancer. A pilot study. J Surg Oncol 77(1):21±24 Dixon E, McKinnon JG, Pasieka JL (2000) Feasibility of sentinel lymph node biopsy and lymphatic mapping in nodular thyroid neoplasms. World J Surg 24(11):1396±1401 Feine U, Lietzenmayer R, Hanke JP, Held J, Wæhrle H, Mçller-Schauenberg W (1996) Fluorine-18-FDG and iodine131-iodide uptake in thyroid cancer. J Nucl Med 37:1468±1472 Grçnwald F, Kalicke T, Feine U, Lietzenmayer R, Scheidhauer K, Dietlein M, Schober O, Lerch H, Brandt-Mainz K, Burchert W, Hiltermann G (1999) Fluorine-18 fluorodeoxyglucose positron emission tomography in thyroid cancer: results of a multicentre study. Eur J Nucl Med 26:1547±1552 Haigh PI, Giuliano AE (2000) Sentinel lymph node dissection for thyroid malignany. Recent Results Cancer Res 157:201±205 Hedinger C, Sobin L (1974) Histological typing of thyroid tumours. (International histological classification of tumours, 4, no 11) World Health Organization, Geneva Johnson LW, Sehon J, Li BD (1999) Potential utility of sentinel node biopsy in the original surgical assessment of Hçrthle cell tumors of the thyroid: 23-year institutional review of Hçrthle cell neoplasms. J Surg Oncol 70(2):100±102 Kelemen PR, Herle AJ van, Giuliano AE (1998) Sentinel lymphadenectomy in thyroid malignant neoplasms. Arch Surg 133:288±292
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Chapter 22 Thyroid Cancer Pelizzo MR, Boschin IM, Toniato A, Bernante P, Piotto A, Rinaldo A, Ferlito A (2001) The sentinel node procedure with Patent Blue V dye in the surgical treatment of papillary thyroid carcinoma. Acta Otolaryngol 121(3):421± 424 Rettenbacher L, Sungler P, Gmeiner D, Kassmann H, Galvan G (2000) Detecting the sentinel lymph node in patients with differentiated thyroid carcinoma. Eur J Nucl Med 27(9):1399±1401 Robbins KT, Medina JE, Wolfe GT, Levine PA, Sessions RB, Pruet CW (1991) Standardizing neck dissection terminology official report of the Academy's Committee for Head and Neck Surgery and Oncology. Arch Otolaryngol Head Neck Surg 117:601±605
Ræher HD, Wahl R (1981) Der kalte Schilddrçsenknoten, eine Stellungnahme aus der Sicht des Chirurgen. Dtsch Med Wochenschr 106:657±662 Sahin M, Yapici O, Dervisoglu A, Basoglu T, Canbaz F, Albayrak S, Citak A (2001) Evaluation of lymphatic drainage of cold thyroid nodules with intratumoral injection of Tc-99m nanocolloid. Clin Nucl Med 26(7):602±605 Schauer A (1984) Pathologie der Schilddrçsentumoren. In: Becker HD, Heinze HG (eds) Maligne Schilddrçsentumoren. Springer, Berlin Heidelberg New York, pp 2±61 Spiessl B, Scheibe O, Wagner G (eds) (1982) TNM atlas. Springer, Berlin Heidelberg New York TNM Supplement (1993) In: Hermanek P, Henson DE, Hçtter RVP, Sobin LH (eds) A commentary on uniform use. Springer, Berlin Heidelberg New York
Chapter 23
Cancers of the Face, Nose, Pharynx, and Oral Cavity
Head and Neck: Introduction Head and neck squamous cell cancers (HNSCC) are the most frequent histopathological subtype of malignant tumors in the upper aerodigestive tract. As in many other tumor types, early cancer detection with accurate diagnosis (staging, grading) and surgical treatment strategies are the most important points in any attempt to increase the healing rates (Ambrosch et al. 1995, 1996; Pitman et al. 1998; Werner et al. 1999). It is depressing that 40±50% of resectable advanced cancers of the upper aerodigestive tract are followed by the development of local recurrences. Even in cases in which the margins of excisates are histopathologically controlled the relapse rates amount to 15±30% (Leemans et al. 1994). That means that clinical local R0 resection can quite frequently be equated with minimal local residual disease (Pantel 1996). Still more difficulty attaches to the development of new strategies for regional tumor clearance, meaning control of the elements of the lymphatic system between the primary and the target lymph nodes, now routinely called the sentinel lymph nodes (SLNs). As in the diagnostic approach adopted in breast cancer, and because of the good accessibility of cervical and facial lymph nodes, ultrasonography is the first step in the staging of naso-pharyngeal and oral cavity cancers. Additional examinations performed in most patients are CT, MRI and 18 F-FDG-PET (see also section contributed by Avril et al. in this chapter). The sensitivity in detection of enlarged lymph nodes is relatively high, while the specificity in prediction of metastatic involvement depends principally on the size and shape of the lymph nodes or the intensity of glucose metabolism. The Sinerem method might be the first diagnostic method to provide histological information (defects in cancer-infiltrated lymph nodes).
Clinically, none of the N-staging methods available (palpation, ultrasound, imaging systems such as CT, MRT, FDG-PET) is adequate to allow reliable statements on N0 status (van den Brekel et al. 1991). In addition, FNAC also gives valuable results in positive cases, but in negative cases cancer involvement can never be excluded (van den Brekel et al. 1999). When the result of lymph node puncture (FNAC) is negative, in many clinics neck dissection is not performed and either a ªwait and seeº strategy is adopted or so-called elective lymphadenectomy is performed (Ambrosch and Steiner et al. 1995, 1996; van den Brekel et al. 1991, 1993, 1994, 1999). The question now current is whether the SLN concept can be helpful in detecting the first lymph node station(s) and with this mark the prevalent ways to sentinel node(s) and through basins for metastasis. Positive results and growing bodies of experiences could be a milestone in the development of new strategies to lower the rate of locoregional recurrence. In intraoperative SLN detection studies in head and neck cancers Dunne et al. (2001) tested a welltype NaI detector (WTD) for gamma ray spectroscopy and also the use of a handheld probe (HGP). Of 18 patients with head and neck squamous cell cancers (HNSCC), 9 had tumor-free sentinel nodes and tumor-free node status. The authors concluded from their results that in cases with advanced lymph node status the search for the sentinel node(s) has no implications for ipsilateral node treatment. However, for the contralateral clinical N-status WTD showed higher activity enrichment overall. Smaller count rates were determined than with HGP. The authors emphasize that the additional use of WTD offers a more precise distinction of intranodal disintegration rates in the draining lymph nodes; it may increase the reliability of the intraoperative SLN search and biopsy.
23
284
Chapter 23 Cancers of the Face, Nose, Pharynx, and Oral Cavity Table 1. Preliminary first results in sentinel lymph node (SLN) search in cancers of the oropharynx, hypopharynx, and larynx seen by the Marburg group in Germany (1999) No. of case
Localization of primary Oropharynx
Hypopharynx
Larynx
9
4
2
3
SLN detection
7/9
In a preliminary clinical study, the German Marburg group (Werner et al. 1999) evaluated the significance of SLN(s) in 4 oropharyngeal, 2 hypopharyngeal, and 3 laryngeal cancers differing in clinical N status (5 N0, 2 N1 and 2 N2c). The results of the search for sentinel node(s) using modern techniques are summarized in Table 1. The authors suggest on the basis of their results that SLN search may also be suitable for the tumor group found in the upper aerodigestive tract, but they point out the well-known problems: a) Too short distance from the primaries to the SLNs b) Drainage changes in cases with cancer-infiltrated SLNs. Ad a) This point highlights the need for technical improvements to give maximal separation of the primary from regional sentinel nodes. Ad b) This problem could be at least partly solved by using FNAC or cancer cell labeling within the nodes following immunoscintigraphic detection by means of monoclonal antibodies directed to surface antigen of the cancer cells.
Significance of PET in Head and Neck Tumor Staging N. Avril, W. Weber, M. Schwaiger
Detection and Staging of the Primary Morphological imaging modalities (CT/MRI, ultrasound) allow for adequate assessments of head and neck tumors to be made concerning size, extent of invasion, and topographical relations to surrounding anatomical structures. Therefore,
Clinical N0
Clinical N1
Clinical N2c
SLN histol. neg.
SLN histol. pos.
SLN neg. ND
SLN pos. ND
4/5
1/5
1/2
1/2
Positive nodes in levels II+III + capsule perforated no enrichment intra-op.
FDG-PET need not be included in the initial Tstaging. Extensive local infiltration and early spread to locoregional lymph nodes are the dominating clinical features of head and neck tumors.
Comparison with CT/MRI Squamous cell carcinomas (SCC) generally show intensive FDG accumulation. Novak et al. (1999) compared FDG-PET (78 studies: 48 in patients with primary and 30 in patients with recurrent head and neck cancers) with CT and MRI; the evaluations concerned 71 patients in total. Sensitivity and specificity in detecting primary tumors were 87% (P < 0.05) and 67% for PET, compared with 67% and 44%, respectively for CT/MRI. Detection of local recurrence revealed a sensitivity of 86% and a specificity of 75%, as against 57% and 92% for CT/MRI. Laryngeal, buccal (cheek) and salivary gland tumors exhibited a significantly lower glucose metabolism than tumors of the hypopharynx. Furthermore, the FDG uptake of G1 tumors was much lower than that of G2 and G3 tumors. The authors concluded that FDG-PET was noticeably more accurate than CT and MRI in detecting head and neck cancer. However, conventional diagnostic procedures including panendoscopy and biopsies are sufficient in most clinical situations.
Regional Lymph Node Evaluation by PET In contrast to the blue stain and 99mTc methods, PET is not used primarily to detect the sentinel node(s) of the primary, whether or not metastasis is present in it (them), but exclusively to evaluate
Cancers of the Face, Naso-pharynx and Oral Cavity and of the Salivary Glands
regional nodes for early or advanced metastatic processes in the regional basins. Analysis of PET imaging has been employed in different ways: some investigators have looked for lymph node metastases, while others have counted the number of involved neck sides and yet others have considered the number of involved lymph node regions. Stuckensen et al. (2000) studied 106 patients with histologically proven SCC of the oral cavity and compared FDG-PET, ultrasound, CT, and MRI with histological tissue evaluation in a prospective study. A total of 2196 neck lymph nodes were investigated. FDG-PET had a sensitivity of 70%, specificity of 82%, and accuracy of 75%, compared with 84%, 68%, and 76% for ultrasound, 66%, 74%, and 70% for CT, and 64%, 69%, and 66% for MRI. Thus, PET had the highest specificity, while ultrasound had the highest sensitivity. In 10 patients, secondary primary tumors or distant metastases were detected only by PET. In a few studies, FDG-PET was found to be slightly more accurate than CT or MRI in detecting lymph node metastases, although other groups noted a similar diagnostic accuracy for PET and morphological imaging techniques. False-negative PET findings occur in micrometastatic disease. Owing to the high number of small lymph node metastases from oral cavity carcinoma, the accuracy of noninvasive neck staging procedures, including FDG-PET, is limited. Therefore, elective neck treatment is still mandatory for patients with SCC of the oral cavity. False-positive findings are due to inflammatory reactions in lymph nodes. In addition, normal structures in the head and neck region, such as tonsils and salivary glands, can take up considerable amounts of FDG, sometimes leading to false-positive results. Nevertheless, the high accuracy of FDG-PET in detecting lymph node involvement may provide additional information that is important for the planning of radiation treatment in patients with advanced disease (Rahn et al. 1998). Although the accuracy of FDG-PET in lymph node staging may surpass that of CT and MRI, these modalities will still be required for precise location of metastatic lesions and adjacent normal anatomical structures prior to a surgical procedure or radiation treatment. Owing to the complex anatomy of the head and neck region, the optimal diagnostic modality may be a ªfusion imageº showing abnormal metabolic lesions superimposed on the anatomical locations.
Significance of PET in Monitoring for Locoregional Recurrence As earlier detection of recurrent disease may improve survival rates, Læwe et al. studied FDG-PET as a surveillance tool in 44 patients with stage III or IV head and neck cancer (Læwe et al. 2000). PET was performed twice during the first posttreatment year: 2 months and 10 months after therapy. On the basis of their tissue biopsies, patients were grouped into those who had achieved a complete response and those who had residual disease. Patients with complete response were further subgrouped into those without evidence of disease and those who had a recurrence within 1 year after completion of therapy. PET performed significantly better than correlative imaging or physical examination in detecting recurrence. Of 30 patients with complete response, 16 had recurrent disease in the first year after therapy and in 5, the recurrence was only detected by PET. Four recurrences were detected by PET and correlative imaging, 5 by physical examination and PET, and 2 by physical examination, correlative imaging, and PET. Only PET detected all recurrences in the first year. Comparing diagnostic methods and modalities, Hçbner et al. (2000) performed a retrospective evaluation of the results of 59 PET scans done on 45 patients with head and neck tumors. PET correctly identified 36 out of 37 malignant tumors and 18 of 22 benign processes, yielding a sensitivity of 97% and a specificity of 82%. Tumor was ruled out in 18 of 19 patients. For CT, the sensitivity was 80% (20/25) and specificity 31% (4/13). These studies show that PET is highly accurate in detecting head and neck tumor recurrence when it may still be undetectable by other clinical methods.
Cancers of the Face, Naso-pharynx and Oral Cavity and of the Salivary Glands The cancer types nominated and summarized are treated by different medical disciplines.
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Because of this fact and because of the differing tumor biology, it is necessary to describe the different cancer types separately. Point 1) Cancers of the skin, predominantly SCC and malignant melanomas, metastasize primarily to the first node related to the different skin regions. Cancer-infiltrated enlarged nodes are often palpable. In many cases the prevalent positions of the SLNs can already be logically derived
when the catchment areas are related to the subcutaneously located nodes or node groups (basins). Metastatic involvement can be suspected on the grounds of CT, MRI, or PET investigations in many cases. As in other sites, at least in the early stages of metastatic lymph node involvement the imaging methods have considerable limitations. Jansen et al. (2000) used the labeling methods (99mTc-nanocolloid and blue dye) in investigating 30 cases of melanomas of the head and neck region. In 27 of the 30 cases (90%) SLNs could be identified, but comparison of the radioactive and blue dye methods showed that only 53% of the sentinel nodes were labeled by both blue dye and 99mTc-nanocolloid. Tumor positivity was obtained in 8 cases, while false-negative sentinel nodes were found in 2 cases (sensitivity = 80%). The conclusion reached by the authors was that sentinel node biopsy in head and neck cancers (melanomas) is a technically demanding procedure. According to Jansen et
Fig. 1. Network of lymphatic vessels of the head and cervical region with drainage to target nodes (sentinel lymph nodes, SLNs) and from there to the important jugular junctional nodes. Overview of localization of SLNs dependent on the localization of the primary. From left to right: Primaries of
the occipital region metastasize primarily into the occipital node groups; in the temporal region localized primaries have their target nodes in the preauricular region; primaries of the medial parts of the face (nose, nasolabial region, chin) have their target nodes in the submandibular node group
1
Facial cancers
2
Naso-pharynx and oral cavity cancers Deep-lying cervical Surgeons cancers (thyroid cancer, paragangliomas, etc.) Salivary gland tumors Otologists and surgeons
3
4
Dermatologists, plastic surgeons, otologists and ophthalmologists Otologists
Cancers of the Face, Naso-pharynx and Oral Cavity and of the Salivary Glands Table 2. Patterns of nodal metastasis suggested by experience Anterior scalp for head and face
Coronal scalp ear and neck
Posterior scalp
Lower neck
Parotidean nodes neck levels I±III
Parotidean nodes neck levels I±IV
Occipital nodes levels I±V
Levels III±V
Table 3. Sensitivity at different levels using computed tomography (CT) in tongue cancer diagnosis. For difference between levels I±II (80.9%) and levels III±V (53.6%), (P = 0.012) Level I
85%
Level II
77.8%
Level III
53.6%
Level IV
66.7%
Level V
25%
al. (2000), the method can help in the decision on whether a neck dissection is necessary, but current opinion is that further improvement and experience are required before the SLN concept can be recommended for standard management, especially for malignant melanomas of the head and neck region. The basins containing the SLNs of the different segments of the skin of the head are demonstrated in Fig. 1 and described in the legend. Pathak et al. (2001) performed a head and neck melanoma investigation (169 cases) to find whether nodal metastases follow a clinically predictable pattern. The predictable pattern based on experience is summarized in Table 2. In a high rate of cases in which parotidean nodes could be involved (half of 169 cases) parotidectomies (44 therapeutic, and 63 elective) were performed. Pathohistologically positive lymph nodes were found in the clinically predicted node groups in 156 of 169 cases (92.3%). Further values obtained were: · No primary with contralateral involvement, but failure in 2.9% after therapeutic dissection · Involvement of nearest lymph node only in 68% · Involvement of a single node only in 59%.
Fig. 2. Flat ulcerated cancerous lesion, sharply delineated in the periphery
Fig. 3. Extensive ulceration of the cancer with ªmarginal wallsº in the peripheral invasive growth front
Point 2) In the oral cavity one of the main localizations of primaries is the tongue. In a large number of cases Ogura et al. (2001) evaluated CT findings related to histopathological diagnosis concerning the presence or absence of metastatic cancer involvement at levels I±IV. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of CT were evaluated for each nodal level. The sensitivity of CT is shown in Table 3. It follows that the sensitivity of CT in detecting cervical node metastases is significantly lower in levels III±V than in levels I±II. Nieuwenhuis et al. (2000) investigated a series of tongue cancers in addition to a series of other oral cavity cancers using 99mTc-labeled colloidal albumin for sentinel node (SN) detection. The most frequent SN localization was level II, and more rarely they were localized in levels I and III (Table 4).
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Chapter 23 Cancers of the Face, Nose, Pharynx, and Oral Cavity Table 4. Summary of the results of SLN investigation of tongue cancers (Nieuwenhuis et al. 2000) (Usg ultrasound-guided, FNAC fine-needle aspiration cytology) Sex
Age (years)
Localization
TN
Visible SN
Level SN
Usg-FNAC
Male
59
Tongue, right
T1N0
1
II
Negative
Male
44
Tongue, right
T1N0
1
II
Negative
Male
73
Tongue, right
T2N0
2
II
No FNAC
Male
52
Tongue, right
T2N0
2
II
Negative
Negative
I
1 ´ USgFNAC negative
Male
49
Tongue, left
T2N0
2
I, II
Negative
Negative
I, II
No USgFNACb
Male
59
Floor of Mouth, left
T2N0
2
II, III
Negative
Male
59
Tongue, right
T3N0
1
II
Negative
Negative
Male
46
Tongue, left
T2N0
1
I
Positive
Positive
SLNs
Level
Other nodes
Histopathology SLNs
Follow-up
Other nodes 1 ´ USgFNAC positivea
Negative
I
3 ´ USgFNAC negative 1 ´ USgFNAC negative
No USgFNACb
I, II
Negative
Negative
Positive
Positive
a
Within 3 months USg-FNAC revealed positive nodes, and a subsequent neck dissection was performed; the patient developed liver metastases and died within 5 months b These patients underwent transoral excision recently and follow-up US-guided FNAC has therefore not yet been performed
In Figs. 2 and 3, two examples (1, 2) of cancers of the oral cavity demonstrate the local state. SN labeling can be performed by peritumoral injection of the labeling solutions. Examples of SCC in the Oral Cavity Some of the SCC that can occur in the oral cavity are: · Ulcerated early cancerous lesion of the oral mucosa with multifocal early stromal invasion. ± Labeling of the regional SLNs by perifocal injection of labeling fluid is already practiced in specialized clinics. · SCC of the oral mucosa that is already ulcerated, located at the palate bow. ± Peritumoral, coronal injection of the labeling fluid is used, in order to reach higher accu-
racy in resection of the lymphatics and consecutive nodes. · Cancers of the oropharynx, hypopharynx and larynx. ± The frequency of these cancer types has increased in recent years, obviously mainly as the result of carcinogens in tobacco smoke. The carcinogenesis seems to be potentiated by abuse of high-percentage alcohol (cellular toxicity by acetaldehyde formation and increase of resorption of the carcinogens in tobacco smoke). ± Therefore, these cancers need special attention, especially with respect to prevention, early detection, and optimal diagnosis and treatment. In most cases the cancers have squamous cell differentiation and different degrees of malignancy (some with high proliferation activity): high mitotic rate, high S-
Cancers of the Face, Naso-pharynx and Oral Cavity and of the Salivary Glands
phase value and high rate of Ki67 (MIB1)positive nuclei. Cancer can be diagnosed by exfoliative cytology and/or histological investigation of biopsy specimens or excision of the whole lesion with controlled tumor-free margins. Orientation by Exfoliative Cytology, FNAC, or Minibiopsies in Diagnosis If SLN labeling is intended, the cancer diagnosis should be confirmed by means of the technique involving the slightest possible injury to the primary (exfoliative cytology, minibiopsy) to prevent
changes to the lymphatic drainage or propagation of cancer dissemination. Most cancers of the oropharynx, hypopharynx, or larynx (excluding rarer cancers, such as Schmincke tumor or adenocarcinoma) show various degrees of differentiation of squamous cells. Investigation of the primaries and their regional lymph node(s) obtained by elective neck dissection makes it possible to confirm the diagnosis, including the N-staging (at least in some cases) preoperatively. This strategy would make a search for SLNs unnecessary in node-positive cases. We must realize, however, that these more schematic strategies of LN clearance can leave involved LNs behind, whereas gamma probe-guided clearance seems to be much more precise. The problem
Fig. 4. Giemsa-staining: The cancer cell nuclei show severe hyperchromasia and polymorphism. Note the blue-stained, partly triangular, cytoplasm
Fig. 5. Metastasis from a squamous cell cancer (SCC). With use of antibodies directed to cytokeratins 5 and 6, the cytoplasm shows an intense positive reaction
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remains that the primary and the SLN(s) are too close together to guarantee optimal guidance in the search for SLN. On the other hand, nodes that have not been included in the elective surgical node removal can be detected. Figures 4 and 5 show the cytology of a moderately differentiated SCC.
Cancers of the oropharynx, hypopharynx and larynx affect similar basins with their metastatic spread. For cancers of the oropharynx and hypopharynx levels II and III are the sites of the main basins containing metastatic spread, but hypopharyngeal cancers also show a relatively high rate of metastasis in level IV (Fig. 6 a, b). For a sentinel node search after peritumoral labeling it is helpful to remember the basins mostly involved for each of the different cancer types mentioned above. The rates given by Mamelle (2000) in Villejuif (Department of Cervicofacial
Surgery, Gustave Roussy Institute) are based on 914 patients who underwent neck dissection. The lymph node involvement rates of the different tumor types are presented below. It is of interest that all subtypes show high rates of extracapsular (extranodal) cancer spread, with very high rates in oropharyngeal and hypopharyngeal cancers (29% according to Li et al. 1996). Therefore, the sentinel node search must also be considered with this in mind. This can be realized ± if it is possible at all ± by way of preparation in continuity. Preparation can be supported by double labeling with both 99mTc-nanocolloids and blue dye solutions. Wei et al. (2001) investigated the pattern of naso-pharyngeal cancer recurrence rates after radiotherapy and found a similar level-related distribution especially for the node groups close to the tumor, whereas the more distally located node groups were characterized by lower rates of involvement by recurrence. These results indicate clearly that primary clearance of the different lymph node basins, possibly
Fig. 6. a Comparison of the lymph node metastases rates (%) in cancers of the oropharynx, hypopharynx and larynx, based on the data presented by Mamelle (2000). b Demon-
stration of recurrences in the lymph node groups of the different levels after radiation therapy (RT) of nasopharyngeal cancers (Wei et al. 2001)
LN Metastasis: Basins Involved
Cancers of the Face, Naso-pharynx and Oral Cavity and of the Salivary Glands
supported by a SLN search, is a very urgent necessity. Rates of recurrence by therapy are indicated in Fig. 6 b. These data demonstrate very impressively that the locoregional cancer clearance obtained by means of radiation therapy is incomplete. In an earlier study by Taylor et al. (2001) in nine patients with oropharynx cancers, when 99m Tc-sulfur colloid was used for SLN labeling in T1 and T2 cases, the sentinel nodes could be localized and investigated in all nine patients. In five patients there were no positive nodes, while in the other four the sentinel nodes were the only nodes that were histopathologically positive. The authors conclude that sentinel node detection is feasible in head and neck cancers and is predictive in cervical metastasis. In addition, it follows that the number of neck dissections can be reduced. Furthermore, in our opinion it must be concluded that at least in the early stages of oropharyngeal cancers adjuvant radiation therapy can be avoided and that with the aid of the sentinel node search the cancer clearance that can be achieved is more nearly complete and the recurrence rate can be reduced. In 100 cases with T3 and T4 stages of laryngeal cancer no longer suitable for sentinel node labeling, 80% of the cases had metastases in stages N1± N2c (dos Santos et al. 2001). The frequencies with which the different levels were involved were similar to those demonstrated in the overview (Fig. 6 a) including all stages. The rates of metastases in the different levels were: level I 2%; level II 59%; level III 17%; level IV 11%. The authors emphasize that primary lymphadenectomy in level I is not necessary in elective neck dissection programs, but this region should also be carefully checked in every case (palpation, imaging systems, etc.). When the available radioimaging procedures (CT, MRI, PET, etc.) are used to localize and measure the diameters of facultatively involved lymph nodes, the clinical N-stage can be roughly estimated even preoperatively. In mucosal cancers, however, and especially in ulcerated stages, intensive inflammatory processes must always be taken into account. Therefore, in doubtful situations FNAC can be helpful to confirm metastatic involvement of nodes. When these prestaging procedures have been successfully carried out, practice of the sentinel node concept can more easily be adapted to the individual case.
Fig. 7. N-Classification of all head and neck tumors according to the system published in the German Society of Otolaryngology's Consensus Report (Bootz 2000), except for naso-pharyngeal cancers and thyroid cancers: N1 solitary metastasis, ipsilateral £ 3 cm; N2a solitary metastasis, ipsilateral > 3 cm < 6 cm; N2b multiple metastases, ipsilateral £ 6 cm; N2c bilateral or contralateral, metastasis £ 6 cm; N3 metastases > 6 cm. The consensus meeting was based on the TNM Classification (Spiessl et al. 1990/1993)
Fig. 8. N-Classification of naso-pharyngeal cancers according to the system published by the German Society of Otolaryngology's Consensus Report (Bootz 2000). N-staging of naso-pharyngeal cancers. N1 = unilateral metastasi(e)s £ 6 cm. N2 = metastasi(e)s in bilateral supraclavicular nodes. N3a = metastasi(e)s > 6 cm, superior to supraclavicular area. N3b = metastasi(e)s supraclavicular
· In cases with lymph nodes assessed as positive on FNAC the sentinel node search can be avoided or can help to answer the question of whether other basins are involved in addition. · In cases without confirmed lymphogenic metastasis the use of both 99mTc-nanocolloid and the
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blue dye method can help in the achievement of a more precise overview for surgical tumor clearance preoperatively. The different N-stages of the head and neck cancers, with exclusion of the naso-pharyngeal and thyroid cancers, are summarized in Figs. 7 and 8. Because the recurrence-rates in cases with locoregional adjuvant radiation therapy are also high, the primary locoregional surgical treatment should be as near-complete as possible.
Dependence of Adjuvant Therapy Regimens in SCCs of the Upper Aerodigestive Tract and the Face on SLN Status SCCs of the localization cited in the heading with local extension >1 cm have an increased risk for metastasis. Therefore, radiotherapists sometimes recommend locoregional radiation therapy, at least in cases with high-grade cancers. This option is also adopted in some cases without suspicious lymph nodes and in cases with investigation of the sentinel nodes that yield a negative result. In a retrospective study on a large melanoma database with > 8000 cases of malignant melanomas (American Joint Committee on Cancer), in 39 cases stage I and II melanomas analyses of the pre- or intraparotidean SLNs were carried out (Olilla et al. 1999). The patients had intraoperative lymphatic mapping to identify the SLNs in the parotid gland area. The following results were obtained (Table 5).
Cancer-infiltrated Cervical Lymph Nodes as Part of a Cancer with Unknown Primary When cancer infiltration of an enlarged cervical lymph node is confirmed by FNAC and no primary can be found in the oral cavity, the oro- or nasopharynx or the larynx, a search for other putative
primary localizations is urgently indicated (e. g. esophageal cancer, stomach cancer with Virchow gland involvement, lung cancer with supraclavicular metastases, Pancoast cancer, Schmincke cancer and thyroid gland cancer including the medullary subtype). In addition, malignant paraganglioma with local spread must be taken into account. Subtyping of the cancer infiltration of the lymph node is often helpful to detect the primary. Subtyping of the cancer tissue of the node again after additional detection of the putative primary can provide further help toward answering the question of what adjuvant therapeutic strategies are appropriate. The most important antibodies used for immunohistochemical detection of primary tumors are listed in Table 6. After localization of the primary and definition of the tumor type by histological examination there are two possibilities: · A ªwait-and-seeº approach, with metastases looked for in the local drainage fields during follow-up. · SLN detection techniques, with extirpation and histological and immunohistochemical exclusion or confirmation of metastasis in subsequent basins. The putative SLNs are often located in the proximal course of the jugular vein. The most important node, i.e., the jugular vein junctional node, must be checked very carefully. Concerning squamous cell cancers opinions differ on whether SLN detection would really be helpful in terms of cure, because efficient radiotherapy (RT) can be offered. On the other hand, high doses of RT are necessary for tumor clearance. Therefore, reliable detection of involved lymph nodes by lymphography would be helpful in an adequate surgical program and allow the avoidance of high-dose RT in more or less extended fields and early or late side effects of RT if RT were not necessary.
Table 5. Localization of the primaries (malignant melanomas) with sentinel nodes in pre- and intraparotidean localizations: detection rates and recurrences Facial melanomas with SLN near or in intraparotid gland
SLN detection rate
39
37 (94.9%)
Localization of the primaries Scalp
Auricle
Face
No. of sentinels per patient; range
19
11
9
2.3; 1±4
Recurrence rate 1/33 = 3.1%
Histology and Cytology of Benign and Malignant Tumors of the Salivary glands (Mainly of the Parotid Gland) Table 6. Marker antibodies mainly used for detection of cancers with cervical lymph node metastasis from cancers with unknown primary Differentiation of the cancer
Cancer type and localization
Antibodies used
Adenocarcinomas
Upper aerodigestive tract lung esophagus
Cytokeratins CK8, 18, 19
SCCs
Oropharynx, hypopharynx, larynx, esophagus, lung (non SCLC)
CK5, 6
Neuroendocrine cancers
Malignant paraganglioma, medullary thyroid cancer
Chromogranin A
Thyroid cancer (extrathyroidal)
Along ductus thyroglossus, upper mediastinum
Antithyroglobulin, antibodies
Lymphomas
B and T
Common leukocyte antibodies
B-cell lymphoma
4KB5, BCl2
T-cell lymphoma
CD43
Ki1 lymphoma
Ki1
Hodgkin lymphoma
Ki1
Histology and Cytology of Benign and Malignant Tumors of the Salivary Glands (Mainly of the Parotid Gland) Salivary (Parotid)-gland Tumors ± A Special Entity Regarding treatment of neoplastic lesions of the salivary glands, the main interest is focused on parotid gland cancers, which are the most frequent. a) The most important problem is complete locoregional surgical clearance of parotid gland cancers and sentinel and/or regional lymph nodes. b) A second problem, which is also important, is pre- and/or intraparotidean or retroparotidean lymph node involvement in malignant cutaneous melanomas or squamous cell cancers of the scalp, auricle, or face. 1. Benign tumors. In the group of parotid gland tumors pleomorphic adenomas (Figs. 9±12) are generally benign. However, focal secondary malignancy in these adenomas or their recurrences may occur in a low rate (4%). In such cases only, it may be valuable to reflect on the possible benefits of an SLN labeling procedure (Figs. 9±12). Another benign cancer is the adenolymphoma (Fig. 13). Two cellular components, epithelial isomorphic formations, some with a glandular pattern, and smaller nucleated typical lymphocytes, are the characteristic features of these tumorous lesions.
In all cases with secure cytological and also postoperative histological diagnosis of a benign lesion no SLN search is indicated. 2. Malignant tumors. Adenoid cystic cancers (cylindromas) (Fig. 14) are a priori malignant and show invasive growth with paralysis of the facial nerve. Most of these cancers show slow infiltrative growth along the nerve sheaths, but they seldom invade the lymphatics. Mostly lymph nodes are invaded directly by cancer formations at the growth front. Therefore, this tumor type seems not to be a valuable candidate within the SLN concept. A second important entity is the group of mucoepidermoid cancers (Fig. 15). As a rule, the epidermoid parts and the degree of malignancy of these components are the important factors in lymphatic and hematogenous spread. According to this, the mucoepidermoid cancers would be candidates for SLN labeling. A third group, the acinic cell cancers (Figs. 16, 17) develop from the regenerative potential of the acinic part of the gland. The clear cell character of this cancer is an important diagnostic feature (Fig. 16). Because, if the cancer is cytologically or histologically diagnosed primarily in material from a regional lymph node, metastasis from clear-cell renal cell cancer or a clear-cell type of thyroid cancer must be included in the differential diagnosis and excluded. Besides the well-differentiated types, other, less highly differentiated cancers can now be identified by means of immunohistochemical support with
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Chapter 23 Cancers of the Face, Nose, Pharynx, and Oral Cavity Figs. 9±13. Benign salivary gland tumors Fig. 9. Cytology of a pleomorphic adenoma of a salivary gland: Note the small isomorphic tumor cell nuclei and some spindle-shaped isomorphic nuclei
Fig. 10. Histology of a pleomorphic adenoma of salivary gland. Note the partly tubular, partly solid, layered tumor cell population with a high degree of isomorphism
Fig. 11. Cytology of pleomorphic adenoma with small isomorphic epithelial layered tumor cells, only focal, with adenoid cell aggregates
Histology and Cytology of Benign and Malignant Tumors of the Salivary glands (Mainly of the Parotid Gland)
Fig. 12. Histology of a pleomorphic adenoma with partly solid, partly glandular epithelial tumor cell pattern and loosely distributed mesenchymal cell populations. Note the high degree of isomorphism
Fig. 13. Cytology of a benign adenolymphoma of the parotid gland. Note the epithelial, partly adenoid, layering of the tumor cells and the intermingled differentiated lymphocytes. High isomorphism of the epithelial cells, no mitotic activity detectable. Conclusion: in none of the listed benign lesions is a search for SLNs indicated
Figs. 14±17. Malignant salivary gland tumors Fig. 14. Adenoid cystic cancer of the salivary gland, showing glandular pattern with secretion product in the lumina and more spindle-cell proliferation framing the gland (myoepithelial proliferation as second component). In FNAC smears of this lesion the two characteristic components of the lesion, namely the epithelial differentiated cells of the tubular or the cystic structures (CK8, 18 positive) and the myoepithelial cells (actin-positive), are highly characteristic for cytological diagnosis
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Chapter 23 Cancers of the Face, Nose, Pharynx, and Oral Cavity Fig. 15. Small segment of a low-grade mucoepidermoid cancer. In right upper part of the picture a cylindrical mucusproducing glandular structure is seen; in left lower part cellular proliferation with squamous cell character is seen
Fig. 16. Acinic cell cancer. The histological picture shows solid clear cell proliferations with mostly central localized small nearly isomorphic cancer cell nuclei. The mitotic activity is low
Fig. 17. FNAC of an acinic cell cancer. Note moderate polymorphous nuclei with multiple, partly prominent nucleoli
Special Subtypes of Ductal Salivary Gland Cancers
epithelial, mesenchymal, smooth muscle and lymphoma marker analysis in the differential diagnosis. In Figs. 14±17 some cancer subtypes are demonstrated, with immunohistochemical evaluations in some cases. In anaplastic cancers the primary diagnosis with documentation of the epithelial characters is important; the epithelial character of lesions can be confirmed by means of cytokeratin antibodies. In addition, lymphomatous lesions must be excluded by using the B- and T-cell lymphoma markers. Figures 18 and 19 show a case of anaplastic small-cell cancer.
Special Subtypes of Ductal Salivary Gland Cancers Special subtypes can develop identical histopathological pictures to those of ductal cancers of the breast: comedo-type structures, cribriform types, and papillary structures. Like ductal breast cancers, these types can also overexpress c-erb B2, and with it p185 protein. In addition to these cancer types, anaplastic, partly small-cell, cancers can occur (Figs. 18, 19). Knowledge of the aspiration cytology of benign and malignant tumors in the head and neck region is frequently helpful in making decisions on performing surgery, extending of operative procedures and operation planning, essentially also with re-
Fig. 18. Shows cytology of an anaplastic small cell salivary gland cancer; metastasis of a small cell lung cancer must be excluded. In lymph node: lymphoma must also be excluded using T- and Bcell antibodies and melanoma using S100 protein Ab and HMB45
Fig. 19. Small-cell anaplastic cancer; antibodies directed to cytokeratins 8 and 18 document anaplastic cancer with origin of adenocarcinoma
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Chapter 23 Cancers of the Face, Nose, Pharynx, and Oral Cavity
spect to SLN labeling and locoregional tumor clearance. Both cancer subtypes developed in primarily benign lesions and malignant tumors in the salivary glands metastasize predominantly by the lymphogenous route, and in later stages, in some cases also hematogenously, mostly into the lungs. This holds true for both highly differentiated and less well-differentiated salivary cancer types. Pre- or intraparotid lymph node involvement or check up of these nodes, for instance in cutaneous malignant melanomas of the face, is rare. In diagnosis of parotid gland tumors (CT, MRI, FDG-PET etc.), 99mTc-nanocolloid labeling and/or blue dye labeling could be used for SLN detection. It is astonishing that no activity has yet been encouraged in this direction: I think this is due not so much to fear of inducing the development of a salivary gland fistula as to lack of knowledge about the newly introduced SLN concept. In summary, a sentinel node concept for primary salivary gland cancers, especially for the parotid gland cancers, does not exist. Up to now, no SLN studies have been carried out and no published results are available. It might be that the imaging systems are sufficient enough to detect pre- and retroparotidean nodes. But the possibility that more precise locoregional cancer clearance can be achieved when the labeling procedures are used also cannot be excluded. Usage of the sentinel node concept in the treatment of face tumors with pre- or intraparotidean SLNs does not seem to involve any great problems (see Table 3). In comparative studies of 99mTc Re (Rhenium) and 99mTc HAS-D (human serum albumin diethylene-triamine pentaacetic acid), Sato et al. (2000) demonstrated that 99mTc-Re was superior to 99mTc HAS-D as an agent. It might be that new compounds with higher efficiency can improve the SLN detection rate and help to overcome the problems encountered when primaries and sentinel nodes are too close to each other.
No Need for Discussion of SLN-Dependent Chemotherapy Strategies The domain of adjuvant therapeutic efforts after surgery for the oropharynx cancers is in the hands of radiotherapists; most aspects of additional adjuvant RT regimens for locoregional tumor clearance are clear and there is no need for them to be discussed, with or without reference to the SLN status. Chemotherapy for cancer patients in the categories discussed depends much less on the SLN status than on the systemic disease. Therefore, for these cancers no separate specific recommendations on chemotherapy are given in Chapter 33.
References Ambrosch P, Freudenberg L, Kron M, Steiner W (1996) Selective neck dissection in the management of squamous cell carcinoma of the upper digestive tract. Eur Arch Otorhinolaryngol 253:329±335 Ambrosch P, Kron M, Fischer G, Brinck U (1995) Micrometastases in carcinoma of the upper aerodigestive tract: detection, risk of metastasizing and prognostic value of depth of invasion. Head Neck 17:473±479 Bootz F (ed) (2000) Oncology of head and neck region (German Society of Otolaryngology consensus report, by order of the Presidium). HNO 48:104 Brekel MW van den, Castelijns JA, Stel HV, Luth WJ, Valk J, Van der Waal I, Snow GB (1991) Occult metastatic neck disease: detection with US and US-guided fine-needle aspiration cytology. Radiology 180:457±461 Brekel MW van den, Castelijns JA, Stel HV, Golding RP, Meyer CJ, Snow GB (1993) Modern imaging techniques and ultrasound-guided aspiration cytology for the assessment of neck node metastases: a prospective comparative study. Eur Arch Oto-Rhino-Laryngol 250(1):11±17 Brekel MW van den, Castelijns JA, Snow GB (1994) Detection of lymph node metastases in the neck: radiologic criteria. Radiology 192(3):617-618 Brekel MW van den, Castelijns JA, Reitsma LC, Leemans CR, Waal I van der, Snow GB (1999) Outcome of observing the N0 neck using ultrasound guided cytology for follow up. Arch Otolaryngol Head Neck Surg 125:153± 156 Dos Santos CR, Goncalves Filho J, Magrin J, Johnson LF, Ferlito A, Kowalski LP (2001) Involvement of level I neck lymph nodes in advanced squamous carcinoma of the larynx. Ann Otol Rhinol Laryngol 110(10):982±984 Dunne AA, Juingclas H, Werner JA (2001) Intraoperative sentinel node biopsy in patients with squamous cell carcinomas of the head and neck-experiences using a welltype NaI detector for gamma ray spectroscopy. Otolaryngol Pol 55(2):127±134
References Hçbner KF, Thie JA, Smith GT, Chan AC, Fernandez PS, McCoy JM (2000) Clinical utility of FDG-PET in detecting head and neck tumors. A comparison of diagnostic methods and modalities. Clin Positron Imaging 3:7±16 Jansen L, Koops HS, Nieweg OE, Doting MH, Kapteijn BA, Balm AJ, Vermey A, Plukker JT, Hoefnagel CA, Piers DA, Kroon BB (2000) Sentinel node biopsy for melanoma in the head and neck region. Head Neck 22(1):27±33 Leemans CR, Tiwari R, Nauta JJ, Waal I van der, Snow GB (1994) Recurrence at the primary site in head and neck cancer and the significance of the neck lymph node metastases as a prognostic factor. Cancer 73(1):187±190 Li XM, Wei WI, Guo XF, Yuen PW, Lam LK (1996) Cervical lymph node metastatic patterns of squamous carcinomas in the upper aerodigestive tract. J Laryngol Otol 110(10):937±941 Læwe VJ, Boyd JH, Dunphy FR, Kim H, Dunleavy T, Collins BT, Martin D, Stack BC Jr, Hollenbeak C, Fletcher JW (2000) Surveillance for recurrent head and neck cancer using positron emission tomography. J Clin Oncol 18:651±658 Mamelle G (2000) Selective neck dissection and sentinel node biopsy in head and neck squamous cell carcinomas (Recent results in cancer research, vol 157). Springer, Berlin Heidelberg New York, pp 193±200 Nieuwenhuis EJC, Colnot DR, Pijpers JH, Castelijns JA, Diest PJ van, Brakenhoff RH, Snow GB, Brekel MWM van den (2000) Lymphatoscintigraphy and ultrasoundguided fine needle aspiration cytology of sentinel lymph nodes in head and neck cancer patients. In: Schlag PM, Veronesi U (eds) Lymphatic metastasis and sentinel lymphonodectomy (Recent results in cancer research, vol 157). Springer, Berlin Heidelberg New York, pp 206±217 Nowak B, Di Martino E, Jånicke S, Cremerius U, Adam G, Zinny M, Reinartz P, Bull U (1999) Diagnostic evaluation of malignant head and neck cancer by F-18-FDG PET compared to CT/MRI. Nuklearmedizin 38:312±318 Ogura I, Kurabayashi T, Amagasa T, Sassaki T (2001) Diagnostic accuracy of computed tomography for cervical metastases at different anatomical levels in carcinoma of the tongue. Dentomaxillofac Radiol 30(5):246±248 Ollila DW, Foshag LJ, Essner R, Stern SL, Morto DL (1999) Parotid region lymphatic mapping and sentinel lymphadenectomy for cutaneous melanoma. Ann Surg Oncol 6(2):150±154 Pantel K, Braun S, Passlik B, Schlimo KG (1996) Minimal residual epithelial cancer: diagnostic approaches and prognostic relevance. Prog Histochem Cytochem 30(3):1±60
Pathak I, O'Brien CJ, Petersen-Schaeffer K, McNeil EB, McMahon J, Quinn MJ, Thompson JF, McCarthy WH (2001) Do nodal metastases from cutaneous melanoma of the head and neck follow a clinically predictable pattern? Head Neck 23(9):785±790 Pitman KT, Johnson JT, Edington H, Barnes EL, Day R, Wagner RL, Myers EN (1998) Lymphatic mapping with isosulfan blue dye in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 124:70±73 Rahn AN, Baum RP, Adamietz IA, Adams S, Sengupta S, Mose S, Bormeth SB, Hor G, Botcher HD (1998) Value of 18 F fluorodeoxyglucose positron emission tomography in radiotherapy planning of head-neck tumors. Strahlenther Onkol 174:358±364 Robbins KT, Medina JE, Wolfte GT, Levine PA, Sessions RB, Pruet CW (1991) Standardizing neck dissection terminology official report of the Academy's Committee for Head and Neck Surgery and Oncology. Arch Otolaryngol Head Neck Surg 117:601±605 Sato T, Yamaguchi K, Morita Y, Noikura T, Sugihara K, Matsune S (2000) Lymphatoscintigraphy for interpretation of changes of cervical lymph node function in patients with oral malignant tumors: comparison of Tc-99m-Re and Tc-99m-HSA-D. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90(4):525±537 Spiessl B, Beahrs OH, Hermanek P, Hçtter RVP, Scheibe O, Sobin LH, Wagner G (1990/1993) TNM classification. Springer, Berlin Heidelberg New York Stuckensen T, Kovacs AF, Adams S, Baum RP (2000) Staging of the neck in patients with oral cavity squamous cell carcinomas: a prospective comparison of PET, ultrasound, CT and MRI. J Maxillofac Surg 28:319±324 Taylor RJ, Wahl RL, Sharma PK, Bradford CR, Terrell JE, Teknos TN, Heard EM, Wolft GT, Chepeha DB (2001) Sentinel node localization in oral cavity and oropharynx squamous cell cancer. Arch Otolaryngol Head Neck Surg 127(8):970±974 Wei WI, Ho WK, Cheng AC, Wu X, Li GK, Nicholls J, Yuen PW, Sham JS (2001) Management of extensive cervical nodal metastasis in nasopharyngeal carcinoma after radiotherapy: a clinicopathological study. Arch Otolaryngol Head Neck Surg 127(12):1457±1462 Werner JA, Dunne AA, Brandt D, Ramaswamy A, Kçlkens C, Lippert BM, Folz BJ, Joseph K, Moll R (1999) Studies on significance of sentinel lymphadenectomy in pharyngeal and laryngeal carcinoma. Laryngorhinootologie 78(12):663±670
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Chapter 24
Lung Cancer
Introduction In recent decades, lung cancer has been divided into two main groups: small-cell lung cancers (SCLC) and non-small-cell cancers (NSCLC). The second group is made up of squamous-, adeno-, and large-cell and giant-cell cancers. This simple scheme is based on the fact that in the past small-cell cancers were regarded primarily as systemic diseases and therefore largely excluded from surgical treatment. In contrast, non-small-cell cancers, at least in their early stages, were regarded as potentially operable. However, the exact N-status can only be documented by pre-, intra- or postoperative histological examination of the locoregional lymph nodes (N1±3). This principle has so far been accepted as essential to postoperative supportive radiotherapy of the locoregional fields and adjuvant chemotherapeutic regimens. However, the therapeutic regimens yield only limited success. Therefore, improvement of therapeutic modalities for both locoregional and distant metastases will not be possible until we also have more accurate preoperative staging methods. Preoperative mediastinoscopy has been shown to have only limited success in lymph node staging (Drings 1998). Therefore, more effective radiological or scintigraphic methods would also be very valuable for surgical planning. Recently, discussion about how to improve surgical treatment in general, and surgical treatment for the early stages of small-cell (oat-cell) cancers in particular, has arisen and intensified throughout the world. In this context, it is clear that a new concept of diagnosis and therapy also needs new synergistic approaches to locoregional lymph node staging.
24
However, before we analyze the methods and possibilities of N-staging, especially with a view to sentinel lymph node (SLN) detection, the principles of detection and localization of lung primaries should be discussed.
Initial Laboratory Investigations other than Radiodiagnosis and Histo-/Cytological Analysis to Assure Diagnosis and Subtype of Lung Cancer Besides biopsy and cytopathological investigations there are some clinical and serological (paraneoplastic) signs that can point us in the right direction in the search for lung cancer. In addition to the question of operability and sentinel node detection, these findings can also be helpful in the differential diagnosis between small-cell cancer, which is mostly not operable, and non-small-cell cancer, which can be more closely evaluated from the aspect of operability. These clinical signs are summarized in Table 1.
Useful Serological Parameters in Confirmation of SCLC In the attempt to achieve an initial separation between small-cell types (oat-cell, or round-cell subtype) of lung cancer for systemic therapeutic treatment, a serological analysis of neural cell adhesion molecule (NCAM) and neuron-specific enolase (NSE) values can be helpful to confirm small-cell anaplastic cancers or at least to detect this type as a component of the neoplastic lesion. The values obtained in the investigation of 221 cases are listed in Table 2.
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Chapter 24 Lung Cancer Table 1. Clinical signs characteristic for different subtypes of lung cancer Subtype of lung cancer
Signs/clinical diagnosis
Hormone activity/ symptoms
Syndrome
Ectopically produced hormone activity and symptoms
Hyperparathyroidism
Parathormone (hypercalcemia)
Squamous cell cancer
Cushing syndrome
ACTH or ACTHlike substance
Small-cell cancer
Hypertension, hypoglycemia, hypokalemia Inappropriate antidiuretic hormone production (SIADH)
Blood sodium low
Clinical diagnosis
Symptoms
Peripheral neuropathy
Weakness of distal extremities
All subtypes, quite common in small cell cancer-cases
Myopathy
Muscular weakness in proximal extremities
All subtypes, quite common in small cell cancer-cases
Small cell cancer
Is N0-status Predictable in Cases with Normal CEA Values and a Tumor Shadow Disappearance Rate of 0.8 or More? Takamochi et al. (2001) investigated 269 cases of pulmonary adenocarcinoma. They found that normal serum CEA values and tumor shadow disappearance rate (TDR) of 0.8 or more on CT investigation were accompanied by a zero N-stage. The authors reviewed contrast-enhanced CT scans and recorded the maximum dimension of each tumor both on pulmonary (pDmax) and on mediastinal (mDmax) window setting images, the largest dimension perpendicular to the maximum axis on both pulmonary (pDperp) and mediastinal (mDperp) window setting images, and the sizes of all detectable hilar mediastinal lymph nodes. The definition of a new radiological parameter, tumor shadow disappearance rate (TDR), is calculated from the following formula: TDR 1
mDmax mDperp=
pDmax pDperp :
Table 2. Neural cell adhesion molecule (NCAM) and neuronspecific enolase (NSE), tumor markers of small cell anaplastic bronchial cancer. Values increase with extension of disease Marker
No. of positive cases
%
Value of measure
NCAM
113/221
51
> 20 ll
NSE
75/221
34
> 25 ll
The conclusion reached by the authors might be helpful in decision making when patients undergo lymph node staging.
Elimination of Peripheral Noncancerous Lesions and Confirmation of Peripheral (Scar) Cancers Primarily unclear results on clinical examination and on imaging investigations sometimes influence the decision on whether a sentinel node search will later be necessary for N-staging. Such lesions are: · The unclear ªperipheral round focus,º which makes extirpation and intraoperative histopathological diagnosis necessary (Fig. 1). Before any cancer treatment the round, mostly infraclavicular, focus must be evaluated: ± Round foci of tuberculosis (formerly known as ªAssmann fociº with dust-like calcifications) must be ruled out (sputum, tuberculin test, search for Simon apical foci, etc.) ± Hamartomas often have a chondroma-like structure with associated glandular bronchogenic structures on X-ray pictures; the chon-
Elimination of Peripheral Noncancerous Lesions and Confirmation of Peripheral (Scar) Cancers
Fig. 1. Peripheral lung cancer, often observed as round focus. NB: A clear cancer diagnosis must be made as early as possible. Approximately 20±30% of lung cancers have more or less peripheral localizations. Labeling of SLN by endoscopic or peritumoral injection of marker solution is possible. Radiological examination reveals a so-called peripheral round focus. Differential diagnosis must include, in particular: (a) cancer, (b) tuberculosis, (c) hamartoma. Diagnosis can be made by endobronchial biopsy or, if this is not possible, by transthoracic aspiration cytology. When (b) or (c) is suspected, excision should be performed via thoracotomy, followed by (b) tuberculostatic therapy or (c) no further treatment. In cancer cases a search for the sentinel lymph node (SLN) should be carried out, as should N-staging
droma-like proliferations often show minimal dust-like calcifications similar to tubercular foci. Intraoperatively these lesions can be identified in frozen sections, and cancer can be ruled out or confirmed. The group of peripheral lung cancers, some decades ago often confused with residual tuberculosis (ªperipheral scar cancerº) and more frequent at that time than scarring is now, is of special interest: ± Because ± as already mentioned ± not all pulmonary foci of this special category are primary lung cancers. ± Because this category can be analyzed and the diagnosis can be made with the aid of video-assisted thoracoscopic lung biopsy. ± The search for sentinel lymph node(s) (SLN) can easily be carried out intraoperatively, for instance by peritumoral blue dye injection.
Fig. 2. Peripheral lung cancer breaking out into the regional soft tissue parts and facultative cancer infiltration of stellate ganglion; cervical lymph nodes may be already involved. Therefore, a SLN search by radioimaging is of no value; in addition, even special labeling of SLNs has no value. Breakout type ? Pancoast tumor with Horner symptom complex in later stages, when stellate ganglion has already been infiltrated by cancer. N- and M-staging should be performed, but no isolated SLN search
However, the real problem is that not all typically located nodules are primary cancerous lesions. In a series investigated by Murasugi et al. (2001), of 81 patients only 44 (55%) had malignancies, which were primary cancers in 28 cases and metastatic lesions in 16. This splitting into primaries and metastatic cancers demonstrates that the sentinel node concept cannot be applied until after the diagnosis has been confirmed by histopathological and, in some cases, additional immunohistochemical evaluations. · Early outbreak of a peripheral cancer into the regional soft tissue (e.g., ªPancoast tumorº) (Fig. 2) ± In most cases, this tumor type is highly aggressive. It is characterized by fast progres-
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Chapter 24 Lung Cancer Fig. 3. Bronchioloalveolar cancer subtype. Because of possible multifocality exact preliminary diagnosis must be made before the SLN search. In bronchioloalveolar cancer there are disseminated cancer foci; this condition is referred to as ªholoblastosisº in older publications and is bilateral in 5±10% of cases. Left: nodal type; right: pneumonia-like tumor growth pattern. Caveat: without due care acute asphyxia can arise during endoscopy in the case of the mucinous subtype, as a result of mucus aspiration
sion and, in most cases, high proliferation activity (high S-phase values, high MiB I values, and high rate of mitoses). · Multifocal peripheral bronchioloalveolar cancers, partly with massive mucus formation (Fig. 3).
Primary Multicentricity of Lung Cancer: Compatibility with the SLN Concept? In lung cancer treatment, in the clinical and radiodiagnostic investigations synchronous multicentricity and back-metastasis to the lungs must be distinguished. It is essential that this is done before mediastinoscopy and/or SLN labeling is started. In this context it must also be emphasized that primary multicentricity does not contraindi-
cate surgical treatment, which can sometimes be curative. With regard to this point, it must be emphasized that, at least in cases with ipsilateral multicentricity, the surgical treatment is basically not different from lobectomy or pneumectomy procedures in cases with unifocal lung cancers. In cases with bilateral cancer foci, in addition to lobectomy or pneumectomy on the side with more intensive cancer involvement, laser and irradiation therapy of smaller foci on the contralateral side are considered and performed, as well as lymphadenectomy. Because some of these multifocal cancer types have low degrees of malignancy, the 78.3% 5-year survival rate published by Kawashima (2002) is not too astonishing. Kawashima et al. collected 33 cases of multicentric carcinomas. The results are listed briefly in Table 3.
Table 3. Data recorded in 33 cases with synchronous multicentricity treated by Kawashima et al. (2002) No. of patients
Male
Female
Mean age/ range
Ipsilateral
Bilateral involvement
Adeno-Ca
Adenoand other types
Overall 5 year survival
33
20
13
67; 51±79
27
6
12 (36%)
6 (18.2%)
78.3%
Significance of PET in Staging Lung Cancer
Stage-adapted Diagnostic Strategies Related to the SLN Concept With regard to the SLN concept and procedures along it, it must be pointed out that · All noninvasive diagnostic procedures can be helpful before the sentinel node search is started. · All invasive surgical procedures serving the staging can locally change the lymphatic flow and make the SLN search impossible. Therefore, we need a very clear-cut diagnostic and staging concept which does not interrupt the normal lymphatic flow and thereby make the SLN search impossible. The following sequence of evaluations seems to be possible: · A first step should be evaluation by radioimaging (PET, PET plus CT or MRI) plus serological investigations (NCAM, NSE, etc.) in order to rule out inoperable cases. · A second step in cases that are not advanced is histo- and/or cytopathological confirmation of cancer in biopsy and/or smear material following endobronchial sampling or transthoracic puncture, etc. · A last step before operation is mediastinoscopy, the aim being:
± Confirmation of the diagnosis: in this case the sentinel node concept (intraoperative peritumoral blue dye injection) can still be applied, or ± Decision between mediastinal lymph node dissection (MLND) versus systematic node dissection (SS), which influences the lymphatic drainage. In such cases application of the SLN concept can lead to inadequate results. The different points are analyzed, explained, and discussed in more detail below.
Significance of PET in Staging Lung Cancer Introductory Remarks There is as yet no uniform system for detecting tumor-free or tumor-infiltrated SLNs in lung cancer with high levels of sensitivity and specificity. It will be easily understood that the development of a plausible and rational basic concept for this tumor type is extremely difficult. With all this in mind, it is clear that any methods that make it possible to detect cancer-infiltrated lymph nodes already in the presurgical stage would be highly valuable with a view to treatment strategies. In addition, it must be said that preoperative N-staging is performed almost exclusively in NSCLC cases and only rarely in cases of SCLC (Fig. 4). Fig. 4. Lung cancer with hilar and mediastinal lymph node metastases. The coronal PET image shows an area of focally increased metabolic activity in the upper lobe of the right lung (P). In addition, there are positive lymph nodes in the right hilar region and in the mediastinum (LN)
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Chapter 24 Lung Cancer
T-staging Supported by FDG-PET FDG-PET is particularly accurate in detecting malignant pulmonary lesions. Lung cancer shows a high uptake of FDG, whereas background activity in the normal lung and mediastinum is generally low. Numerous studies have demonstrated that FDG-PET is the most accurate noninvasive method of detecting and staging lung cancer. The evaluation of solitary pulmonary nodules was one of the earliest applications of FDG-PET for extracranial tumors. Prospective studies have shown that FDGPET has both sensitivity and specificity of approximately 90% in the evaluation of solitary pulmonary nodules (Coleman 1999; Marom et al. 2000). False-positive findings are caused by inflammatory processes, such as tuberculomas, aspergillosis, and coccidioidomycosis. Accordingly, the specificity of FDG-PET tends to be lower in countries where these diseases are endemic. False-negative findings can be due to several factors: for example the sensitivity of current PET scanners for lesions with a diameter of less than 1 cm is lower than for larger lesions owing to partial volume effects. More importantly, some subtypes of malignant tumors, e.g. carcinoids and bronchioloalveolar carcinomas, show only a small amount of FDG accumulation and may give falsenegative results despite being greater than 1 cm in diameter (Erasmus et al. 1998; Higashi et al. 1998). Kalff et al. prospectively studied the impact of FDG-PET on the clinical management of 105 patients with NSCLC (Kalff et al. 2001). Indications for PET were primary staging (n = 59), restaging (n = 34), and suspected malignancy, subsequently confirmed as NSCLC (n = 12). In 27 (26%) of the 105 cases, PET results led to a change from curative to palliative therapy after up-staging of disease extent. PET appropriately down-staged 10 of 16 patients initially scheduled for palliative therapy, allowing potentially curative treatment in 4 patients and no treatment in 6 patients. PET influenced the radiation delivered in 22 (65%) of 34 patients who subsequently received radical radiotherapy. Twelve patients considered ªprobably inoperableº on conventional imaging studies were down-staged by PET and underwent potentially curative surgery. PET missed only 1 primary tumor, which was a 5mm scar carcinoma. CT and PET understaged 3 of 20 surgical patients, 2 with N1 lesions (< 5 mm) and 1 with un-
recognized atrial involvement, and PET failed to detect 1 small intrapulmonary metastasis that was apparent on CT. No pathological N2 disease was missed by PET. FDG-PET changed or influenced management decisions in 70 patients (67%) with NSCLC: patients were frequently spared unnecessary treatment, and management was more appropriately targeted. However, FDG-PET cannot be seen as a replacement for invasive diagnostic procedures.
N-staging [Search for Cancer-infiltrated SLN(s)] by FDG-PET Comparisons with Results of CT Several studies have evaluated the application of FDG-PET for mediastinal staging of lung cancer. The criteria for the analysis of mediastinal lymph node involvement varied between studies. Some investigators reported sensitivity and specificity on a patient basis, while others determined the number of mediastinal sites involved, and still others analyzed the number of lymph node regions involved. Nevertheless, in all studies reported so far, FDG-PET was found to be significantly more accurate than CT for mediastinal staging of lung cancer. Vansteenkiste et al. performed a prospective study of 690 lymph node stations from 68 patients with potentially operable NSCLC (Vansteenkiste et al. 1998). CT correctly identified the nodal stage in 40 patients (59%), with understaging in 12 patients and overstaging in 16 patients. PET combined with CT was accurate in 59 patients (87%), with understaging in 5 patients and overstaging in 4 patients. For detecting locally advanced disease (N2/N3), the sensitivity, specificity, and accuracy for PET combined with CT were 93%, 95%, and 94% respectively, compared with 75%, 63%, and 68% for CT alone. Pieterman et al. prospectively compared the ability of a standard approach including CT, ultrasonography, bone scanning, and, when indicated, needle biopsies with FDG-PET to detect metastases in mediastinal lymph nodes and at distant sites in 102 patients with resectable NSCLC (Pieterman et al. 2000). The sensitivity and specificity of PET for the detection of mediastinal metastases were 91% and 86%, respectively; the corresponding values for CT were 75% and 66%. When the results of PET and CT were adjusted for each other,
Stage Values of PET-CT-MRI Pre-evaluation, Mediastinoscopy and SLN Search in N-staging of NSCLC
only PET results were positively correlated with the histopathological findings in mediastinal lymph nodes. PET identified distant metastases that had not been found by conventional imaging modalities in 11 of 102 patients. The sensitivity and specificity of PET for the detection of both mediastinal and distant metastatic disease were 95% and 83%, respectively. An important finding in this study was that when FDG-PET was used to identify the stage of disease a different stage was found from that determined by standard methods in 62 patients: a lower stage in 20 and a more advanced stage in 42. Gupta et al. assessed the comparative efficacy of FDG-PET in the evaluation of small (< 1 cm), intermediate (1±3 cm), and large (> 3 cm) lymph node lesions in 54 patients (Gupta et al. 2000). PET was accurate in 94% of patients in lymph node staging, as opposed to 61% with CT. Overall, the sensitivity, specificity, and accuracy of PET for staging mediastinal lymph nodes (N = 168) was 96%, 93%, and 94%, as against 68%, 65%, and 66% with CT. The positive and negative predictive values of PET in detecting mediastinal adenopathy were 86% and 98%, as opposed to 47% and 82%, respectively, with CT. PET was also very reliable and had superior accuracy (95%) in detecting lymph nodes smaller than 1 cm in size. Farrell et al. used FDG-PET for nodal staging in 84 patients with stage I NSCLC (Farrell et al. 2000). On comparison of stages determined by PET and by histopathological investigation, the disease was found to have been accurately determined by PET in 72 (86%) patients, understaged in 2 (2%), and overstaged in 10 patients (12%). The overall sensitivity and specificity of PET were 82% and 86%, respectively. For a meta-analysis of FDG-PET and CT for detecting mediastinal nodal metastases in patients with NSCLC, 14 studies involving 514 patients assessed by FDG-PET and 29 studies involving 2226 patients studied with CT were selected. PET was significantly more accurate than CT in the demonstration of nodal metastases. The mean sensitivity and specificity were 79% and 91%, respectively, for PET and 60% and 77%, respectively, for CT.
Conclusions Generally, false-positive PET results occur because of inflammatory reactions in lymph nodes (e.g., sarcoidosis). Therefore, it is mandatory that mediastinoscopy is performed for histological confirmation of positive PET results. However, owing to its high sensitivity for mediastinal lymph node involvement, FDG-PET may assist in the selection of surgically curable candidates. Thus, patients with negative PET scans may proceed to surgery without further invasive diagnostic procedures. In addition, whole-body PET studies detect metastatic disease that is not found by conventional imaging modalities and demonstrate that some of the anatomical abnormalities shown on CT are benign. Management has been reported to be changed in up to 41% of patients on the basis of the results of whole-body studies.
Stage Values of PET-CT-MRI Pre-evaluation, Mediastinoscopy and SLN Search in N-staging of NSCLC Limited Value of Regional Surgical Cancer Clearance Lloyd and Silvestry (2001) have appealed more than once for every effort to be made to carry out accurate investigation of the mediastinal nodes in cases of NSCLC, specifying that CT should be supplemented by PET and endoscopic ultrasound sonography. In addition, for histo- and cytopathological confirmation of the cancer diagnosis transbronchial and/or transcarinal punctures should be carried out. With further research using the new improved techniques: CT, PET, endoscopic ultrasound sonography, and transbronchial biopsy or fine-needle aspiration cytology (FNAC), widespread improvement in the accuracy of pretreatment staging of NSCLC will be possible. Quite lately, McManus et al. (2001) published an overview of the pattern- and organ-related frequencies of distant metastases from NSCLC evaluated by prestaging PET investigations in the different stages. The results are shown in Table 4.
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308
Chapter 24 Lung Cancer Table 4. Rates of distant metastases from non-small-cell lung cancers (NSCLC) obtained by pre-PET stage No. of cases with NSCLC
Stage I
Stage II
Stage III
PET detected distant metastasis/es
Abdominal
Adrenals
Liver
Other
Lung
Bone
167
39
28
100
24 (19%)
17
7
4
6
10
6
PrePET stage
7.5%
18%
24%
Pattern of Distant (Hematogenous) Metastases from Lung Cancer The pattern summarized for distant metastasis is highly characteristic for lung cancer, and especially for the small-cell (anaplastic, ªoat-cellº) type; but high-grade adenocarcinomas and anaplastic squamous cell cancers also develop metastases in the organs listed (see Fig. 5). After confirmation of the diagnosis of lung cancer by biopsy or cytology and before local SLN labeling, N-staging, and surgical treatment (lobectomy, pneumectomy) the organs listed and the skeleton must be carefully checked by radiodiagnostic imaging to exclude the presence at least of any currently detectable distant metastasis. Besides the well-known possibility of metastatic involvement of brain, liver, kidney, and skeleton, the possibility of so-called endocrine metastasis into the thyroid gland, the adrenals, and the pancreas must also be considered and should be carefully checked for by means of the radiodiagnostic imaging techniques (Fig. 5).
Confirmation of the Lung Cancer Diagnosis Using Histo- and Cytopathological Principles J Routine Methods Bronchoscopy, in which minibiopsy specimens are taken from suspicious areas and which can reach bronchi of the fourth, or sometimes even the fifth order of ramification, and endobronchial cytology (smears) are the main sources of material for confirmation of the diagnosis of lung cancer. As a rule, this diagnostic principle can also make it possible to discriminate between small-cell and non-small-cell cancer.
If the diagnosis cannot be made by these techniques, there are still further methods that can make it possible: transcarinal lymph node puncture (especially for cancers of the lower lobes) (Fig. 6) and transthoracic FNAC for peripheral lung cancers. J More Aggressive Diagnostic Principles In most lung cancer clinics mediastinoscopy is one of the methods routinely used in diagnosis. This method is used to confirm a diagnosis of lung cancer on the one hand, and to exclude other malignant diseases, such as lymphomas, thymomas and Hodgkin's disease, on the other. In addition, mediastinoscopy is helpful in lung cancer staging. Whereas in bilateral lung cancers N1 sites can seldom be reached for biopsy, biopsies of more centrally localized N2 positions can regularly be taken for diagnostic purposes. Contralateral sites (N3) can also be monitored. The histopathological results allow further conclusions on operability and whether a pre- or intraoperative search for sentinel lymph nodes should be made. After using computer-supported tomography (CT) in a study, Ota et al. (2001) published data on the frequencies with which lung cancers in different localizations (upper lobes, right-sided middle lobe and lower lobes) involve the highest risks for the development of metastases. But with regard to the sensitivities of radioimaging techniques, at least some of the sites thought on clinical examination and CT to be cN1 sites are in reality already N2 sites. Whether or not a case of lung cancer is operable depends on the localization of the nodes involved and needs to be assessed individually in each case. The data on lymphatic spread to the different basins are summarized in Fig. 5.
Stage Values of PET-CT-MRI Pre-evaluation, Mediastinoscopy and SLN Search in N-staging of NSCLC
Fig. 5. Overview of the pattern of metastasis characteristic for lung cancers. Distant metastasis: skin (M1) = stage IV.
The patients should be checked for operability; approximately 40% of all cases are operable
If peripheral lung cancer is suspected but the primary diagnosis cannot be made from a transthoracic FNAC, a minithoracotomy near to the putative cancerous region is the last chance of confirming the diagnosis without performing thoracotomy when a reliable histo- or cytopathological diagnosis has not been achieved preoperatively. As already mentioned, in every case the first diagnostic effort must include subtyping and tumor grading in addition to confirmation of the cancer diagnosis. This is easy to understand, because in small-cell cancers the search for SLNs is only of importance in a very early stage, whereas in nonsmall-cell cancers reflections on curative treatment, including locoregional cancer clearance, are important in a higher proportion of cases. Our own experience is based on the diagnosis of more than 15 000 cases, if clinically necessary also ruling out non-lung cancers (e.g. thymoma, lymphoma, Hodgkin's disease, etc.) by means of immunohistochemical markers. We obtained most
of the biopsies or cytological smears from the same large center. Our experience underlines the necessity for experienced pathologists and lung clinics to work together to obtain reliable diagnoses. The results obtained during a very long period of cooperation clearly demonstrated that histologically, and in some cases also cytologically confirmed diagnoses of lung cancer, including qualified subtyping, was absolutely secure, with no misinterpretations. It must be borne in mind that this standard was only made possible by constant diagnostic work by the same specialists (pulmonologists, to obtain suitable material for use in diagnosis, and one pathologist who was highly experienced in lung tumor pathology and immunohistochemistry). It is very helpful to have a histo-/cytopathologically based diagnosis available preoperatively. This makes therapy planning and communication with the patients much easier.
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ma markers (limited only when the biopsies are too small), diagnosis by cytopathology is more limited, because the significant material needed for diagnosis is often scarce, often with only a few smears of different quality available. This means that the possibility of extending the spectrum of immunohistochemical evaluations is limited in many cases. Figures 8±10 show a series of cytology smears demonstrating the different diagnoses. The next series (Figs. 11±14) shows cytopathological pictures of FNAC smears of small-cell lung cancer (Giemsa and immunohistochemical staining for cytokeratins 8, 18, 19). This nonaggressive (noninvasive) method in connection with other clinical results (imaging investigations) helps to define whether the search for SLNs is indicated and whether the cancer is operable. Figures 15±17 demonstrate carcinoids with different degrees of differentiation and malignancy as seen on histological investigation (Figs. 15±17).
Exclusion of Primary Mediastinal Neoplastic Lesions in Differential Diagnosis Against Mediastinal Metastases of Primary Lung Cancers
Fig. 6. Frequencies of cN1 positions of lymph node metastases depending on lobe-related localization of the primary lung cancer
Figure 7 demonstrates the ways available for obtaining specimens (biopsies) or cytological material from lesions in central, intermediary and peripheral locations.
Demonstration of Lung Cancer Diagnosis in Scarce Tissue by FNAC Whereas in diagnostic efforts a histopathological diagnosis can generally be made easily by using HE, cytokeratin staining, carcinoid markers (chromogranin A), and immunohistochemical lympho-
Primary lung cancers can be very small and are primarily not detected by the diagnostic methods described. The primaries can be masked when cancer-related bronchial stenosis has resulted in retention pneumonia. In such cases, often with small primaries, large mediastinal lymph node metastases may have developed. These can mimic primary mediastinal neoplasms. Therefore, in biopsy specimens obtained by mediastinoscopy, primary mediastinal cancers must be ruled out or definitely confirmed by histopathological investigations. The most important primary mediastinal cancers are: 1) Hodgkin's disease 2) Lymphomas 3) Thymomas These are illustrated in Figs. 18 and 19.
Exclusion of Primary Mediastinal Neoplastic Lesions in Differential Diagnosis Against Mediastinal Metastases Fig. 7. Combined histo- and cytopathological techniques applied to ensure lung cancer diagnosis. a Endoscopic biopsy techniques plus exfoliative cytology. b Transthoracic aspiration cytology (FNAC). c Transcarinal puncture of bifurcation lymph node(s) in advanced cases. Diagnoses made by investigations including typing by histopathology only in biopsies were secure in 84% of cases, whereas when all histo- and cytopathological techniques are used the diagnoses are secure in 96%
Figs. 8±10. Diagnosis of small cell lung cancers (SCLCs) in primaries and lymph node metastasis Fig. 8. SCLC: small cancer cell cluster with spindle-shaped nuclei and sparse cytoplasm. In MiB I reaction, in most cases 70±80% of the nuclei are stained, but mitoses hardly detectable
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Chapter 24 Lung Cancer Fig. 9. SCLC: strongly positive cytoplasmic reaction with antibodies directed to cytokeratins
Fig. 10. SCLC: FNAC of a suspect lymph node. The very small cancer cell clusters with partly spindle-shaped and partly round nuclei together with cytokeratin positivity allow the diagnosis of SCLC. Ultrarapid immunohistochemical reaction can be performed intraoperatively for an immediate decision on operability
Figs. 11±14. Diagnosis of adenocarcinomas with exclusion of carcinoids in FNAC smears Fig. 11. Adenocarcinomas of the lung (non-small-cell lung cancer; NSCLC): highly differentiated adenocarcinoma with moderately polymorphous nuclei located eccentrically in the cytoplasm. A carcinoid character of the lesion must be ruled out using antibodies directed to chromogranin, synaptophysin, etc. The antibody MiB I should be used for determination of proliferative activity. SLN search can give a reliable indication of whether or not lesion is operable
Exclusion of Primary Mediastinal Neoplastic Lesions in Differential Diagnosis Against Mediastinal Metastases Fig. 12. Cytology of moderately differentiated adenocarcinoma (NSCLC). SLN search and intraoperative staging help to clear the question of operability
Fig. 13. Polymorphous cellular lung cancer, with giant cell formation in parts. It is important to exclude metastasis from a polymorphous cellular thyroid cancer or e.g. polymorphous nuclear cancers from other sites (ovary, endometrium: type II etc.)
Fig. 14. Differentiated carcinoid of the bronchus. Staining with antibodies directed to chromogranin A. SLN search is very valuable as surgery can then be adapted for stage
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Chapter 24 Lung Cancer Figs. 15±18. Bronchial carcinoid Fig. 15. Differentiated bronchial carcinoid with isomorphic tumor cell nuclei, low rate of mitosis and a tubulo-alveolar growth pattern
Fig. 16. Bronchial carcinoid: positive immunohistochemical reaction with antibodies directed to chromogranin A
Fig. 17. Bronchial carcinoid: silver staining according to Grimelius. Note: Bronchial carcinoids must be identified at the earliest possible time point by additional special diagnostic methods (immunohistochemical procedures in biopsy and cytopathological material and clinical examinations (5-hydroxyacetic acid excretion with urine, etc.), because precise diagnosis can influence the radiological imaging (somatostatin receptor imaging for general and N-staging) and operative principles (see also Chapter 27: neuroendocrine tumors)
Exclusion of Primary Mediastinal Neoplastic Lesions in Differential Diagnosis Against Mediastinal Metastases Fig. 18. Biopsy taken from a patient with Hodgkin's disease, showing typical Sternberg-Reed cells stained with the Ki1 antibody
Fig. 19. This smear shows loosely layered cell populations, some with epithelial character and some with typical lymphocytic features. Further immunohistochemical reaction must be performed to confirm the diagnosis of thymoma
Differential Diagnosis of Anaplastic Lung Cancers J How to distinguish the Small-cell Type of Lung Cancer In biopsy specimens taken endoscopically from the primaries and in cytological smears of these, in the case of cancers with a low grade of differentiation it is sometimes difficult to discriminate between small-cell lung cancers and low-differentiation adenocarcinomas and squamous cell cancers. As frequently demonstrated by pathologists, mixed-type cancers with small-cell and squamouscell differentiation in the same microscopic field can be observed. These difficulties are documented in Fig. 20.
This difficulty in histological and cytological subtyping can be at least one of the important factors in deciding whether a lesion is operable, because the small-cell type has the highest tendency to hematogenous metastatic spread. As Tables 5 and 6 show, immunohistochemical investigations of different markers help to differentiate clearly between different round-cell neoplastic lesions of the lung and to exclude metastatic processes of an anaplastic cancer. In our experience anaplastic (low-differentiation) squamous-cell cancer, low-differentiation adenocarcinoma and small-cell anaplastic lung cancer look quite similar and are sometimes difficult to differentiate (see Fig. 20).
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Significance of Immunohistochemical Lymph Node Analysis for Up-staging and Prognosis As in the case of other tumor entities (e.g., breast cancer), the question arises of whether immunohistochemical lymph node evaluations contribute to more exact lymph node staging (up-staging) and more adequate application of surgical and adjuvant therapy regimens. This question is of vital interest, especially when preoperative N-staging by mediastinoscopy is carried out. Recently Gu et al. (2002) analyzed this problem to obtain a more significant overview of the individual state of lymphatic spread. Their results are briefly summarized in Table 7. Fig. 20. Reflection on differential typing of low-differentiation lung cancer subtypes Table 5. Differential diagnosis of SCLC against other anaplastic cancers or round cell proliferations Diagnosis
Immunohistochemical investigations to check the diagnosis
Small cell anaplastic bronchial cancer
Cytokeratins 8, 18, 19 Pancytokeratin
Small cell cancer intermediary type versus bronchus carcinoid
Pancytokeratin only ? small cell cancer Chromogranin A NSE, S100 Protein 5-Hydroxytryptamine ? bronchial carcinoid
Differential diagnosis: plasma-cell granuloma, immune-cell hyperplasia, malignant lymphoma
CD 45, 4KB5, L26, antibodies directed to j and k, IgG, IgA, CD43
Metastatic cancer
Cytokeratins 7, 8, 18, 19 Estrogen, Progesteronereceptor proteins (breast cancer) Oncoproteins (e.g. c-erbB1-B3) Suppressor genes (mutated): p53, etc.
New Approaches Concerning Cancer Cell Proliferation Ramnath et al. (2001) compared the significance of cancer cell nuclei-related minichromosome maintenance protein expression (MCM2) with Ki67 expression rate for survival in NSCLC patients. He found that immunostaining of tumor tissue for MCM2 helps in the prediction of prognosis and that MCM2 seems to be an important independent prognostic parameter. Interpretable results were obtained in more than 96% of paraffin-embedded specimens. Staining of under 25% of the cancer cell nuclei signals a favorable prognosis. In the series of cases investigated 35% belonged to this group. Lately Fukuse et al. (2000) obtained 5-year survival rates of 66% among pN2-positive cases with low proliferation reflected in PCNA measurements and only 21.5% among cases with high proliferation in PCNA stainings. Analogous results can be obtained using the antibody Ki 67 (MiB I). Because as a rule similar proliferation activity to that in the primaries is found in lymph node metastases, immunohistochemical measurements in biopsy material from the primaries would allow an approximate estimate of the tendency to locoregional spread. Tanaka et al. (2000) see mutated p53 activity and higher proliferative activity as an indication for mediastinoscopy in NSCLC even when CT is negative. They base this on their observation that the rate of false-negative results was 24.1% in their series with p53 positivity and above-normal proliferative activity in the biopsy specimen taken from the primary.
N-level-dependent Survival Table 6. Differential diagnosis of the different subtypes of bronchial cancers against other cancers breaking through into or metastasizing to the bronchial system Most important subtype
Differential diagnosis
Confirmation of diagnosis: primary of the lung
Exclusion of other cancers
SCLC
Non-Hodgkin and Hodgkin lymphoma
Immunohistochemical: cytokeratin 8, 18, etc. positive MiB I = mostly high proliferation > 80% positive
Non-Hodgkin lymphomas: CLA
Thymoma
B-Cell markers (CD20 = L26, CD22 = 4KB5) T-Cell markers (CD3 = UCHL1, CD43) negative Hodgkin lymphoma: CD30 negative Thymoma: see addendum *
NSCLC: squamous cell cancer
Breakthrough of esophageal carcinoma
Bronchoscopy with biopsy for confirmation
Esophagoscopy for exclusion of esophageal cancer
NSCLC: adenotype(s)
Metastatic process
Immunohistochemical demonstration of typical cytokeratin pattern: CK 8, 18, 19, 21
Colon cancer Breast cancer Prostatic cancer, etc. Exclusion by clinical investigations
* Thymus neoplasms: Subtyping in Type A, AB, B1, B2, B3 and C; lymphocyte poor types A, B3, C Epithelial differentiated thymomas: Thymic carcinoma (TCA). Invasive thymic neoplasm of epithelial type (TNET) Lymphocyte rich thymomas: Three distinct subpopulations of lymphatic cells (see Li et al. 2004). Analysis of antigen expression pattern: The presence or absence of T-cell associated antigen deletion and the expression of CD10 and CD34 by 4-colour flow cytometry can help differentiate thymoma from T-cell ALL/LBL.
Table 7. Rates of cancer-positive nodes in cases diagnosed as N0 on HE staining, including rates of mutated p53 positivity (LN lymph nodes) CK+ cells
p53+
CK AE1/ AE3 in N0 nodes
p53 in N0 nodes
CK + p53 in N0 nodes
35/474 LN
20/263 LN
17/49 patients
10/25 patients
22/49
7.4%
7.6%
34.7%
40%
44.9%
N-level-dependent Survival Basic Data for Comparison with Results of Future Sentinel Node Detection Programs Andre et al. (2001) investigated the survival rates of 702 patients treated in the Department of Medicine in Villejuif for NSCLC with ipsilateral mediastinal lymph node involvement (N2). The authors analyzed the prognosis of patients with resected N2 NSCLC, with the aim of proposing homoge-
neous patient subgroups. The results obtained are displayed in Table 8. These data, documenting different subgroups of N2 involvement, are of interest for comparisons of results obtained by treatment in accordance with the SLN concept, especially with the group developing skip metastasis (see Schinkel et al. 1999). The benefit 10% of mediastinoscopy with lymph node dissection for intended N-staging has been clearly demonstrated by Oosterhuis et al. (2001). This limited but far-reaching N-staging procedure is of benefit in supporting the following aims:
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Chapter 24 Lung Cancer Table 8. Five-year survival rates of patients with different subtypes of NSCLC (different types of lymph node involvement). Preoperative chemotherapy was associated with a better prognosis for cases [L1 one level involved, L2 multiple levels involved, c clinical involvement, m minimal involvement with cN2 (P < 0.0001)] Cancers treated with primary surgery
558
mN2L1
mN2L2
cN2L1
cN2L2
n = 244
n = 78
n = 118
n = 122
34%
11%
8%
3%
Table 9. Value of mediastinoscopy for staging and further decision making in NSCLC cases Consecutive cases (n)
Mediastinal node dissection
Unsuspected N2 disease
Reduction in no. of unsuspected node involvement by IHC
Benefit from neoadjuvant therapy
183
158
24 (15%)
15 ?10%
10%
Table 10. Applicability of mediastinoscopy for regional staging in NSCLC No. of cases
For staging
For diagnosis
For operability
After chemotherapy
Sensitivity
Specificity
Accuracy
224
59.2%
30.6%
5.4%
4.8%
87%
100%
93%
No. of cases
Sensitivity
Specificity
Accuracy
Overall positive and negative predictive value
42
76.7%
100%
83.3%
100% and 87%, respectively
· Detection of unsuspected N2 involvement. · Selection of patients for neoadjuvant chemotherapy. The results of this investigation are summarized in Table 9. The general clinical value of cervical mediastinoscopy has been recently evaluated by Ebner et al. (1999). The indications for it have been summarized as follows: · Staging of NSCLC and SCLC · Diagnosis of mediastinal masses or lung tumors without previous histological examination · Restaging after primary chemotherapy · Assessment of prognosis in patients with borderline operability The results of Ebner's estimates are summarized in Table 10.
have cancer infiltration of these nodes. However, in contrast to these findings even small nodes can be cancer infiltrated. No. of cases
Sensitivity
Specificity
Accura- Overall positive cy and negative predictive value
42
76.7%
100%
83.3%
100% and 87%, respectively
These results published by de Leyn's group are shown in Tables 11 and 12. In spite of these widely known facts, many surgeons believe that a mediastinum seen as normal on CT does not need to be investigated preoperatively. Table 11. Basic results: Cancer infiltration, extra nodal infiltrates and infiltration of more than one level
N-positive Rates in Relation to T-stage In 1997, de Leyn et al., investigating 235 cases of NSCLC, estimated that only 50% of patients with enlarged mediastinal lymph nodes were found to
No. of cases
Mediastinoscopy, nodes positive
Extranodal cancer infiltrates in N2
More than one level involved
235
47 (20%)
21
16
N-level-dependent Survival Table 12. Rates of positive lymph nodes in N0 cases with different stages (CT) cT1N0
cT2N0
cT3N0
cT4N0
9.5%
17.7%
31.2%
33.3%
Table 14. Mediastinoscopy as a routine method of assessing operability Exclusion of operability
? Contralateral lymph nodes involved in metastatic process (histology: tumor positive) ? Extranodal cancer infiltration histologically confirmed ? Unresectable superior mediastinal nodes involved (histology or needle biopsy)
Limited chance of operability in other stages than I and II
? In confirmed stage III cases surgical treatment can be put forward as best course in special cases
Table 13. Five-year survival rates Cancers
< 20 mm
21± 30 mm
31± 50 mm
> 51 mm
48.1%
27.7%
31.2%
16.7%
In the studies conducted by Watanabe et al. (1999) in 218 stage IIIA-N2 patients, overall survival of 23% was found. The survival rate increased to 30% in those in whom complete resection (R0) was achieved. In these studies the 5-year survival rates of IIIA-N2 cases depended clearly on the extension of the primaries (Table 13). It might be possible to increase the relatively high survival rate of 48% in cases with cancers that, while small (< 20 mm), were already classed as stage N2 by more complete N-staging involving labeling procedures. In Motta et al.'s (1999) series of patients with stage I (T1N0 to T2N0) disease, the survival rates decreased at the size cut-off point of 3 cm in the primary. Mediastinoscopy is a valuable preoperative method of excluding or confirming operability and the nature of non-lung-cancer lesions, such as · Thymoma · Mediastinal teratoma · Hodgkin's disease · Non-Hodgkin lymphoma and for sentinel node detection and/or N-staging. The above different tumor entities require different treatment strategies. Therefore, mediastinoscopy and histopathological examination together are valuable in diagnosis and in planning of therapy in general, and this technique cannot be seen only as a means of lymph node staging in bronchial carcinoma. In the main it is used to clarify the question of operability in advance of an attempt at surgery, and with this also that of N(SLN) staging. Points leading to the exclusion or confirmation of operability are summarized in Table 14.
Approach to Testing Operability of NSCLC The following scheme gives a rough overview of operability: · Mediastinoscopy with lymph node investigations. · Radiodiagnostic techniques including PET, CT are the diagnostic methods that can be applied preoperatively. · Intraoperatively, N-staging with exact lymph node investigations (frozen sections, cytology, etc.) and ultrarapid immunohistochemistry (see Chapter 17) are the most helpful methods. Concerning the N-positions of cancer-involved lymph nodes with a view to operability after earlier location of the primary by radioimaging and mediastinoscopy, N3-positions can be confirmed or ruled out. In the case of lymphatic metastasis to the contralateral side a stage of N3 must be assumed, which corresponds to extensive disease (Fig. 21). In the case of cancer infiltration of a peribronchial lymph node near to the primary only, the N1-situation (limited disease) seems to be possible (Figs. 22, 23). In the case of lymph node connections of the tracheo-broncho-pulmonary situs exact knowledge is necessary for preoperative (via mediastinoscopy) or intraoperative (frozen section combined with imprint cytology) staging investigations. Positive peribronchial lymph nodes less than 2 cm from the trachea and/or positive nodes of the aortic-pulmonary window as well as positive nodes at the bifurcation of the trachea are critical for ascertaining operability. Preoperative M-staging
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Chapter 24 Lung Cancer Fig. 21. Evaluation of limited [a lymph node involvement on same side as primary only (N1)] and of extensive disease [b lymph node involvement of contralateral nodes (N3)]
for exclusion of distant metastases is obligatory (see Tables 13, 15, 21).
Is There a Role for Routine Mediastinoscopy in Patients with Peripheral T1 Lung Cancers? Quite a large number of patients with small peripheral lung cancers harbor radiographically occult lymph node involvement. In these cases especially, mediastinoscopy helps in the identification of patients with regionally advanced disease (mediastinal/precardial nodes positive) prior to resection (Fig. 24). Diagnosis by methods of this kind excludes the search for sentinel nodes, but allows the indication for neoadjuvant chemotherapy to be recognized and makes it possible to avoid unnecessary operations (Tahara et al. 2000).
Special Approaches for Obtaining Specimens for Cancer Diagnosis a) Endoscopic ultrasound-guided transesophageal fine-needle aspiration (EUS-FNA). b) Transpleural techniques for NSCLC diagnosis. Ad a) EUS-FNA: Ryan et al. (2001) reported briefly on the methods of lung cancer biopsy. The authors emphasize the possibility of using EUS-FNA biopsy of mediastinal nodes. The sensitivity in the diagnosis of carcinoma in lymph nodes was more than 90% in their own studies, with no complications. In an earlier study by Gress et al. (1997) EUSFNA had a specificity of 96% for nodal involvement, compared with 49% for CT. In addition, Serna et al. (1998) recorded a sensitivity of 86% for EUS-FNA, compared with 100% for mediastinoscopy, but the authors emphasized that both methods had both a specificity and a positive predictive value of 100%.
N-level-dependent Survival Fig. 22. Broncho-aortopulmonary situs: preoperative staging should perhaps be performed with a view to ascertaining whether or not the lesion is operable. Use of mediastinoscopy MRI-Sinerem imaging, PET, etc. might allow clearer planning of any operation
Table 15. Comparison of relapse rates after transpleural and transbronchial diagnosis of lung cancer Transpleural technique
Transbronchial technique
Relapse rate total
Transpleural transbronchial
Transpleural transbronchial distant vs local
Survival transpleural vs transbronchial (%)
n = 45
n = 194
42
7
4/3 vs 20/15
79.4 vs 60.3
35
(P = 0.90)
Ad b) The possibility that transpleural techniques for NSCLC diagnosis might involve a danger of relapse and worsening of prognosis has been discussed. Recently Sawabata et al. (2001) published the results obtained in their comparative studies on the frequencies of local and distant recurrence rates after transpleural and transbronchial procedures for NSCLC diagnosis, in which they investigated 45 and 195 cases, respectively.
Neither local nor distant relapse rates showed statistically significant differences. The survival rates were better in the transpleural diagnostic group (P = 0.04). The results are summarized in Table 15. The authors concluded from their results that transpleural diagnosis is an appropriate way to diagnose operable lung cancer that is difficult to verify by bronchoscopy, because this method does not affect relapse rates or prognosis.
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Chapter 24 Lung Cancer Fig. 23. Topography of the situs with lymph node groups (N1±N3 positions) relevant for pre- and intraoperative node staging and decision making on operability. N1 = bronchopulmonary nodes. Overview of the localizations of bronchopulmonary and tracheobronchial nodes. This scheme is basic to the development of radiological imaging-systems to localize sentinel node(s) and gives preoperatively answers about operability
Fig. 24 a, b. Preoperative staging using imaging systems (N1 position see Figs. 21, 23). a Evaluation of the nodes in aortopulmonary ªwindowº (N2); b mediastinal nodes (N3). Demonstration of the exact localization of the nodes in the ªaortopulmonary windowº
Comparative Studies of Mediastinal Lymph Node Dissection with Systematic Node Sampling Table 16. Intraoperative sentinel node search using
99m
Tc-nanocolloid
No. of cases
Mean time labeling 99mTc 63 (23±170) min
SLN identification rate (%)
SLN positive
SLN positive, no other metastases
Inaccurate SLN detection
SLN nodes mediastinal (N2 positive)
45
63 min
37 (82%)
12 (32%)
35/37 (94%)
2 (5%)
8 (22%)
Skip Metastasis of NSCLC Makes N-staging More Difficult
Comparative Studies of Mediastinal Lymph Node Dissection with Systematic Node Sampling
Sentinel Node Detection Rates in NSCLC and Significance of Skip Metastasis
Such studies can be seen as a basis for the later comparisons with the results of sentinel node projects. Keller et al. (2000) compared mediastinal lymph node dissection (MLND) with systematic sampling (SS). The results are summarized in Table 17. They document that completeness of locoregional cancer clearance depends on the quality of the surgical strategy on the one hand and the side where the cancer is localized and, depending on this, on the different side-related surgical benefits on the other. In a recently published Chinese study (Wu et al. 2001) of 504 patients with NSCLC treated by lobectomy or pneumectomy, radical lymphadenectomy (RL) and conventional lymphadenectomy (CL) were compared and referred to the different tumor stages. RL was statistically superior in clinical stage I cases (P < 0.014), but not in higher stages (Table 18). This means that even in stage II cases the possibility of surgical locoregional clearance is already past in many cases and the rate of systemic spread has already increased, limiting the likelihood of survival. In conclusion, based on these facts, the question arises of whether a sentinel node showing solitary cancer infiltration, but located near the hilus or in the carina region, can be regarded as a N1 site but in an unusual basin deviating from the UICC scheme. Comparison of the survival rate could give some insight in this direction (Table 19). Keller et al. (2000) compared the results of systematic lymph node sampling (SS) with those of mediastinal lymph node dissection (MLND). In 373 patients the median survival was 57.5 months for those who had undergone complete MLND and 29.2 months for those who had undergone SS (P = 0.004). The survival advantage was limited to patients with right-sided lung cancers (66.4 months versus 24.5 months) (P < 0.001). The authors emphasize that in their nonrandomized study SS was as efficacious as complete MLND in staging patients
The numbers of cases in which a search for sentinel nodes has been carried out are mostly low so far. In Liptay et al.'s (2000) studies there were 45 evaluable cases. The results are summarized in Table 16. These results demonstrate that a gamma probe-guided SLN search also helps to obtain a clear-cut overview for improved locoregional cancer clearance in cases with positive N2 positions.
Does the Rate of Skip Metastasis Hamper Use of the Sentinel Node Concept? If the rate of skip metastasis is very low, as it is in breast cancer (*3%), the presence of such metastases do not prejudice the sentinel node concept. However, when the rate is much higher, the practicability of using this concept in daily routine is called in question. In 1999 Schinkel et al. published their data, which are based on 170 cases of NSCLC (stage I: n = 15, stage II: n = 42, stage III a: n = 113). The authors found N2 disease in 68 cases, and a rate of 81% with skip metastases. This rate is extremely high, and we did not find other systematic evaluations to this problem. But against the backdrop of an abundantly developed network of lymphatics along the tracheobronchial system and within the mediastinum, it seems inevitable that primary regional lymph nodes will be by-passed. Therefore, the strong UICC concept (Figs. 25±27) is more a working formulation and does not correspond with the sentinel node concept in every case.
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Chapter 24 Lung Cancer Figs. 25±27. Overview of N-staging in stages N1±3 of lung cancer (Spiessl et al. 1990/1993) Fig. 25. Stage N1
Fig. 26. Stage N2
Table 17. Comparison of mediastinal lymph node dissection (MLND) with systematic node sampling (SS), related to side of localization and survivala SS
MLND
No. of cases (n)
N1
187
40%
N2
60%
No. of cases (n)
N1
N2
186
41%
59%
P = 0.004 a Comparison (right vs left side; % survival) Right side Left side Months Months 66.4 24.5 P = 0.001
N2 total
222
Metastases MLND
SS
30%
12%
Median survival (months) MLND
SS
57.5
29.2
Comparative Studies of Mediastinal Lymph Node Dissection with Systematic Node Sampling Fig. 27. Stage N3
Table 18. Survival of patients after radical (RL) and conventional (CL) lymphadenectomy in NSCLC, stage I Total no. of cases
RL
320
160
CL
160
No. of nodes in RL (average)
No. of nodes in CL (average)
Stage I survival in RL group
Stage I survival in CL group
1
3
5
9
1
3
5
9
9.49
3.63
91.8
86.9
81.4
74.2
88.7
72.5
58.5
52.1
Table 19. Rates of unexpected N2 disease in lung cancer cases (NSCLC) Authors
No. of cases
SLN Positive
Negative
Unexpected N2 positivity 5
Little et al. (1999)
9
9
Oda et al. (1998)
10
7
with NSCLC. However, complete MLND identified significantly more levels of N2 disease.
Lymph Node Sampling Strategy in NSCLC Cases Systematic lymph node dissection is considered to improve local control at least in early stages (Wu et al. 2001). Naruke et al. (1999) investigated 1815 cases. The lymphatic routes from each lobe were analyzed by examining which nodes had the most likelihood of metastasis or to find out in the case of small tumors which node was the SLN and suitable for video-assisted thoracic surgery (VATS).
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Chapter 24 Lung Cancer
The results allowed the following conclusions: · In clinical T1N0 cases, SLN sampling should be done first. · If the nodes are negative on histological serial sectioning, complete MLND can be omitted. · If the SLNs are positive, complete MLND dissection is required for curative treatment. The value of complete MLND is the subject of some controversy. However, improved survival has been demonstrated in randomized settings for patients with locally advanced, resectable disease (N2) when preoperative induction chemo(radio)therapy has been given (Korst 2001). These results indicate that in N2 cases too, improvements can be achieved when the sentinel node concept is applied by using 99m Tc-nanocolloids and blue dye for more accurate locoregional cancer clearance and that this also makes it possible to attain higher survival rates.
Difficulties in Preoperative SLN Detection and N-staging In contrast to breast cancer and melanoma, in the case of lung cancer it is not easy to apply the contrast medium in the area surrounding the primary tumor in the lung. Therefore, it has been necessary to devise new approaches, which include: · Peritumoral endoscopic administration transbronchially or into the submucosa in the tissues surrounding the tumor. · Transthoracic administration of 99mTc-labeled colloid or contrast media in cases with peripheral lung cancer. · Administration of 99mTc-labeled colloids or contrast media during mediastinoscopy into tissue close to the primary for labeling of an N1 site. · Peritumoral administration of the blue dye during operation. A systematic approach is generally necessary for an acceptable staging system. The following possibilities should be discussed: a) Routine 18F-FDG-PET for the detection of involvement of small lymph nodes. This method has recently been connected with a high level of acceptance in tumor consensus papers (Reske 1996). b) A general contrast method can be used to mark lymph nodes.
It is possible to use ultrasmall iron oxide particles (USPIO) taken up by the sinus histiocytes of the lymph nodes, which are a component of the macrophage system. When lymph nodes or parts of them are destroyed by metastasis their extinction (because of missing sinus histiocytes in these areas) or partial defects can be seen in the radiological image analysis. c) Labeling of cancer cells by antibodies directed to surface structures such as CD44, EGFR, etc. d) It might be possible to increase the cell membrane permeability of cancer cells induced by tumor necrosis factor (TNF) and after the application of TNF to bring labeled anticytokeratin antibodies into the cytoplasm of the cancer cells. It could then be possible to detect the metastases by nuclear medical systems. Method (b) could be a desirable approach when a CT contrast agent is used. Up to now, no tissuespecific CT contrast agent, i.e. macrophage-contrasting substance especially for the sinus histiocytes of lymph nodes, has been developed. In recent years 18F-FDG-PET has emerged as a staging procedure of choice. Nonetheless, additional new methods are urgently required, because optimal knowledge of tumor progression and pattern of spread is imperative for adequate treatment. Some arguments have been raised against staging methods involving the use of imaging techniques: these focus on calcification after tuberculosis, scar formation in cases with abortive forms of silicosis or after dust inhalation, or anthracosis of the nodes. Established imaging methods have only a limited impact on the staging of lung cancer. But the aforementioned factors in destruction of the functional structures of the lymph nodes are of little or no interest, because in the middle-aged and elderly in Central European countries and the United States tuberculosis is no longer an important problem and scar formation is also less important than earlier, because of the increasing protection of persons exposed to inhaled fibrosing factors. In addition, the incidence of lung cancers is steadily increasing in the female population. In women of working age scar formation seems to be much less frequent than in the male population, though a far larger proportion of men work in dust-producing industrial companies. Therefore, chemical substances that are systemically stored by sinus histiocytes as targets, such as USPIO, should indeed be suitable for pilot studies.
Is the SLN Concept Helpful in Correct Node Staging?
It would be very helpful for surgeons to have consistent information on the following points: · Involvement of peribronchial nodes (2 cm distant from carina = N1) or hilus lymph nodes (= still N1) (a in Fig. 21) justifies use of the term ªsentinel nodesº · Involvement of mediastinal or subcarinal lymph nodes (b); see also Fig. 21 (= N2). · Involvement of the N3 position (contralateral, mediastinal hilar, ipsi- or contralateral scalene or supraclavicular node) (see also Figs. 4 and 6). These findings determine whether a lesion is inoperable.
Experience in the series of patients currently under review has shown that the rates of locoregional spread and survival do not depend directly on the local extension of the infiltrative and growing cancer, but clearly on its proliferative activity. Yanagi et al. (2000) therefore pointed out that it would not be helpful to subdivide the group of lung cancers in stage pT1 (diameter £ 2 cm), because the tumor size does not have a role within the group. The question of the significance of proliferative activity has often been investigated in different tumor types. Results of SLN Search Using the Intraoperative Blue Dye (Isosulfan) Labeling Method
Currently, CT and MRI are not adequate for precise preoperative staging. Furthermore, inflammatory pulmonary reactions caused by retention of infected mucus secretion with regional lymphadenitis sometimes lead to enormous enlargement of the nodes; therefore, it is impossible to rely on lymph node diameter in imaging investigations as a reliable parameter. At the moment the techniques of nuclear medicine cannot solve these problems, because PET also has a limited resolution of about 3±5 mm. Consequently, new approaches have to be developed for labeling sinus histiocytes of the nodes and improving the Weissleder techniques.
This straightforward working method has the advantage that nuclear medical activities and nuclear medical devices are not necessary. Little et al. (1999) evaluated the effectiveness of this option. In 36 consecutive patients undergoing lung resection peritumoral tissue was infiltrated with isosulfan blue dye solution, and the first lymph node to stain was identified as a sentinel node. The final results of this preliminary investigation are summarized in Table 20. Shian et al. (2000) evaluated 99mTc-methoxyisobutylisonitrile (Tc-MIBI) for detection of mediastinal lymph node-metastasis in patients with NSCLC. The results showed that the diagnostic sensitivity, specificity, and accuracy of 99mTc-MIBI SPECT examination of the chest was more sensitive and accurate than CT in the evaluation and detection of mediastinal lymph node involvement in these NSCLC patients.
Is the SLN Concept Helpful in Correct Node Staging? Because the T-stage often cannot be precisely determined preoperatively and the primary can break out through the visceral pleura even in the early stages, and because it is difficult to obtain an overview of the intrapulmonary, peribronchial, peritracheal, and mediastinal lymphatic network, preoperative staging by means of the available radiodiagnostic imaging systems has an important role: · For implementation of the sentinel node search. · For the question of how to reach R0 resection.
Significance of Postoperative Death Rates and Survival Rates Referred to Tumor Stage Lung cancer operations (lobectomy and pneumectomy) decided on because of the regional lymph node (SLN) staging do not make sense unless primary M-staging and lymph node staging including
Table 20. Summary of the results obtained by SLN labeling using blue dye solution in a small patient collective No. of consecutive cases
Sentinel node detection rate
Sentinel nodes negative
Unexpected N2 (as SLN)
No SLN found
Final status N0
N1
N2
36
9/17
9/9
5
19
13
5
1
327
328
Chapter 24 Lung Cancer Table 21. Five-year survival rates in NSCLC (%) Stage
Survival rate
I
45±47
II
27±30
III a
10±12
III b
*5
SLN determination are optimized. For an overview, some basic data are displayed in Table 21.
Operability of NSCLC and Postoperative Death Rates About 40% of all cases of NSCLC are operable. Cases in stages I and II are mostly operable, and occasionally cases in stage III a. The postoperative death rates recorded are 7% for pneumectomy and 3% for lobectomy. J Adjuvant Lung Cancer Treatment in Dependence on the SLN Status Small-cell lung cancer (SCLC) is very seldom detected in the early stages of local development, and it is therefore generally regarded as a systemic disease. Because of the frequent presence of occult metastatic disease, adjuvant chemotherapy is recommended for all patients with limited stages, irrespective of lymph node involvement or postoperative R-status. When the results of the (sentinel) node search are positive it is of critical importance that radiation therapy (RT) be administered in addition to chemotherapy, even after R0 resection; it is recommended in N2 disease (and if the tumor has not been completely removed: R1/2). To avoid cumulative effects of Adriamycin and RT on the heart different schemes are used, depending on the localization of the primary. In cancer cases with the primary in the left lung a cisplatin-etoposide regimen (Chapter 33) plus RT is used. In cases with a right-sided primary a chemotherapy regimen containing Adriamycin, cyclophosphamide and vincristine (ACO) plus RT is recommended (see Chapter 33). In NSCLC (squamous cell cancer, adenocarcinoma and large cell cancer, polymorphous cell cancer) in stage I lobectomy alone is recommended, with no adjuvant chemotherapy.
Data strongly suggest that there is a benefit of neoadjuvant therapies in disease stages II±IV, but clinical trials are still in progress. Patients with disease stage III should receive neoadjuvant chemotherapy, if possible in the context of clinical studies. In stage II (positive lymph nodes, e.g., SLN) a benefit of neoadjuvant or adjuvant therapy is likely, but confirmation awaits further studies. Schemes used are the same used for recurrent or advanced diseases. (See Chapter 33 for combinations of paclitaxel with either cisplatin or carboplatin.) Stage III b is not operable: Down-staging can be attempted with combination chemotherapy using a platinum preparation combined with mitomycin, ifosfamide, or etoposide (see Chapter 33).
References Andre F, Grunenwald D, Pignon JP, Dujon A, Pujol JL, Brichon PY, Brouchet L, Quoix E, Westell V, Le Chevalier T (2000) Survival of patients with resected N2 non small cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 18:2981±2989 Coleman RE (1999) PET in lung cancer. J Nucl Med 40:814± 820 De Leyn P, Vansteenkiste J, Cuypers P, Deneffe G, Van Raemdonck D, Coosemans W, Verschakelen J, Lerut T (1997) Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan. Eur J Cardiothorac Surg 12(5):706±712 Drings P (1998) Expert round table, Berlin 1998. Initiated by Schering AG, Berlin (minutes held at Schering) Ebner H, Marra A, Butturini E, De Santis F (1999) Clinical value of cervical mediastinoscopy in the staging of bronchial carcinoma. Ann Ital Chir 70(6):873±879 Erasmus JJ, McAdams HP, Patz EF, Goodman PC, Coleman RE (1998) Thoracic FDG PET: state of the art. Radiographics 18:5±20 Farrell MA, McAdams HP, Herndon JE, Patz EF (2000) Nonsmall cell lung cancer: FDG PET for nodal staging in patients with stage I disease. Radiology 215:886±890 Fukose T, Hirata T, Naiki H, Hitomi S, Wada H (2000) Prognostic significance of proliferative activity in pN2 non small cell lung carcinomas and their mediastinal lymph node metastases. Am Surg 232:118±128 Gress FG, Savides TJ, Sandler A, Kesler K, Conces D, Cummings O, Mathur P, Ikenberry S, Bilderback S, Hawes R (1997) Endoscopic ultrasonography, fine needle aspiration biopsy guided by endoscopic ultrasonography and computed tomography in the preoperative staging of non small cell lung cancer: a comparison study. Ann Intern Med 127:604±612 Gu CD, Osaki T, Oyama T, Inoue M, Kodate M, Dobashi K, Oka T, Yasumoto K (2002) Detection of micrometastatic tumor cells in pN0 lymph nodes of patients with completely resected non small cell lung cancer: impact on recurrence and survival. Ann Surg 235:133±139
References Gupta NC, Graeber GM, Bishop HA (2000) Comparative efficacy of positron emission tomography with fluorodeoxyglucose in evaluation of small (< 1 cm), intermediate (1 to 3 cm), and large (>3 cm) lymph node lesions. Chest 117:773±778 Higashi K, Nishikawa T, Seki H, Oguchi M, Nambu Y, Ueda Y, Yuasak Tonami H, Okimura T, Yamamoto I (1998) Comparison of fluorine-18-FDG PET and thallium-201 SPECT in evaluation of lung cancer. J Nucl Med 39:9±15 Kalff V, Hicks RJ, MacManus MP, Binns DS, McKenzie AF, Ware RE, Hogg A, Ball DL (2001) Clinical Impact of (18)F fluorodeoxyglucose positron emission tomography in patients with non-small-cell lung cancer: a prospective study. J Clin Oncol 19:111±118 Kawashima O, Kakegawa S, Otani Y, Kamiyoshihara M, Sugano M, Morishitta Y (2002) Clinical study of synchronous multiple primary lung cancers; problems in diagnosis and treatment. Kyobu Geka 55(19):20±24 Keller SM, Adak S, Wagner H, Johnson DH (2000) Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer. Eastern Cooperative Oncology Group. Ann Thorac Surg 70(2):358±365 Korst RJ, Ginsberg RJ (2001) Appropriate surgical treatment of resectable non small cell lung cancer. World J Surg 25:184±188 Li S, Juco J, Mann KP, Holden JT (2004) Flow cytometry in the differential diagnosis of lymphocyte rich thymoma from precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. Am J Clin Pathol 121(2):268±274 Liptay MJ, Masters GA, Winchester DJ, Edelman BL, Garrido BJ, Hirschtritt TR, Perlman RM, Fry WA (2000) Intraoperative radioisotope sentinel lymph node mapping in non small cell lung cancer. Ann Thorac Surg 70:384± 389 Little AG, Delloyos A, Kirgan DM, Arcomano TR, Murray KD (1999) Intraoperative lymphatic mapping for nonsmall cell lung cancer: the sentinel node technique. J Thorac Cardiovasc Surg 117(2):220±234 Lloyd C, Silvestri GA (2001) Mediastinal staging of nonsmall-cell lung cancer. Cancer Control 8(4):311±317 MacManus MP, Hicks RJ, Matthews JP, Hogg A, McKenzie AF, Wirth A, Ware RE, Ball DL (2001) High rate of detection of unsuspected distant metastases by PET in apparent stage III non-small-cell lung cancer: implications for radical radiation therapy. Int J Radiat Oncol Biol Phys 50(2):287±293 Marom EM, Erasmus JJ, Patz EF (2000) Lung cancer and positron emission tomography with fluorodeoxyglucose. Lung Cancer 28:187±202 Motta G, Carbone E, Spinelli E, Nahum MA, Testa T, Flocchini GP (1999) Considerations about tumor size as a factor of prognosis in NSCLC. Ann Ital Chir 70(6):893± 897 Murasugi M, Onuki T, Ikeda T, Kanzaki M, Nitta S (2001) The role of video-assisted thoracoscopic surgery in the diagnosis of the small peripheral pulmonary nodule. Surg Endosc 15(7):734±736 Naruke T, Tsuchiya R, Kondo H, Akayama H, Asamura H (1999) Lymph node sampling in lung cancer: how should it be done? Eur J Cardiothorac Surg 16[Suppl 1]:S17±S24
Oda M, Watanabe Y, Shimizu J, Murakami S, Ohta Y, Sekido N, Watanabe S, Ishikawa N, Nonomura A (1998) Extent of mediastinal node metastasis in clinical stage I non small cell lung cancer: the role of systematic nodal dissection. Lung Cancer 22:23±30 Oosterhuis JW, Theunissen PH, Bollen EC (2001) Improved pre-operative mediastinal staging in non-small-cell lung cancer by serial sectioning and immunohistochemical staining of lymph-node biopsies. Eur J Cardiothorac Surg 20(2):335±338 Ota S, Inaba H, Yoshida H (2001) Rational lymph node dissection for lung cancer according to the occurrence lobe and histological type. Kyobu Geka 54:1073±1078 Pieterman RM, Putten JW van, Meuzelaar JJ, Mooyaart EL, Vaalburg W, Koeter GH, Fidler V, Pruim J, Groen HJ (2000) Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 343:254±261 Ramnath N, Hernandez FJ, Tan DF, Huberman JA, Natarajan N, Beck AF, Hyland A, Todorov IT, Brooks JS, Bepler G (2001) MCM2 is an independent predictor of survival in patients with non-small-cell lung cancer. J Clin Oncol 19(22):4259±4266 Ryan A, Banks J, Roberts S (2001) Methods for lung cancer biopsy. Lancet 358(9296):1909±1910 Sawabata N, Maeda H, Ohta M, Hayakawa M (2001) Operable non-small cell lung cancer diagnosed by transpleural techniques: do they affect relapse and prognosis? Chest 120(5):1595±1598 Schinkel C, Mçller C, Reinmiedl J, Hoffmann H, Zimmer S, Dienemann H, Fuerst H (1999) Mediastinal lymph node infiltration in non small cell lung cancer and its role in curative surgery. Scand Cardiovasc J 33:286±288 Serna DL, Aryan HE, Chang KJ, Brenner M, Tran LM, Chen JC (1998) An early comparison between endoscopic ultrasound guided fine needle aspiration and mediastinoscopy for diagnosis of mediastinal malignancy. Am Surg 64:1014±1018 Shiau YC, Hsieh JF, Tsai SC, Ho YJ, Sun SS, Kao CH (2000) Technetium-99m methoxy-isobutyl-isonitrile chest single photon emission computed tomography to detect mediastinal lymph node metastasis in patients with non small cell lung cancer: comparison with computed tomography. Anticancer Res 20(5C):3751±3754 Spiessl B, Beahrs OH, Hermanek P, Hçtter RVP, Scheibe O, Sobin LH, Wagner G (1990/1993) TNM Classification. Springer, Berlin Heidelberg New York Tahara RW, Lackner RP, Graver LM (2000) Is there a role for routine mediastinoscopy in patients with peripheral T1 lung cancers? Am J Surg 180:488±491 Takamochi K, Nagai K, Yoshida J, Suzuki K, Ohde Y, Nishimura M, Sasaki S, Nishiwaki Y (2001) Pathologic N0 status in pulmonary adenocarcinoma is predictable by combining serum carcinoembryonic antigen level and computed tomographic findings. J Thorac Cardiovasc Surg 122(2):325±330 Tanaka F, Yanagihara K, Otake Y, Li M, Miyahara R, Wada H, Ito H (2000) Biological features and preoperative evaluation of mediastinal nodal status in non-small cell lung cancer. Ann Thorac Surg 70(6):1832±1838
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Chapter 24 Lung Cancer Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Bogaert J, Maes A, Deneffe GJ, Nackaerts KL, Verschakelen JA, Lerut TE, Mortelmans LA, Demedts MG (1998) Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 16:2142±2149 Watanabe Y, Murakami S, Oda M, Ohta Y, Watanabe S, Nozawa H, Kamesui T, Nozaki Y, Nonomura A, Minato H, Kitagawa M (1999) Tumor size and extension of lymph node metastases in N2 lung cancer. Ann Ital Chir 70: 889±892
Wu Y, Wang S, Huang Z (2001) Extent of lymphadenectomy in stage I±IIIA non-small cell lung cancer: a randomised clinical trial. Zhonghua Zhong Liu Za Zhi 23(19):43±45 Yanagi S, Sugiura H, Morikawa T, Kaji M, Okushiba S, Kondo S, Katoh H (2000) Tumor size does not have prognostic significance in stage Ia NSCLC. Anticancer Res 20(2B):1155±1158 Yang ST, Zhou YZ, Zeng J (1999) 99mTc-MIBI single-photon emission-computed tomography in diagnosis of lung cancer and mediastinal metastasis lymph nodes. Zhongguo Yao Li Xue Bao 20(9):800±804
Chapter 25
Malignant Melanoma
Introduction In most cases, malignant melanomas spread first into lymph nodes, before hematogenous metastases develop. However, as is well known, ªexplosiveº and disseminated, hematogenous metastasis can also occur in very early stages (Fig. 1).
Exclusion of Nonmalignant, Nonmelanoma Lesions of the Skin In the early 1960s some German dermatologists propagated the opinion that malignant melanomas should be diagnosed ªby eye and by palpationº and that radiation therapy should then follow. This opinion was certainly mistaken and was also dangerous, because it meant that benign nonmalignant lesions were treated with high-dose radiation therapy. Every experienced dermatologist and pathologist is familiar with these melanoma-like lesions, which are: · Pigmented seborrhoic verrucae · Hemangiomas with local bleeding and siderin deposits stored in macrophages · Pigmented basaliomas · Tinea nigra Dermatoscopic investigations are useful in the differential diagnosis. Subtle changes in surface structures: pigmented network, brown globules, white spots or grayish-blue areas are changes or criteria that can be of diagnostic value. Photodocumentation can also be helpful, making it possible to follow unclear lesions over a certain time period. It is not permissible to use such procedures for observation in cases where there is a high suspicion of malignancy, however. When molecular biological methods are used for melanoma staging, detection of tyrosinase activity in the blood is important, as tyrosinase is a
25
precursor enzyme for melanin formation. Detection of tyrosinase-coding mRNA as a marker for melanoma cells can theoretically be usefully attempted in blood and lymph node investigations. Because in normal conditions no tyrosinaseproducing cells or messenger RNA of such cells are present in either the corpuscular or the liquid components of the bloodstream, investigations of the blood by the highly sensitive RT-PCR procedure are helpful in follow-up investigations, while assumptions of lymph node infiltrations based on positive RT-PCR results seem to be of questionable value (see also Chapters 4, 21). There are various pitfalls that we should try to avoid: · mRNA coding tyrosinase released from apoptotic or necrotic cancer cells of malignant melanomas can be transported via the lymph stream to the node(s) and give a false-positive reaction. · Normal or preneoplastic nevus cells can also be transported to the node and give false-positive reactions suggesting neoplastic spread of malignant melanoma cells. These are obviously the main points that can leading to false conclusions.
Macroscopic Criteria for Malignant Melanoma Development in Pre-existing Nevi Internationally, there have been many campaigns for early detection of malignant melanomas. It is clear that all doctors in all the different medical disciplines must be familiar with the characteristics of this cancer. This is easy to understand, because even specialists responsible for different branches of medicine can detect primaries in their own ªworking fieldsº within the human body. Some striking features are summarized in the socalled ABCD formula:
332
Chapter 25 Malignant Melanoma Fig. 1. Explosion-like metastasis from malignant melanoma into the lung, which had pigmented and amelanotic metastases
A stands for Asymmetry, which is consistent with focally increased growth activities, especially in the margins. B stands for Begrenzung (German for delineation), meaning lack of sharpness in the periphery with incipient horizontal invasive growth. C stands for Colorit, meaning changes in the homogeneity of coloration, which can take the form of either decoloration or hyperpigmentation, according to the progression of subclonal growth. D stands for Diameter (German ªDurchmesserº), changes in this corresponding to growth. All these features are well known and should therefore only need to be mentioned in this context as a prelude to stressing the absolute imperative of recognizing that, in any case of these alarming signals developing in nevi, there is no time to lose and treatment must be begun immediately. This is stated so emphatically because even now, in many cases treatment is not started until 2±3 months after malignancy is first suspected.
Initial Risk of Tumor Progression, Risk of Recurrence, and Definitive Risk to Survival In a multicenter study conducted at the M. D. Anderson Cancer Center in 580 melanoma patients, the SLN status was found to be the most significant prognostic factor with respect to disease-free survival and disease-specific survival according to
univariate and multiple covariate analyses. Although the thickness of the primaries and ulceration influenced survival in SLN-negative cases, these properties provided no additional prognostic information in SLN-positive cases. Therefore, SLN exploration is beneficial, allowing an idea of the prognosis and the identification of patients who may benefit from early lymphadenectomy (Gershenwald et al. 1988, 1999). The locoregional recurrence rate in melanoma patients seems to be important for judgments about the value of the SLN concept. To obtain clear-cut information, Gershenwald et al. (1998) looked for recurrence rates and patterns in 243 stage I and II melanoma cases in which SLNs were negative. The results were: 11% with negative SLNs developed local, in-transit, and regional nodal and/or distant metastases. In 4% metastases developed in the basin investigated. In 80% of the primarily negative nodes tumor cells were detected in serial sections supported by immunohistochemistry (see also Chapter 21). These data definitely show that node examinations performed by pathologists using only HE staining were incomplete, and that, as a consequence of the false-negative histopathological results, the clearance of the basins was also incomplete. It follows from this that improvements to quality and cooperation in early diagnosis can help to lower the recurrence rates.
Clinical Staging of Malignant Melanoma Based on EORTC Evaluation
Clinical Staging of Malignant Melanoma Based on EORTC Evaluation The clinical stages related to the progression of malignant melanomas and the corresponding survival rates are valuable parameters that are helpful in all further diagnostic procedures and adjustments to treatment. The current data published by the EORTC are presented in Table 1. With the successful introduction of the SLN clearance concept (SLCC), it became necessary to ask what the indications for its implementation might be. Because we do not possess clearly defined cellular grading criteria, which could help in decisions on whether SLN extirpation should be performed, we have to look for other ways of determining current growth activity. One important method is measurement of the proliferative activity in tumor sections after staining with the antibody MiBI. From our own investigations with this antibody in melanoma research, we know that there is a close correlation between the percentage of MiBI-positive cancer cells and regional metastatic cancer progression, but we cannot exploit this fact in decision making, especially when decisions on SLCC have to be made, because there are many other factors, such as microsatellite instability, that also influence the metastatic potential. More informative and useful for decision making are the data on degree of invasion, which can be easily obtained early in the course as specified by Clark and Breslow (see Tables 2, 3). When these two wellknown schemes are compared for practicability we cannot avoid the observation that the scheme oriented on the specific subepidermal fiber structures Table 1. Basic stage-related data of malignant melanomas presented by EORTC Stage
Tumor status
5-Year surviving rate
Stage I
Primary without signs of lymph node involvement
~ 80%
Stage II
Regional metastasis:
~ 35%
a) Satellite or in transit metastases b) Lymph node metastases Stage III
Distant (hematogenous) metastasis
~ 5%
Table 2. Degree of invasion of malignant melanoma according to Clark et al. Level I
Intraepidermal melanoma = melanoma in situ
Level II
Perforation of basement membrane and infiltration of stratum papillare
Level III
Infiltration to the border of stratum reticulare
Level IV
Infiltration of stratum reticulare
Level V
Infiltration into subcutis
Table 3. Prognostic risk groups by tumor thickness according to Breslow (1970, p 902) Tumor thickness (mm)
Risk scale
5-Year survival rates (%)
³ 0.75
Minimum
96±99
0.76±1.5
Low
87±94
1.51±4.0
Intermediate
66±77
> 4.0
High
< 50
(Clark) is too anatomically slanted and therefore much more difficult than measurement of the depth of invasion as described by Breslow. While we agree that local Breslow-scheme-based staging is a very important factor in the assessment of 5-year survival, there is some uncertainty about whether investigation of the SLN(s) is necessary. There seem to be three possibilities: · Investigation of the SLN(s) in all cases with invasive malignant melanoma · A threshold set at a depth between 0.75 and 1.5 mm, derived from the survival rates (see Table 3) · Adaptation to the different Clark levels (Table 2). The Breslow risk scaling and results already obtained have given rise to the following scheme for intervention: · a) Sentinel node extirpation in all cases of malignant melanoma of nodal type and clearance of the basins in lymph node-positive cases. · b) Same procedure in superficial spreading malignant melanoma with a depth of invasion > 0.75 mm. Because of the worldwide campaigns to reduce the incidence of malignant melanoma, in recent decades
333
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Chapter 25 Malignant Melanoma
more patients have been diagnosed in earlier stages and with thinner primary lesions. [For information on stage I disease see Veronesi et al. (1977), Balch et al. (1982) and McCarthy et al. (1985).] This is a very important advance, because after locoregional progression with lymph node involvement the 5-year survival rate is reduced by 40% (Mazzuka et al. 2000). A high proportion of patients with thin (< 0.76 mm) melanomas are cured by surgical excision only. However, 2±18% of such patients (Fearfield et al. 2001) relapse over 0±11 years with local or distant metastases, and some of these die. So far, we have no significant molecular markers that allow accurate determination of which very thin (early) melanomas will relapse. No absolutely clear basis for recommendations on these features is possible at present, because the biological behavior can vary widely even in cases with very small primaries and cannot be anticipated (a high degree of subcloning may play an important part); in addition, it is impossible to set up prospective randomized studies, as these would be unacceptable for ethical reasons. These are not the only problems: we also have to ask whether the SLN concept has to be adapted
for the different subtypes within the malignant melanoma family. The main features of each of the different entities are listed in Table 4. The two most important subtypes are superficial spreading melanoma (65±70%) and the nodular type of malignant melanoma (15±25%). Whereas the superficial spreading melanoma grows predominantly horizontally in the early stages (invasion depths of > 0.75 mm are seldom reached, or only late in the course), the nodular type grows primarily vertically from the start and therefore reaches a greater depth even in short time periods. It is mostly younger or middle-aged people who develop this type. Because of the poor prognosis in view of the fast growth, operative removal of the primary, including the lymphatics to the sentinel node(s) (if possible) and the SLN(s) themselves, must be performed immediately. A third entity in the melanoma family is lentigo maligna melanoma. This is characterized by a long-term precancerous status signaling genetic instability. It develops mostly in sun-exposed skin areas. This type accounts for only approximately 5% of all melanomas, i.e., is far less common than either of the main types discussed above. Sponta-
Table 4. Tumor types and biological behavior of the different subtypes of malignant melanoma (m.m.) of the skin Clinical and histopathological subtype of m.m.
Percentage in total group
Superficial spreading malignant melanoma (SSM)
65±70
Nodular type of m.m. (NM)
15±25
Preferred age group (years)
Clinical characteristics
Prestages
Macroscopic features
Prognosis
40±60
Anamnesis short
Nevi with junctional activity
Long-term horizontal tumor growth
Good
20±40
Anamnesis short
Nevi with junctional activity
Fast vertical tumor growth ulceration frequent, bleeding possible
Poor
Lentigo maligna melanoma (LMM)
5
> 60
Long-time precancerous state (decades)
Precancerosis with development to fully malignant melanoma
Flat tumor with discoloration zones of vertical growth in sun-exposed epidermis
Intermediate, partly with local, spontaneous regression of tumor growth
Acrolentiginous melanoma (ALM)
5
65 approx.
Aggressive tumor, phalanges, palmar, plantar epithelium
Irreg. pigmentation, erosions, hyperkeratosis
Lentiga maligna like DD.: Tinea nigra
Poor in some, because of difficulties in surgical treatment
In Transit Metastasis, Double or Multiple Drainage, Bypass and Atypical Metastasis
neous regression with scar formation is sometimes found, which may be connected with instability of the genome. In a consideration of the features described the following points are of interest with reference to the clinical treatment to be administered: · The slow development of the terminal malignant lesion gives time for good practice in therapy planning. · It seems clear that the lesion should be operatively excised with sufficiently wide tumor-free margins, which must be monitored in all parts by the pathologist involved. · The sentinel node(s) can be labeled preoperatively when the lesion has been present for so long that signs of malignant transformation (increasing discoloration, focal increased vertical growth) must be seriously expected and regional lymphatic spread cannot be excluded. · In incipient developmental stages (check the history) of a precancerous lesion that has remained stable for an accurately measurable period, preparation of the lymphatic cord together with SLN resection seems like overtreatment. The fourth entity in the melanoma family, acrolentiginous melanoma with localization in the periphery of the extremities and in mucosal areas, is also rare and does not basically involve a higher degree of malignancy, but as far as locoregional tumor clearance is concerned its treatment is more difficult. When it is localized in the lower leg, SLN detection can help in selection of the cases in which it seems popliteal node excision would be of value and of those in which inguinal lymph nodes should be excised and histopathologically investigated (see also Fig. 2). Clinical staging of malignant melanomas according to the EORTC scheme is a valuable way of measuring the 5-year survival rates under the conditions that were in place at the time of the initial histopathological diagnosis. With respect to the SLCC, it can be concluded that improvement of the radiodiagnosis in terms of finding the locoregional lymph nodes, and by strong and more precise definition of the SLN(s) in a very high percentage of cases, we can be certain that the stage I position can be improved from approximately 80%, as now, to 90% or more. In stage II, the development of satellite and in transit metastases, which have an important role in malignant melanomas on the legs, cannot be influenced,
Fig. 2. Sentinel node localizations in dependence on location of primaries: a Tumors of sex organs (penis, scrotum, vulva) and of the anal region have their sentinel nodes predominantly in the medial group of the inguinal nodes (for upper medial group see also Chapters 28, 29). b Malignant melanomas, synovial sarcoma etc. on the thigh (skin and deeper localizations, e.g., myogenous or developing from fasciae) metastasize into the node along the femoral vein, while c the corresponding tumors on the lateral and dorsal parts of the lower leg and foot metastasize via the popliteal nodes
but the more clear-cut definition or localization of the SLNs in the case of melanomas of the trunk and their excision in node-positive cases with meticulous examination of the sentinels and the nodes in the basins may improve the success rate.
In Transit Metastasis, Double or Multiple Drainage, Bypass and Atypical Metastasis In transit melanomas are characterized by an aggressive behavior with recurrence and are associated with a poorer prognosis than other types of metastasis. Intralymphatic trapping of melanoma
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cells between the primary and the regional lymph nodes seems to be the reason for local adhesion and breakout from the lymphatics. Nakayama et al. (2001) found a loss of heterozygosity (LOH) in 19 (76%) of 25 cases. The cancer cells of the in transit metastases were clonal in origin. In parallel with these results, free circulating DNA microsatellites with LOH can be found in melanoma patients. Taback et al. (2001) detected LOH in 32 of 57 patients (56%) and found a significant correlation between LOH and microsatellite marker D1S228 in the plasma of patients with advanced disease (P = 0.0009). The authors suggest that blood testing for circulating tumor genetic markers may provide prognostic information that can be turned to good account in further treatment planning. How in transit metastases in the subcutaneous tissue can be detected in early stages remains an open question. Preliminary data are discussed in some published case reports (Vidal et al. 1998). Multiple drainage pathways have been seen in more than half of the cases in melanoma studies. These results help surgeons towards correct staging (Mudun et al. 1996). With respect to bypass metastasis, direct lymphatic drainage from the skin tumor on the forearm to the supraclavicular lymph nodes, bypassing the axillary lymph node group, has been demonstrated by lymphoscintigraphy. This makes it possible to identify patients with such metastases before extensive axillary revision is planned or performed (Uren et al. 1996). Scintigraphic sentinel node imaging also reveals unexpected and atypical drainage patterns deviating from the conventional anatomical patterns following the lymphatics and their basins. Uren et al. (1993, 1994, 1996, 1998, 2000), for instance, in a case of a melanoma on the left side of the back, found direct lymphatic drainage to retroperitoneal and paravertebral nodes but no drainage to axillary or inguinal node fields or those in the triangular intermuscular space, which are the drainage areas that would normally be expected.
Interval Metastases Definition and Significance It must be recognized that interval metastases are similar to so-called in transit metastases in the gravity of their prognosis. In transit metastases are at least sometimes outgrowths of melanoma cells or cell clusters from lymphatics connecting the primary tumor region with the SLN, with infiltrative growth seen as cancer cell nodule(s) in the skin, while an ªinterval metastasisº is a metastasis in a tiny lymph node located as an ªintermediate stationº between the primary and the sentinel node. Interval nodes have been described as the forgotten SLNs (Uren et al. 2000). All lymph nodes that receive any of the total lymphatic drainage, regardless of their location, can contain malignant cells, and with these the initial stage of a metastasis. This is also consistent with the knowledge that the main draining lymphatics lead directly to welldefined lymphatic basins. The interval nodes, as transitory lymphatic stations, lie along mostly long lymphatic ways leading to the main basins and can sometimes be seen or detected using the gamma probe in the course of lymphatic mapping for the sentinel node biopsy. When these sometimes very small lymph nodes are disregarded and left behind, the resulting metastatic melanoma can be the source of a recurrence. Such interval nodes are more common with primaries on the trunk than with primaries on the legs. The hypothesis tested in Krew's studies was that micrometastases are just as likely to develop in an interval node as in the original SLNs in the welldefined basins. In his 13-year study program, Uren et al. (2000) found interval nodes in 148 (= 7.2%) of their 2,045 patients. Micrometastases were found in 14% of these nodes. The frequency of metastatic involvement of these nodes is similar to that of metastatic involvement of SLNs connected to a characteristic basin. The important conclusion drawn by Uren et al. (2000) is that surgeons should be advised to remove interval nodes along with the sentinel nodes, in order to avoid relapses in the intermediate region between primary and the SLN(s).
Morphological Stages of Development of Malignant Melanoma and Different Main Subtypes
Morphological Stages of Development of Malignant Melanoma and Different Main Subtypes Differential Diagnosis against Pigmented or Nonpigmented Malignant Schwannomas Sometimes it is difficult to delineate dysplastic nevi from malignant melanomas. Figure 3 is a macroscopic picture that may give an impression of the changes in pigmentation. Figure 4 shows the main histological features of a superficial spreading melanoma. This subtype is more suitable for preoperative labeling to detect sentinel node positions than are extended nodal types. In Figs. 5 and 6 nodal types of malignant melanoma are shown. In such cases sentinel node labeling can be performed before (when the tumor is small) or after excision of the tumor (in extended lesions).
Fig. 3. Dysplastic nevus of the skin. The nevus shows partial hyperpigmentation (discoloration) (from WHO, personal gift)
Pigmented or nonpigmented malignant schwannomas (Fig. 7) must be considered in the differential diagnosis against subcutaneous metastases from malignant melanomas. These tumors can be related to neurofibromatoses (Recklinghausen's disease).
Routine versus Elective Lymph Node Dissection Routine lymphadenectomy without exact correlation with localization of the primary, stage, age, etc. did not result in a statistically significant advantage. Therefore, primary lymph node dissection was abandoned by many surgical dermatologists for some time (Tilgen 1995). This has been confirmed in four randomized prospective clinical trials at Sloan Kettering Cancer Center (Hochwald and Coit 1998). However, elective lymph node dissection according to the SLN concept did give improved outcomes for patients aged < 60 years with melanomas 1±2 mm thick, with or without ulceration. Many studies have demonstrated that growth activity can be regarded as a parameter that is valuable in assessment of the risk of regional lymph node metastasis. Studies performed together with Korabiowska et al. (1994) showed that there was a good correlation between the proliferation of oral and skin melanomas and lymph node involvement, whereas there was no significant correlation with local tumor extension of the primary. In earlier investigations Kaudewitz et al. (1989) had already found a close correlation between Ki Fig. 4. Superficial spreading melanoma. Note the intraepithelial cancer cells within the epidermis surrounded by a halo, pigment incontinence with phagocytosis in the upper corium. Loosely spread melanoma cells directly subepidermal
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Fig. 5. Malignant melanoma that has developed in a pre-existing pigmented nevus (nodular type). Note the pronounced elevation with flattening of the epidermal relief (kindly donated by Prof. Kælmel, University of Gættingen)
Fig. 6. Nodal type of malignant melanoma. Only in the marginal area (left) is a small rest of a pre-existing pigmented nevus seen (kindly donated by Professor Kælmel, University of Gættingen) Fig. 7. Malignant schwannoma with positive S-100 reaction. Note: spindle-cellshaped malignant melanomas show the same histological pattern. They are also S100 positive. They can be discriminated by means of the antibody HMB45 (specific for malignant melanoma, schwannoma negative)
67 index and thickness of melanomas determined according to the Breslow scheme. In most recent investigations in melanomas of man, positive nodes have been found in more than 25% of melanomas > 0.75 mm thick. Alex et al. (1998), also investigating head and neck melanomas, suggested that preoperative lymphoscintigraphy and intraoperative mapping with a gamma probe was a powerful approach for exact localization of SLN(s). The 99mTc-labeling solutions used for lymphoscintigraphic diagnosis depend on the place of their production. The compounds and their frequency of usage on the different continents are listed in Table 5.
For animal studies, a mouse model has been suggested by Nathanson et al. (1997). The authors conducted a mathematical study to check for a connection between primary extension of melanomas and metastatic risk. They found that metastasis to SLNs increased in frequency with progressing tumor growth (g = 0.976, P = 0.001). In accordance with the findings of these human studies and animal experiments, surgeons and dermatologists advise that the lymphatic basin should be rechecked after extirpation of the SLNs. Furthermore, there is at least some hope of further improvements to treatment in connection with the introduction of interferon alpha 2b (IFNa 2b) therapy. The implications of introducing re-
Historical Overview of SLN Diagnosis for Melanomas Table 5. Use of radiopharmaceuticals for lymphoscintigraphy at the different continents Radiopharmaceutical
Continent where most frequently used
99m Tc-Human serum albumin (SHSA) a
North America
99m
Tc-Sulfur colloid (SC)
North America
99m
Tc-Nanocolloid albumin
Europe
99m Tc-Antimony trisulfide colloid a
Australia
See Bedrosian et al. (1999)
combinant IFNa 2b into adjuvant therapy regimens have been successfully tested by different clinical research groups in recent years (Kokoschka et al. 1990; Kirkwood et al. 1996, 1997, 2002 a±c; Hazard et al. 2000; McMasters et al. 2003); in spite of their results, however, it must be suggested that prospective studies with larger numbers of patients in the different stages are still needed. (For further information on interferon therapy the reader is referred to Chapter 33.) Overall, sentinel lymphadenectomy seems to yield a better basis for further treatment and also better final results than a ªwait-and-seeº strategy.
Historical Overview of SLN Diagnosis for Melanomas Despite all that has been said above, Munz et al. (1982) and Wanebo et al. (1985) had already used 99m Tc in the 1980s to identify the lymphatic drainage from cutaneous melanomas. Combined techniques using 99mTc and blue dyes are meanwhile excellent after intensive development and are used routinely. It is sufficient to administer 99mTc the day before surgery and inject the blue dye shortly before operation (Silverstein et al. 1994; Pijpers et al. 1995, 1997; Thompson et al. 1996, 1997). This method is also good from the point of view of operating teams and pathologists, the radioactive dose being kept as low as possible. The investigations of Alex et al. (1993, 1996, 1998) were focused on head and neck melanomas and showed that in cases in which SLNs were not recognized regional metastases later developed. Their group confirmed the greater benefit of the lymphoscintigraphic method (96%) than of blue dye lymphatic mapping (75%).
In recently published animal studies, a contrast agent comparable to Sinerem, Combidex (Advanced Magnetics, Mass., USA), was administered s.c. and made rapid localization and identification of peripheral SLNs possible (Rogers et al. 1998). These results added to the diagnostic staging of malignant melanoma achieved with MRI; however, at the moment they do not actually replace the nuclear medicine approach. In general, all criteria for a useful SLN biopsy, such as sensitivity, specificity, positive and negative predictive values, accuracy, false-positive and false-negative rates, are met in the case of melanoma diagnosis (Morton et al. 1984, 1992, 1993, 1997; Caldwell and Spico 1988; Gershenwald et al. 1988, 1999; van der Veen et al. 1994; Karpteijn et al. 1995, 1996, 1997; Krag et al. 1995; Albertini et al. 1996; Miliotes et al. 1996; Mudun et al. 1996; Reintgen et al. 1996, 1997; Ross 1996; Thompson et al. 1996, 1997; Leong et al. 1997; Ramnath et al. 1997). In recent years, several authors have clearly demonstrated the effectiveness of locoregional node dissection with biopsy (Bowsher et al. 1986; Caldwell and Spiro 1988; Drepper et al. 1993, 1994; Krag et al. 1995; Bostick et al. 1999; Peters et al. 1996; Winter et al. 1996; Alex et al. 1998; Bçchels et al. 1998; Cafiero et al. 1998; Dresel et al. 1998; Gogel et al. 1998; Goldfarb et al. 1998; Hochwald et al. 1998; Schneebaum et al. 1998). Experience clearly documents that precise surgical treatment of melanoma with wide excision and nodal staging is the most efficient procedure as far as saving life is concerned. Meanwhile, in many hospitals at least the blue dye method is used, with much higher lymph node detection rates than when it was first introduced. The sentinel node detection rates and the rates of false-negative cases recorded throughout the world in different centers and clinics are summarized in Tables 6 and 7. The question of whether the distance between the tumor and the site of injection of the radiocolloid modifies the result of lymphatic mapping in melanoma cases was investigated by Martinez-Essibano et al. (2001): after obtaining informed consent they performed two lymphoscintigraphies in each of 19 patients following narrow excisional biopsy. Intradermal injections were given 1.5 and 0.5 cm from the primary. Similar channels and sentinel nodes were revealed by both lymphoscintigraphies. This means that injections given less than 1.5 cm from the margins of a biopsy scar (or from the melanoma margins) still result in optimal results in terms of node labeling.
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Chapter 25 Malignant Melanoma Table 6. Series of melanomas treated with use of the sentinel node concept Authors
Year of publication
No. of cases
Routine lymph node dissection
Sentinel node detection rate Total
Dye
Probe
SN positive
SN false negative
Morton et al.
1992
223
+
82%
82%
±
22%
1%
Reintgen et al.
1994
42
+
100%
100%
±
19%
0%
Krag et al.
1995
121
±
98%
91%
98%
12%
±
Thompson et al.
1995
118
+
87%
87%
±
21%
1.70%
Albertini et al.
1996
106
±
96%
80%
±
15%
Leong et al.
1997
163
±
98%
74%
98%
18%
Lingam et al.
1997
35
±
100%
100%
±
26%
Morton et al.
1993
72
±
90%
90%
±
15%
Bostick et al.
1999
87
98%
94%
92%
17%
Gershenwald et al.
1999
612
93%
±
15%
Morton
1999
1135
97%
99%
19%
radiological lymph node dissection
reg. Recurrence
30%
1 case
Labeling method used
Bçchels et al. Temple London Experience 2000
2000 2000
micro metastasis
53.10%
99m
99.30%
56
99m
98%
Tc-sulfur colloid 10±15 MBq
Experience of management of the sentinel node biopsy and lymphatic mapping collected in most countries of the world in recent years (1998±2001) has made it clear that use of the SLN concept improves melanoma treatment. Therefore, the World Health Organization and the Sunbelt Melanoma Clinical Trial support the SLN concept as a standard of surgical care of malignant melanomas (see McMasters 2001). In the Sunbelt Melanoma Trial, 1184 patients with cutaneous melanomas 1 mm or more thick (Breslow) were analyzed for sentinel nodes using the isosulfan blue dye and 99mTc-colloid labeling methods (McMasters et al. 2001). In 24% of the cases sentinel node metastases were found. Blue dye staining was found in 86.3% of the histopathologically positive sentinel nodes.
95%
SLN detection rate
274
Tc-colloid
±
SLN in unpredicted localization 32%
±
1.30%
SLN scintigraphy, vs operation 2.3/ 2.2%
In 40 of 306 positive nodal basins (13.1%) the most highly radioactive node was negative, whereas another, less markedly radioactive, sentinel node was positive for tumor. Therefore, the authors recommend that all blue-stained nodes in which radioactive counts 10% or more above the ex vivo counts are measured and the hottest sentinel lymph node should be harvested for optimal detection of node metastases. Chao et al. (2002), also analyzing Sunbelt Melanoma Trial patients, report that early regional lymph node recurrence was very uncommon after sentinel node biopsy and lymphadenectomy, whereas patients with positive SLNs were more likely than those with negative SLNs to develop both local and transit recurrences and distant metastases within a short follow-up period.
Possible Ways of Searching for the Primary in Atypical or Nondermal Localizations Table 7. Further series treated according to the SLN concept (ELND elective lymph node dissection, SLND sentinel lymph node dissection) Authors
Year of publication
No. of cases
Labeling method used
SLN found
Rate of metastases
Pizzocaro et al.: Brescia Experience (Italy)
2000
71
99m
70/71 (98.5%)
9/69 (13%)
Fliquete et al.
2000
65
9 Blue dye
63/65 (97%)
8/65 (12%)
Tc colloid
Specific remarks
99m
Tc56 colloid 99m Tc-nanocolloid, 15±20 MBq
24/29 (83%)
6/24 (25%)
Elective node dissection in 5 (20%)
103 > 0.12 mm Breslow, Clark II
99m Tc-sulfur colloid
99%
Micrometastases in 10%
False negative rate: 8%
2001
Review of literature on head and neck melanoma cases (n)
99m Tc colloid/ blue dye solution
95±100%
Clary et al.
2001
152
ELND concept n = 329
SLND metastasis rate 20%
ELND metastasis rate 13%
Local recurrences SLND vs ELND: 72% vs 39% (p = 0.01)
Tremblay et al.
2001
36 (18 male, 18 female), mean Breslow thickness 2.35 mm
99m
SLN detection rate 97.2%
Average no. of SLN 1.97
8 (22%) positive SLN 2/7 positive nodes in complete node dissection
Mazzuka et al.
2000
Jacobs et al.
2001
Davison et al.
Tc-sulfur colloid 0.5 mCi
Possible Ways of Searching for the Primary in Atypical or Nondermal Localizations In approximately 5±10% of malignant melanomas detected by their metastatic spread it is difficult ± even in the case of terminal metastatic spread and on autopsy examination ± to find the primary. In such cases, all visible nevi are usually investigated both in vivo and at autopsy, but no primary with clear-cut indicators of malignancy (cellular atypia, pigment incontinence, and invasive growth) can be ascertained. However, as we know, there are three possible explanations for this. · It has been found on histological serial sectioning that small primaries of malignant melanomas can develop maximal regression with phagocytosis of the apoptotic or necrotic melanoma cells and loss of pigment from the hair in the
7.7±10.4%
pre-existing melanoma area. These facts can be ascertained by immunohistochemical staining with antibodies directed to macrophages such as CD68 or MAK387 and antibodies directed to S100 protein or the HMB45 antibody for staining of characteristic melanoma antigens, which do not require intact melanoma cells. In double staining, melanoma antigens can then be found in the cytoplasm of macrophages. · A second possibility is that dysplastic cells of nevi are drained into lymph nodes and develop their full malignancy there. · The third, and still more important, possibility must be seen in the fact that the primaries of malignant melanomas can be localized within the orifices of the body, meaning ± oral cavity ± anal circle mucosa (see Fig. 8) ± head sinuses
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that has to be borne in mind: that dendritic reticulum cells even show positive S100 protein reactions in their cytoplasm, but these cells can nearly always be delineated on the basis of their dendritic cytoplasmic structures.
Malignant Melanomas of the Anal Circle and the Rectum Search for the SLNs
Fig. 8. Malignant melanoma of the anal epithelium, with strong pigmentation in parts (overview). Note transition to rectal glandular structured mucosa in marginal areas. These tumors are sometimes wrongly diagnosed and not detected until an inguinal metastasis is histologically verified (picture kindly provided by Dr. Helmke, Department of Pathology, University of Heidelberg)
± rectal mucosa approximately up to Kohlrausch's fold ± pharyngeal mucosa ± esophageal mucosa ± vulva, vagina ± urethra. Very occasionally, primaries develop in ovarian teratomas or on the spinal cord. [For information on treatment of gynecological melanoma treatment readers are referred to Kroon and Nieweg (2000).] All these possible localizations must be checked when metastatic processes become obvious and no primary can be detected. In such cases with suspicious lymph node(s) in a defined basin, these can be investigated for melanoma cells after extirpation, histologically or before operation by aspiration cytology. In suspicious cells pigment can often be seen in the cytoplasm as a dark greenish-brown color after Giemsa staining. Antibodies directed to S-100 protein or the antibody HMB45 can make specific staining of the melanoma cells possible. There is only one fact
Compared with patients with cutaneous melanomas, those with anal or rectal melanomas (0.1± 4.6% of all anal malignancies; 2±3% of all malignant melanomas) have a worse prognosis (Ben Izhak et al. 1997; Helmke et al. 2001). The 5-year survival rate is less than 10%, which is the same as in cutaneous melanoma stage IV (Coit 1993). The reason for this unfavorable biological behavior is not fully understood (unfavorable location? different genetically based tumor development and growth activity than in UV-induced cutaneous melanomas?) (Balch et al. 1979; Liw et al. 1996). Only one point seems to be clear: in contrast to malignant melanomas located higher in the rectal mucosa, melanomas of the anal circle may invade hemorrhoidal veins early and metastasize directly into the lungs via the azygos veins. In patients with rectal melanomas, in the search for SLNs the same principles can be applied as in the case of rectal cancer (see Chapter 26, pp. 391± 393). On the basis of new developments, peritumoral 99mTc-labeling and the search for retrorectal lymph nodes using the gamma probe seems to be a method that would reward further development. In melanomas of the anal circle (see Fig. 8), as well as rectal amputation the search for retrorectal lymph nodes (followed by en bloc resection) is obligatory in cancer clearance. In addition, it is necessary to search for inguinal and/or para-iliacal lymph nodes as possible sentinel nodes. Individual surgical treatment along these guidelines is the method of choice (Weinstock 1993; Whooley et al. 1997). So far there are no data on benefits of adjuvant chemotherapy (Vorpahl et al. 1996). In conclusion, no scheme has yet been developed that would make it possible to find a single SLN or node groups in the different possible basins.
Possibilities for Cytopathological Confirmation of the Diagnosis of Malignant Melanomas
Immunohistochemical Support in the Diagnosis of Dysplastic Nevi and Early Invasive Malignant Melanomas For the diagnosis of dysplastic nevi and very early intraepidermal melanoma development, as well as early stromal invasion, immunohistochemical double staining, for instance using antibodies directed to S100 protein and proliferative nuclear antigen (Ki 67, MiBI), is very helpful. Double staining of S100 protein and Ki 67 (MiBI) active against the proliferation acthive protein helps to exclude increased proliferation, and with this malignancy, on the one hand (Fig. 9), or to confirm increased proliferation of S100-positive
nevus cells that are already atypical on the other (Fig. 10). In addition, early stromal invasion can be detected by these immunohistochemical staining procedures.
Possibilities for Cytopathological Confirmation of the Diagnosis of Malignant Melanomas in Cancer-infiltrated Lymph Nodes in Cases with Primarily Undetected Primaries In cases in which no locoregionally located malignant melanoma or other primary has been detected, suspicious, mostly enlarged, lymph nodes can be aspirated by way of a fine needle and the smears can
Fig. 9. Dermal nevus cell nevus. The intraepithelial and the dermal nevus cell populations are intensively stained with the antibody directed to S100 protein. Only a few nuclei are stained with MiBI, almost exclusively basal cells of the epidermis
Fig. 10. Small sector of a dysplastic nevus cell nevus. Besides basal cells, in some higher cell layers a few nevus cells (S100 protein, positive with brownstained granules) are also MiBI positive. Some intraepithelial nuclei show apoptotic changes
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Chapter 25 Malignant Melanoma Fig. 11 a±d. Diagnosis of occult malignant melanomas in fine-needle aspiration cytology (FNAC) from lymph nodes (Giemsa and immunohistochemical stainings). a FNAC of an amelanotic malignant melanoma with partly epithelial layered cell populations; no pigment can be detected. Note round nuclei, some with central prominent nucleoli. b Amelanotic malignant melanoma, same tumor, stained with the melanoma-specific antibody HMB45. c Malignant melanoma cell populations with strongly positive reaction using antibodies directed to the mesenchymal cell marker vimentin (intermediary filament). Note: All malignant melanomas are vimentin positive
Exclusion of Systemic Disease in Malignant Melanoma Cases and N-staging Supported by FDG-PET Fig. 11 d. Malignant melanoma cell populations stained with antibodies directed to cytokeratins. Note: Newer results show that a small percentage of malignant melanomas show coexpression for cytokeratins. The cytokeratin positivity can result in a pitfall with the diagnosis of carcinoma
be analyzed by Giemsa staining and immunohistochemically. Some characteristic stainings, illustrated in Fig. 11 a±d, document the characteristic antigenic features of malignant melanomas.
Exclusion of Systemic Disease in Malignant Melanoma Cases and N-staging Supported by FDG-PET N. Avril, W. Weber, M. Schwaiger
Introduction In patients with cutaneous malignant melanoma the clinical demands made of imaging modalities are the identification of locoregional lymph nodes and of distant metastases (Macfarlane et al. 1998). FDG-PET has been successfully applied in the detection of metastases from malignant melanoma in high-risk patients (tumor thickness: > 1.5 mm or invasion of Clark level IV). In numerous studies, FDG-PET has been shown to be at least as effective as combined standard diagnostic tests including CT of chest and abdomen, MRI of brain, and ultrasound examination of the abdomen and of the regional lymph nodes (Figs. 12, 13). It is clear that in cases with positive node basin(s) sentinel node staging using the blue stain and/or 99mTc method should only be performed when diagonal metastasis seems possible or becomes obvious.
Fig. 12. Melanoma with axillary lymph node metastases. The coronal PET image shows an intense focus of increased metabolic activity in the region of the left axilla, representing a single axillary lymph node metastasis
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Fig. 13. Melanoma with inguinal lymph node metastasis. The coronal PET image demonstrates areas of focally increased metabolic activity in the left inguinal region, representing lymph node metastases
Locoregional T- and N-staging Macfarlane et al. (1998) conducted a preoperative study in 23 patients with primary lesions larger than 1.5 mm who were scheduled for lymph node dissection with FDG-PET. In 13 of these patients therapeutic lymph node dissection (LND) of 14 node basins was performed, while 9 patients underwent elective LND of 10 node basins. With reference to the regional node basins, PET imaging demonstrated 11 true-positive, 10 true-negative, 2 false-negative, and 1 false-positive findings, resulting in an overall accuracy of 88%. It is important to note that PET failed to detect micrometastatic disease; nevertheless, Holder et al. (1998) suggested a role for FDG-PET as a first-line tool in the staging of melanoma. They examined 76 patients with stage II±IV malignant melanomas to compare FDG-PET and CT scanning. In 103 PET scans a sensitivity of 94.2% and a specificity of 83.3% were noted, as opposed to 55.3% and 84.4%, respectively, for CT.
Misinterpretations in the PET staging investigations occurred in cases with papillary carcinoma of the thyroid, bronchogenic carcinoma, inflamed epidermal cyst, Warthin's tumor of the parotid gland, surgical wound inflammation, leiomyoma of the uterus, suture granuloma, and endometriosis. Such lesions must be clinically excluded by topographical reflections and by the exclusion of inflammatory lesions, etc. The 4 false-negative scans were thought to be due to small (< 0.3±0.5 cm) and diffuse areas of melanoma without a mass effect. Several recent studies have demonstrated the limited value of anatomically based CT scans for evaluation of stage III patients. In a prospective study, Tyler et al. (2000) performed 106 whole-body PET scans in 95 patients with clinically evident stage III lymph node(s) and/or in transit melanoma. In all, 234 areas were evaluated pathologically, 165 of which were confirmed by histological examinations to be melanoma. PET scanning identified 144 of the 165 areas of melanoma, yielding a sensitivity of 87.3%. The 21 areas of melanoma that were missed included 10 microscopic foci, 9 foci less than 1 cm in diameter, and 2 foci greater than 1 cm. There were 39 areas of increased PET activity that were not associated with malignancy, resulting in a positive predictive value of 78.6%. Of the 39 false-positive areas, 13 could be attributed to recent surgery, 3 to arthritis, 3 to infection, 2 to superficial phlebitis, 1 to a benign skin nevus, and 1 to a colonic polyp. However, by employing pertinent clinical information, the predictive value of a positive PET scan was improved to 90.6%. Thirty-six (19.7%) of the total of 183 abnormal areas scanned by PET proved to be unsuspected areas of metastatic disease. These findings led to a change in the planned clinical management of 16 patients following 106 PET scans (15.1%). Eigtved et al. (2000) considered the value of FDG-PET in the detection of ªsilent metastasesº from malignant melanomas by comparing FDGPET findings and those obtained with conventional imaging methods. Thirty-eight patients with clinical stage II (local recurrence, in transit, and regional lymph node metastases) or stage III (metastases to other sites than those in stage II) were included in the study. For all foci, FDG-PET had a sensitivity of 97% and a specificity of 56%, as opposed to 62% and 22%, respectively, for the conventional imaging methods used. For intra-abdom-
Accumulating Experiences in Sentinel Node Detection in Malignant Melanomas
inal foci, the sensitivity and specificity were 100% for both imaging approaches. However, corresponding figures for intrathoracic and pulmonary metastases were 100% and 33%, respectively. An important finding in this study was that 34% of patients would not have been staged correctly by conventional methods alone. However, Krug et al. (2000) were not able to confirm such positive results for PET imaging. In a retrospective analysis of 94 melanoma patients, including 40 patients with evidence of lymphogenous and 42 with evidence of hematogenous metastasis, they found FDG-PET to be inferior to CT in the diagnosis of lung and liver metastases. In a meta-analysis of the 13 papers in the literature on detection of recurrent melanoma by FDG-PET, an overall sensitivity of 92% (95% confidence level 88.4%±95.8%) was calculated, together with an overall specificity of 90% (95% confidence level 83.3±96.1%) (Schwimmer et al. 2000). From the limited data available a directed change in management value of 22% was indicated for FDG-PET. Overall, FDG-PET was found to be insensitive as an indicator of occult regional lymph node metastases in patients with melanoma, because of the small tumor volumes in this population (Wagner et al. 1999). In a prospective study the same authors included cutaneous melanoma with a Breslow's depth greater than 1 mm (stage T2±4N0M0) or localized regional cutaneous recurrence (stage Tx,N2b,M0). Eighty-nine lymph node basins were evaluated by FDG-PET and sentinel node biopsy in 70 evaluable patients. Eighteen patients (25.7%) had lymph node metastases at the time of FDGPET imaging: in 17 these were confirmed by sentinel node biopsy (24.3%) and in 1 by follow-up examination (1.4%). The sensitivity of sentinel node biopsy for detecting occult regional lymph node metastases was 94.4%, and the specificity was 100%. The sensitivity of FDG-PET was 16.7%, and its specificity 95.8%. These results clearly indicate that FDG-PET cannot help in the staging of regional nodes in patients with clinically localized melanoma. The inability of PET to identify microscopic disease suggests that it is of limited use in evaluating patients with stage I±II disease. Detection of brain metastases is also limited owing to the high glucose utilization of normal gray matter. Finally, small lung metastases may be detected with higher sensitivity by spiral CT of the chest.
Concluding and Comparative Remarks However, FDG-PET is a sensitive method and superior to conventional methods for detecting widespread metastases, and it is useful as a supplement to clinical examination in melanoma staging.
Accumulating Experiences in Sentinel Node Detection in Malignant Melanomas Report given by Dråger et al. in Berlin in December 2000 Between 1995 and 2000, a total of 863 patients with malignant melanomas were seen in the Department of Dermatology, Charit Berlin, and 1145 sentinel lymph node biopsies were performed in all these patients. When the cancers were located on the trunk, upper arm, and thigh and in the head and neck region, SLN excision was combined with lymphoscintigraphy-guided en bloc excision from the primary along the lymphatic pathways to the SLN(s). In their latest report, Dråger et al. (2001) summarized the results of a melanoma consensus conference held in 1999 in Berlin: · The search for SLN(s) is indicated for melanoma patients with Breslow thickness > 0.75 mm and/or Clark level > 3 (pT2±4). · The sentinel node search can be performed in patients with melanoma and also in patients who have already undergone a wide excision (>1 cm safety margin). The authors explicitly emphasize that after excision the injections must be given very carefully, because lymphatic pathways and flow can be altered. The following points are seen as essential: · Performance of a lymphatic outflow scintigraphy (LAS) using 99mTc-nanocolloid, 40±20 MBq injected around the tumor. · Intracutaneous injection 0.5 cm away from and around the tumor or the scar after the melanoma operation, optimally 20±24 hours before operation. · Scintigraphy should be stopped when a clear lymphatic pathway and the location of the SLN appear. The positions of the SLN(s) and pathway(s) are then marked distinctly on the skin. · Double injection (blue dye and 99mTc-nanocolloid) is essential in head and neck melanomas and in perianal and genital melanomas owing
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Chapter 25 Malignant Melanoma
to the complexity of lymphatic drainage, to different basins in some cases. The current results obtained by the Berlin group in investigations on 863 patients with 1145 SLNs are summarized in Tables 8±11. Sugranes et al. (2001) give an overview about the positive and negative rates for SLNs in dependence on the clinical stage, pooling stages I and II for comparison with stage III. In stage III the sentinel positive rate is approximately threefold that in stages I and II (Table 12). A short overview of the overall survival rates related to the different melanoma stages reported by Dråger et al. (2001) is shown in Table 13. Whereas in stage pT3 (1.51±4.0 mm invasion) the primary is still resectable and elective lymph node dissection (ELND) is still possible, these options rapidly recede in the presence of pT4 tumors.
Table 8. pT Classification (UICC) of 863 patients with newly diagnosed cutaneous malignant melanoma with 1145 SLN Patients n
n
%
pT1
2
0.2
2
0.2
pT2
404
46.8
549
47.9
pT3
363
42.1
474
41.4
pT4
94
10.9
120
10.5
Total
863
100.0
1145
100.0
Table 9. Variability of the lymphatic system. Results of identification and localization of the SLN by use of a combination of preoperative lymphatic outflow scintigraphy (LAS), intraoperative use of hand-held gamma probe and intraoperative coinjection of a vital dye (LM) in 863 patients with newly diagnosed cutaneous malignant melanoma with 1145 SLN Patients
SLN %
n
%
1
646
74.9
646
56.6
2
166
19.2
332
29.0
3
37
4.3
111
9.7
4
14
1.6
56
4.9
863
100.0
1145
100.0
total
Country
Germany Austria Total
Patients with SLNB n
ELND in case of positive SLN n
%
1591
255
16.0
290
46
15.9
1881
301
16.0
Table 11. Examination of SLN and Non-SLN. ELND was performed after SLNB. SLN and Non-SLN were examined by histopathology and immunohistochemistry in 327 cases (100%)
n %
SLN negative/ non-SLN negative
SLN positive/ non-SLN negative
SLN positive/ non-SLN positive
SLN negative/ non-SLN positive
217
67
32
11
66.3
20.5
9.8
3.4
SLN %
n
Table 10. Patients with SLN biopsy (SLNB) and number and percentage of positive SLN (at histopathology and immunohistochemistry) with consecutive elective lymph node dissection (ELND) ± data from 43 centers in Germany and Austria
These data may be used as the basis for comparative studies (5-year and 10-year survival rates) after SLN dissection and after detection of positive SLNs followed by more extensive controlled node dissection in the different basins.
Does it depend on Topographic Constellations whether Localization of the SLNs is Calculable or Incalculable? In the case of melanomas on the legs, femoral and inguinal lymph nodes can be viewed as the sentinels, because the small popliteal nodes are very difficult to detect and sometimes tumor cells bypass them, leading to skip metastases. In rarer cases, however, especially in melanomas localized laterally on the foot and lower leg, the popliteal lymph nodes can be the sentinels with enlargement of volume and outgrowth of the cancer. One third of primaries are located in the face (often on the cheeks and in the temporal region). For primaries in these regions, the buccal, facial, submental and cervical nodes are the ones of first involvement (see also Chapter 23). However, there is no single sentinel node that can be assumed to
Accumulating Experiences in Sentinel Node Detection in Malignant Melanomas Table 12. Comparison of positive SLNs of the stages I and II with stage III Stage I/II (n)
24
SLNs harvested
34
SLN pos.
6
neg.
28
Control lymphadenectomy No. of nodes
pos.
160
0
Stage III
16
SLNs harvested
22
SLN pos.
14
neg.
8
Control-lymphadenectomy (n) No. of nodes
pos.
In SLN pos. cases neg.
89
44
45
Table 13. Overall survival rates of patients with primary malignant melanoma (clinical stage I of the skin in dependence of pT classification (UICC), i.e. in dependence of Breslow tumor thickness) Reference
Comments
Balch et al. 1998
All tumor locations, with and without ELND
pT2 (0.7±1.5 mm)
pT3 (1.51±4.0 mm)
pT4 (> 4 mm)
87%
66±75%
47%
90%
67%
43%
5-Year overall survival
99%
91%
60%
10-Year overall survival
96%
88%
60%
5-Year overall survival
100%
91%
52%
10-Year overall survival
100%
88%
52%
100%
90%
66%
100%
96%
87.5%
5-Year overall survival Orfanos et al. 1994
All tumor locations, with and without ELND 10-Year overall survival
Winter et al. 1996
All tumor locations, with ELND
Tumor location on the trunk, with continuity dissection (including ELND)
Tumor location on the upper arm, with continuity dissection (including ELND) 5- and 8-Year overall survival Tumor location on the thigh, with continuity dissection (including ELND) 5- and 8-Year-overall survival
be especially important. The significance of the jugular vein junctional node seems to be quite similar in tumors of ear, nose, and throat. More interest attaches to the question of the sentinel nodes when a melanoma is located on the trunk, especially in the mid-line of the back, or in the thoracic or the abdominal region on the ventral side. Concerning these options, there may also be two or three SLNs, e.g., in the case of primaries localized medially on the trunk with sentinels at
both sides in the axillary or inguinal node groups or in the contralateral axillary and inguinal nodes. When sentinel nodes corresponding to primaries on the back were looked for, in a few cases sentinels were also observed in retroperitoneal abdominal areas. For these locations of the primary, labeling of a sentinel node would be helpful, because too-late extirpation of initial metastases, e.g. in axillary node(s), would decrease the chance of survival.
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Chapter 25 Malignant Melanoma
Performance in Labeling of SLNs in Cases with Skin Tumors In injection of blue dye solution and/or 99mTc-nanocolloid solution the assumed direction of lymph flow is important in the decision on whether injections of the labeling solution should be given in a circular or semicircular formation. For instance, when the malignant melanoma is located on the skin of the trunk a circular arrangement of injections around the malignant melanoma is appropriate in practically all cases, and when the primary
has been excised and scars have formed, precursive and perifocal ªcircular injectionº is also necessary, because diagonal (axillary and inguinal lymph nodes) or bilateral (axillary or inguinal) metastasis is possible (see Fig. 14). When the primary is located on the face or extremities (arms, legs), where lymphatic flow normally runs in only one direction semicircular injection seems to be the method of choice (Figs. 14, 15). This helps to restrict the quantity of solution injected or concentrate the 99mTc dosage on the side where the semicircle of injections is given.
Fig. 14. Different localizations of cutaneous malignant melanomas: circular and semicircular injection of the labeling solution referred to localization of the primary and possible drainage direction of the lymphatic flow
Accumulating Experiences in Sentinel Node Detection in Malignant Melanomas
nomas of the trunk, demonstrating the possible directions of the lymphatic flow, is shown in the Figures 17 a and b. · Puncture or particle biopsy of malignant melanomas can propagate cancer spread and contrast solutions must therefore be injected outside the neoplastic lesion in every case. · Because removal of the primary is an urgent priority and because of difficulties in delineating the margins of the neoplastic infiltrations in malignant melanoma cases, the SLN search (see Fig. 17) is often started after excision of the primary with monitoring for tumor-free margins. In such cases the SLN search is done in the same way, by injecting the labeling solutions(s) outside the wound or scar formation. The rate at which popliteal lymph nodes are identified as sentinel nodes is very low. Thompson et al. (2000) looked for the frequency of metastatic involvement of these nodes in their collective of 4,262 cases with malignant melanomas located distal to the knee. Only in 13 cases (0.31%) were popliteal metastases found. The conclusion of the authors is that surgical popliteal clearance should only be performed when there is clinical suspicion of popliteal metastatic involvement. Demonstration of Blue Dye and in Malignant Melanoma Cases
Fig. 15. For malignant melanomas of the dorsal side of the body the same criteria apply as for ventral melanomas. Note the possibility of interval metastases in popliteal nodes
Details of Injection Technique for Patent Blue Dye Solution and/or 99mTc-nanocolloid Solution Some important points must be observed: · During the injection the angle of the needle to the surface of the skin should not be more than 158 (see Fig. 16). · The injection should be performed in the opposite direction to the melanoma infiltration. A four point injection scheme, used e.g. in mela-
99m
Tc-labeling
Figure 18 shows the labeled lymphatic flow from distal to proximal in the arm, marking the direction of the drainage. Figure 19 shows early labeling of the SLN in the right axilla. The storage of the nanocolloids can be perfectly seen as soon as 20±45 minutes after injection and is still visible next day for the intraoperative search with the gamma probe. In Fig. 20 fast labeling of two scattered lymph nodes is shown in another case. This picture includes the possibility of skip metastasis. Figure 21 demonstrates a lymph node that is the first to show up as labeled after injection of the nanocolloids and is obviously the sentinel node, but further secondary node labeling is already visible 45 minutes after injection. Figure 22 documents a malignant melanoma with the primary located on the back. After peritumoral injection rapid drainage to the right-sided axillary lymph node(s) developed, but very soon drainage to the left-sided axillary nodes also started.
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Chapter 25 Malignant Melanoma Fig. 16. Injection technique before tumor excision in malignant melanoma cases. The same injection technique can be used when the solution(s) is/are injected after primary excision
Fig. 19. Between 20 and 45 min the SLN in the right axilla can be localized in a gamma camera study; it needs to be marked on the skin surface to allow its localization next day in the operating room Fig. 17 a, b. The four-point injection sites to be used before tumor excision in the case of malignant melanomas on the trunk. Lymphatic drainage can take a one b two or in some cases more directions. In peripheral melanoma localizations (face, legs, hands, etc.) injections need only be given in a semicircle of sites
Fig. 18. After injection of more than 30 MBq 99mTc-nanocolloids at regular intervals around the melanoma, the lymphatic drainage from the tumor site can be visualized (right arm)
Fig. 20. If the sequence of the images is fast enough (5 s/image), the dynamic of the lymphatic flow can be followed and the first lymph node, which is the sentinel, can be defined, because often a second lymph node rapidly appears in the scan. This difference is important, because in theory a skip sentinel node is possible
Accumulating Experiences in Sentinel Node Detection in Malignant Melanomas
Fig. 21. Image recorded 45 min after peritumoral melanoma injection of 99mTc-nanocolloids in the right leg, already showing more lymph nodes in the iliacal region, because the sentinel has already been passed and the second and third nodes are visualized. We therefore prefer to record dynamic images
Fig. 23. If a skip metastasis from the lesion is seen on sentinel node scintigraphy of the lower leg, the sentinel node may be in the iliacal area, either superficially or deep in the pelvic area, which needs a more complicated surgical approach. To differentiate between superficial and deep lymph nodes, image fusion between CT and sentinel node SPECT may be helpful. The images show a typical iliac superficial sentinel node
Fig. 22. Peritumoral melanoma injection in the back, with rapid lymphatic drainage to the right axillary lymph nodes but also to the left axilla. Drainage starts at the bottom of the image on the left (arrow). An image of the left axilla shows lymph node uptake there as well
Figures 23 and 24 illustrate a sentinel node scintigraphy in a case of malignant melanoma on the leg, with labeling of a superficial iliacal SLN and also early labeling of a second SLN in the pelvic area, which may have developed because the superficial iliacal node has been bypassed. In contrast to typical iliac superficial sentinel node shown in Fig. 24 a sentinel node of a leg melanoma in the pelvic area (Fig. 25) seems to be really rare.
Fig. 24. Typical late image (60 min after injection in the left leg), with several 99mTc-nanocolloid-stained lymph nodes. The first lymph node to appear is the sentinel. The lower image corresponds to a higher plain in scintigraphic control, illustrating the state of flow of the labeling solution to the iliacal lymph nodes in the pelvis at a later time
Examples of Daily Routine In this section, results of patent blue labeling techniques obtained in individual cases are shown. Figure 26 illustrates the strategy of patent blue labeling with semicircular injection around a scar with multifocal melanoma recurrence. Fig. 27 shows lymphangiogram using patent blue injected intrader-
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Chapter 25 Malignant Melanoma
Fig. 25. Solid sentinel lymph node metastasis in pelvic site in a case with malignant melanoma of the leg (Skip-metastasis?)
Fig. 27. Injection of blue dye solution subcutaneously into dorsum pedis for SLN-labeling. A blue-stained inguinal node is seen (:) and an unstained lymph node located on the right side (*) (Fig. 28)
Figs. 26±28. These illustrations were kindly made available to us by Dr. Kretschmer, Department of Dermatology, University Clinic of Gættingen Fig. 26. Injection of patent blue solution strongly intradermally in a case with extensive acrolenticular malignant melanoma (ALM) of the planta pedis.
mally on the dorsum pedis after amputation of the second toe in a case with ALM. Figure 28 shows a patent-blue-labeled SLN in the inguinal basin in a patient with malignant melanoma of the foot. A small, easily portable, gamma probe device and the results of labeling a malignant melanoma on the back and the regional lymph nodes are demonstrated in Figs. 29±33 b. Fig. 34 a and b demonstrate the excision of a blue stained and a brownish unstained SLN in another case. In Fig. 35 a±c partly labeled (c: focally
Fig. 28. Patent blue-labeled SLN in the inguinal basin in a case of malignant melanoma of the foot. To the right of the stained lymph node an unstained, slightly prominent lymph node can be seen located in the fatty tissue (see *)
blue stained) partly unlabeled enlarged metastatic lymph nodes are shown. Cytological, Histopathological, and Immunohistochemical Investigations of the SLN(s) for Metastasis of Malignant Melanomas J Technique of Lymph Node Investigation Various general points must be observed: · Small lymph nodes < 5 mm in maximal thickness can be cut into two halves for paraffin embedding.
Accumulating Experiences in Sentinel Node Detection in Malignant Melanomas
Figs. 29±35. Figures donated by Dr. Brodersen, Chief, Hannover, Dermatological Surgical Unit of the Medical Faculty, Hannover, illustrating a small, easily portable, gamma probe device and the results of labeling the area of a malignant melanoma on the back and the regional lymph nodes Fig. 29. A new, very good and compact gamma probe device that is suitable for daily use in a practice (Navigator GPS)
· Nodes that are larger, but still 7 mm in maximal thickness, should be cut into two outside slices and a middle slice. · All larger nodes should also be cut into slices, the number depending on their thickness, with none of the slices thicker than 2 mm, or up to a maximum of 3 mm. Every cut surface can be used for imprint cytology. In Giemsa stainings the intracellular melanoma pigment can be seen as greenish-brown coloration. In other smears immunohistochemical stainings for S100 protein and HMB45 can be performed. This additional imprint cytology and the possible immunohistochemical stainings are helpful as they can give information on the superficial layer of the node slices; after paraffin embedding and initial cutting procedures (which are necessary to obtain the whole surface of the sections used for investigations) the superficial parts are lost. The thickness of the slices differs from one pathology laboratory to another. In some, slices little more than 1 mm thick are taken and at least five slices of each node. (This is the policy followed by Professor Wagner in Augsburg, Germany, for example.) However, it is clear that special techniques are needed to cut such thin slices from the nodes. According to Wagner's procedure the five slices are brought in one block and at least five sections of each block are obtained. Nonetheless, there are
Fig. 30. Cutaneous malignant melanoma on the back over the medial margin of the shoulder blade with localization (x) of a subcutaneous lymph node in a paravertebral site above the primary. Note the clearly detectable discoloration of the prominent malignant melanoma (nodal type). Note the subcutaneous lymph node (marked by cross) sited medially above the tumor, which may be an in transit metastasis. A pigmented benign seborrhoic verruca is seen to the side of the melanoma at the same level
many other laboratories in which the principles listed above are practiced and serial sections are taken from every portion of the node at intervals of about 50 lm. This means about 50 sections from every slice. These sections are alternately stained with HE and by immunohistochemical techniques, at present with the aid of immunohistochemical staining machines. At this juncture it must be pointed out that these investigations, which are needed when the SLN concept is to be applied, require high staffing levels for performance of the staining and of the examinations. The procedures can hardly be performed in institutes where the levels of investment are low in terms of personnel and of finance for equipment. Therefore, health policy must be changed to take account of such modern and extremely important advances in medical treatment strategies.
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Chapter 25 Malignant Melanoma Fig. 31. Same case as in Fig. 30: view from directly above showing intradermal injection of patent blue diluted 1 : 1 with the local anesthetic agent Xylonest 1%. The labeling solution should not be injected > 1.5 cm away from the lesion. The injection sites are arranged in a triangle (blue dots)
Fig. 32. Same lesion as in Figs. 30, 31; the skin has been incised in a dumbbell-like shape with the recommended distance from the primary lesion observed. A prominent, partly depigmented node can be clearly seen within the lesion at this higher magnification
Improvement of Diagnosis with Immunologically Supported Methods As already pointed out, the detection of single tumor cells or tumor cell clusters in serial sections of lymph nodes is made easier by immunohistochemical staining methods using antibodies
against S100 protein or the antibody HMB45, because amelanotic tumor cells can be similar in appearance to sinus histiocytes or reticulum cells. These staining techniques help to avoid false-negative diagnoses (see also Bachter et al. 1998). For pathologists, it should be pointed out that dendritic reticulum cells can be stained with antibodies directed to S100 protein. However, these cells are localized mainly in the germinal centers of the Bfollicles, whereas incipient tumor cell metastasis is mostly found in marginal sinuses. Bartolomei et al. (1998) found that use of the same or other antibodies, or even fragments of these, e.g., Fab' fragments, for clinical radioimmunodiagnosis yielded no advantage in the detection of sentinel nodes. Comparison of routine histological examination of SLN with reverse transcriptase-polymerase chain reaction (RT-PCR) investigations carried out by Shivers et al. (1998) showed differences in recurrence rates and overall survival, with a P-value of 0.02 for disease-free and overall survival. These results show the superiority of RT-PCR over simple histological examination, but give no insight into how it compares with immunohistochemistry.
Method for Detection of Tyrosinase Transcripts in Blood This molecular biological method was initially used in blood (Johansson et al. 2000), but modifications have made it suitable for use in investigations of tissues in addition. The individual steps in probe analysis are detailed below.
Accumulating Experiences in Sentinel Node Detection in Malignant Melanomas
Fig. 33 a, b. Preparation in direction of a labeled, already palpable, lymph node. a The node can already be palpated with the instrument in the subcutaneous fat tissue. b The
small blue and brownish lymph node is now visible and can be removed
Fig. 34 a, b. Removal of small sentinel nodes from the axilla of a further melanoma patient. a The node is intensely
stained with patent blue after labeling. b The SLN detected by the gamma probe is removed
Fig. 35 a±c. Lymph node metastases of a malignant melanoma removed after labeling with patent blue. Note the dark
brown, strongly pigmented, partly prominent metastatic nodules within the lymph nodes
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Chapter 25 Malignant Melanoma
· For detection of tyrosinase transcripts in the peripheral blood 10 ml of blood is taken into a sterile EDTA monovette and the following procedures are followed: ± Centrifuge at 1000 rotations/min (rpm), 10 min, 4 8C. ± Decant plasma. ± Dissolve cellular sediment in 5 ml lysis buffer, shake carefully and transfer the mixture to a 50-ml tube. ± Make up to 50 ml with buffer. ± Incubate for 10 min. ± Lyse the erythrocytes and perform a second centrifugation (1000 rpm, 120 min, 4 8C). ± Dissolve pellet in 1 ml PBS buffer solution and carefully resuspend the cells. ± Wash first with 25 ml PBS buffer solution in 50-ml tubes and then with 1 ml PBS buffer solution in 2-ml tubes, with same conditions for centrifugation (1000 rpm, 10 min, 4 8C), deep-freeze the pellet (after shock-freezing), and store at ±80 8C. ± For the sensitivity check, record corresponding values in RT-PCR blood of a healthy person after infecting it with the ME WO melanoma cell line in dilutions of 106 to 102 cells in 10 ml blood. · mRNA extraction ± Use an mRNA isolation kit (Oligotex/Direct mRNA MidiKit (Qiagen) as directed by the manufacturer. ± For investigations of the pellets prepared from the blood specimens repeated aspiration of the probe through a cannula in a 5-ml one-way syringe is sufficient. ± After adding the dilution buffer solution and centrifugation (10 000 rpm, 17 min, 28 8C) incubate with Oligotex solution at room temperature. ± Centrifuge again to obtain a pellet, which is resuspended with washing buffer and inserted in one of the columns provided with the Oligotex kit. After repeated washing and centrifugation (1 min, 14 000 rpm, 25 8C) dissolve the mRNA in a heated elution buffer (70 8C). ± Take the amount of mRNA needed for cDNA synthesis immediately and use this for further investigations. Deep-freeze the rest at ±80 8C. · c-DNA synthesis: Synthesize cDNA as a starting point for the PCR directly after RNA extraction, using the GIBCO preamplification system as instructed by the manufacturer.
± Mix 100 ml of the prepared RNA with 2 ll of Random Hexamer Primer. ± Incubate the mixture at 70 8C (and then cool it on ice). ± Add a reaction mixture made up of: 2 ll PCRbuffer (200 mM Tris HEE, pH 9.4, 500 mM KCl), 2 ll MgCl2 (25 mM), 1 ll deoxynucleotide triphosphate (dNTP, dATP, dCTP, dTTP, dGTP each 10 lM), 2 ll dithiothreitol (DTT 0.1 M). ± After incubating this for 5 min at 25 8C 1 ll add superscript reverse transcriptase (200 U/ ll) and incubate the probes (5 min at 25 8C, 50 min at 42 8C, and 15 min at 70 8C). ± After cooling the reaction vessels on ice, add 1 ll RNaseH (2 U/ll) for degradation of RNA not transcribed to cDNA. · RT-PCR: Prepare the following mixture for the reaction: 1.5 ll sterile H2O; 7.5 ll PCR buffer solution; 7.5 ll MgCl2 (25 mM); 3.0 ll dNTP (10 mM dATP, dCTP, dGTP, dTTP each); 0.4 ll Apli Taq Polymerize (5 U/ll); 1.5 ll of each primer. ± Add 3 ll cDNA to this reaction mixture. ± Cover the solution with a drop of mineral oil. ± For PCR in the thermocycler, after incubation of the probes for 5 min at 90 8C, run 30 cycles (denaturation for 90 s at 94 8C, annealing for 90 s at 60 8C, extension for 90 s at 72 8C). ± To evaluate the quality of extracted mRNA for each probe, first perform a PCR under the mentioned conditions with primers for the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This procedure can be used as a control for correct preparation of the mRNA transcriber to cDNA. ± When the result of GAPDH RT-PCR is negative, repeat the procedures, with extraction of mRNA or cDNA synthesis. ± With the same PCR conditions, use the primers for the gene encoding tyrosinase. ± For the PCR tested using an external pair of primers (HTYRI and II), first amplify a 284nucleotide base pair. ± Dilute the PCR products 1 : 50 in water for a second PCR using an internal primer pair, HYTR 3 and 4, instead of DNA in the reaction process. · The procedure yields a PCR product of 207 pairs of nucleotides; as a negative control use 3 ll sterile water instead of cDNA. · Use cDNA from peripheral mononuclear blood cells of healthy control persons as positive controls for GAPDH RTPCR, mRNA and cDNA de-
Accumulating Experiences in Sentinel Node Detection in Malignant Melanomas
rived from the melanoma cell line MEWo and as a positive control for tyrosinase RT-PCR. · In order to exclude false-positive PCR results by contamination of genomic DNA, include reverse transcriptase-negative probes in the PCR; these are those for which no transformation into cDNA has developed in reverse transcription. If a positive band develops in electrophoresis this can only be attributable to pollution with genomic DNA.
Electrophoresis Evaluate the PCR product by 2% agarose gel electrophoresis. · Dissolve 29 agarose in 100 ml TBE buffer, heating and adding 10 ll ethidium bromide. Add 8 ll PCR product after adding 2 ll loading buffer. · Separate 12 ´ TBE buffer at 60 V for 1 h; using molecular weight marker. · Evaluate the gel under UV by photographing using a video gel documentation system. In order to test whether the PCR products are really of the nucleotide pairs, test probes distinguished in thermogradient gel electrophoresis. Perform separation as advised by Qiagen.
Sequencing · Excise the amplificates produced by the internal primer pair HYTR3 and HYTR4 from the agarose gel, purify by using test subgel extraction kit (Genomed) and put them into the sequencing reaction. · For every reaction use 50 ng DNA as a model for 5 ng of the HTYR3 or HTYR4 primers. · After 25 cycles, extract with phenol chloroform and evaluate with the sequencer.
Statistics The McNemar test can be used to compare the sensitivity of the user methods, including immunohistochemical analysis with tyrosinase RT-PCR. In this test the probes evaluated are displayed in a four-field table. As values of interest, the positive results of both investigative procedures are included in evaluation of the v2 value.
RT-PCR negative RT-PCR positive
Histology negative a f v2 = e±f
Histology positive e b v2 = e+f
The zero hypothesis is ruled out when the v2 value is higher than the critical value of the v2 distribution for a chosen probability error, a. For a probability of error a = 5% the critical value amounts to 3.84. Therefore, RT-PCR with detection of mRNA, coding tyrosinase as a marker for detection of malignant melanoma cells in SLN staging, must be regarded as doubtful. Septicemia may reasonably also result from the unsolved problem that the high rates of positive sentinel nodes in RT-PCR investigations are in contrast to the much lower positive rates obtained in combined HE and immunohistochemical investigations using the markers S100 protein and/or HMB45. Based on all these experiences, tyrosinase coding mRNA is of only limited use as a marker for lymph node investigations, but seems to be useful for blood tests in follow-up studies. Nonradioactive Imaging in Follow-up Control Studies The follow-up after melanoma operations should include active involvement of the patients in the form of self-inspection and palpation (Kroon and Nieweg 2000). Clinically, high-resolution ultrasound is used for prediction of lymph node metastasis in malignant melanoma cases. Uren's investigations (1999) proved this method accurate for the diagnosis of nodal metastases during follow-up. In these investigations it was found to have a sensitivity of 94% and a specificity of 87%, with an accuracy of 89%. Nodal metastases were present in all cases investigated in which the thickness of the nodes was found to be greater than two thirds of their length and the echoes in the node were at a low level. Present Opinions on the Actual Status Like patients with other tumors, such as breast cancer, a relatively high percentage of melanoma patients do not seem to need extensive lymph node dissection.
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Glass et al. (1998) recently suggested that complete lymph node resection was avoidable in nearly 85% of SLN-negative cases, whereas sentinel nodepositive cases might require adjuvant therapy regimens. In spite of high rates of confirmation of SLN in melanoma cases (98%), Morton (1984, 1992, 1993, 1997) recently stated that he had come to see lymphatic mapping and selective (sentinel) LND as an investigational procedure with unproven therapeutic utility: at first glance this opinion seems disappointing and difficult to understand in view of the recent encouraging data. However, these statements clearly show that we need well-planned long-term multicenter studies and Kaplan-Meier evaluations, with emphasis on the different localizations of the primaries and the quite different biological behaviors of the various malignant melanoma subtypes.
Final Version of the Staging System for Cutaneous Melanomas Recommendation of the American Joint Committee on Cancer Staging In summary, the following points are clearly significant: · Thickness (not level of invasion) and ulceration (except T1) are the first important points that must be documented. · Number of involved lymph nodes (rather than gross dimension) and delineation: ± clinically occult (microscopic) ± clinically apparent (macroscopic). · Metastases should be evaluated: sites of distant metastases and presence of elevated serum lactic dehydrogenase (used in M category) are important points. · Up-staging of stages I, II, III is necessary in ulcerated melanoma cases. · Merging of satellite and in transit metastases to a single staging entity grouped in stage III should be planned. · A convention of taking account of staging information from intraoperative lymphatic mapping and SLN biopsy in clinical and pathological staging must be established. The revision became official with the publication of the sixth edition of the AJCC Cancer Staging Manual (see Betsas et al. 2002).
Treatment of Malignant Melanomas Related to the SLN Status The short statements below summarize the latest published results of international clinical studies. For routine treatment protocols used in N-positive cases see Chapter 33. In malignant melanoma treatment two factors are important for postoperative adjuvant therapy: · Type of melanoma (superficial spreading or nodal subtype). · Involvement of the regional lymph node(s), i.e., the SLN(s). ± It is accepted that in cases with a superficial spreading melanoma in the early stages no search for sentinel nodes is performed. ± In cases with more advanced lesions (invasion of > 0.75 mm, corresponding to Breslow pT2) and in all nodal types SLN detection is started. In cases with superficial spreading melanoma with negative sentinels no additional therapy is performed, whereas in nodal cases with or without cancer infiltration of the sentinel node(s) interferon therapy is given after surgical clearance of the basin.
Interferon Alpha and Cytostatics Melanoma Treatment in SLN-negative and in Advanced Cases As demonstrated in the current literature (Kirkwood et al. 1996; Grob et al. 1998; Pehamberger et al. 1998), INFa significantly inhibits melanoma progression. As adjuvant treatment it delays recurrence and prolongs tumor-free survival, and in some cases it obviously also extends overall survival. When given in combination with chemotherapy in advanced cases with lympho- and/or hematogenous metastasis it improves response rates. The aim for the near future is to find out what chemotherapy agent combined with INFa gives the best result in terms of tumor-free survival.
Experience with Adjuvant Treatments In a French-Austrian cooperative study on melanoma, 800 patients in stage II were treated with lowdose INFa (see Table 14).
Final Version of the Staging System for Cutaneous Melanomas Table 14. Summary of French and Austrian studies (obs observation, pts patients) Frencha
Austrianb
3 MIU s.c.
3 MIU s.c.
3 times per week for 18 months
Daily for 3 weeks, then 3 MIU s.c. 3 times per week for 49 weeks
Patient numbers
INFa, 244; obs, 245
INFa, 154; obs, 157
Follow-up
INFa, 5.0 years; obs, 5.1 years (median)
41 months (mean)
No. of recurrences
INFa, 100 pts; obs, 119 pts
INFa, 37 pts; obs, 57 pts
5-Year relapse rate
INFa, 43%; obs, 51%
Not determined
No. of deaths
INFa, 59 pts; obs, 76 pts
INFa, 17 pts; obs, 21 pts
5-Year mortality rate
INFa, 24%; obs, 32%
Not determined
INFa regimen
Relapse-free survival
Overall survival
a b
Grob et al. (1998) Pehamberger et al. (1998)
Table 15. Summary of results from studies investigating biochemotherapy regimens involving IFNa. (Eton et al. 2000) a (CVD cisplatin, vinblastine, dacarbazine)
a
Treatment
CVD, IFNa, IL-2
CVD
Patient number
91
92
Overall response rate
48% (7 CR)
25% (2 CR)
P = 0.001
Median TTP
4.6 months
2.4 months
P = 0.0007
Median survival
11.8 months
9.5 months
P = 0.055
Table 16. Results yielded by chemotherapy combined with interferon (CR complete response, PR partial response) Cisplatin, dacarbazine, carmustine, IFNa, IL2 a
Significance
No. of patients
109
Overall response rate
38.5% (12 CR, 30 PR)
Median survival
Responders ± 18 months; stable disease ± 11 months; progressive disease ± 4 months
Cisplatin, dacarbazine, IFNa, IL2
For further references see Eton (1999), Eton et al. (2002) a b
The results have already been published: · For the French group by Grob et al. (1998) · For the Austrian group by Pehamberger et al. (1998). A comparison of adjuvant-treated patients and standard observations showed a benefit for the adjuvant-treated patients (P = 0.035 in the French group and P = 0.02 in the Austrian group). In the French study a trend toward an increase in overall survival was documented. The role of INFa in stage III melanoma is still unclear (WHO-16 study).
No. of patients
18
Overall response rate
39% (1 CR, 6 PR)
Median time to progression
10 months
Median survival
15 months
As administered by Kamanabrou et al. (ASCO 2000, abs. 2248) As administered by Tres et al. (ASCO 2000, abs. 2251)
Two ECOG studies (USA) compared high-dose IFNa with observation in stage III. In both studies significant improvements in disease-free survival were found (Kirkwood et al. 1996), but the E11690 study (Kirkwood, ASCO 1999) failed to confirm the overall survival benefit.
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Chapter 25 Malignant Melanoma Table 17. Summary of results yielded by temozolomide (TMZ) alone and in combination with IFNa or thalidomidea (SD stable disease)
a
Treatment
TMZ
TMZ, IFNa
TMZ, thalidomide
Overall
No. of evaluable patients
17
15
11
43
Responses
1 PR, 4 SD
4 PR, 4 SD
3 PR, 3 SD
8 PR, 11 SD
Overall response rate
6%
27%
27%
19%
Arance et al. (ASCO 2000, abs. 2257)
Table 18. Summary of results yielded by TMZ alone and in combination with IFNa + GM-CS
a
Treatment
TMZ, 150 mg/m2 IFNa, GM-CSF
TMZ, 200 mg/m2 IFNa, GM-CSF
TMZ, 250 mg/m2 IFNa, GM-CSF
Evaluable patients (n)
6
18
18
Responses
1 PR
1 CR, 5 PR
4 CR, 3 PR
Overall response rate
17%
33%
39%
Kersten et al. (ASCO 2000, abs. 2244)
Experience in Metastatic Disease
References
Studies in cases with metastatic disease have clearly demonstrated the effectiveness of IFNa used together with cytostatic agents. Tables 15±18 list the schemes used and the median survival times.
Albertini JJ, Cruse CW, Rapaport D, Wells K, Ross M, DeConti R, Berman CG, Jared K, Messina J, Lyman G, Glass F, Fenske N, Reintgen DS (1996) Intraoperative radio-lymphoscintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223:217±224 Alex JC, Krag DN (1993) Gamma-probe guided localization of lymph nodes. Surg Oncol 2:137±143 Alex JC, Krag DN (1996) The gamma-probe-guided resection of radiolabeled primary lymph nodes. Surg Oncol Clin North Am 5:33±41 Alex JC, Weaver DL, Fairbank JT, Rankin BS, Krag DN (1993) Gamma-probe-guided lymph node localization in malignant melanoma. Surg Oncol 2:203±208 Alex JC, Krag DN, Halow SP, Meijer S, Loggie BW, Kuhn J, Gadd M, Weaver DL (1998) Localization of regional lymph nodes in melanomas of head and neck (see comments). Arch Otolaryngol Head Neck Surg 124:135±140 ASCO (American Society of Clinical Oncology) (2000) Proceedings of ASCO Meeting, 2000, abstract 2257 (Arance et al) ASCO (American Society of Clinical Oncology) (2000) Proceedings of ASCO Meeting, 2000, abstract 2248 (Kamanabrou et al) ASCO (American Society of Clinical Oncology) (2000) Proceedings of ASCO Meeting, 2000, abstract 2244 (Kersten et al) ASCO (American Society of Clinical Oncology) (2000) Proceedings of ASCO Meeting, 2000, abstract 2251 (Tres et al) Bachter D, Balda BR, Vogt H, Bçchels H (1998) Primary therapy of malignant melanomas: sentinel lymphadenectomy. Int J Dermatol 37:278±282 Balch CM, Murad TM, Soong SJ, Ingalls AL, Richards PC, Maddox WA (1979) Tumor thickness as a guide to surgical management of clinical stage I melanoma patients. Cancer 43:883±888
Adjuvant Therapy Regimens in Soft Tissue Tumors Depend More on Degree of Malignancy than on SLN Status As already pointed out, synovial sarcoma and rhabdomyosarcoma have the highest rates of regional (sentinel) lymph node involvement (30% and 8%, respectively). It is difficult to make any recommendations on adjuvant chemotherapy regimens. In sarcomas of adults with grade I and II tumors without node involvement only surgical treatment with sufficiently wide tumor-free margins (2±3 cm horizontally and at least 2±2.5 cm in depth) are necessary. Local excision, compartment extirpation, and amputation must be calculated by the surgeon concerned. As a rule of thumb, in grade I and II soft tissue tumors without positive nodes no adjuvant therapy regimen is indicated, while in grade III sarcomas both with and without positive nodes regimens including anthracyclines are used.
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Kapteijn BAE, Nieweg OE, Liem I, Mooi WJ, Balm AJ, Mçller SH, Peterse JL, Valdes Olmos RA, Hoefnagel CA, Kroon BB (1997) Localizing the sentinel node in cutaneous melanoma: gamma probe detection versus blue dye. Ann Surg Oncol 4:156±160 Kapteijn BA, Nieweg OE, Mçller SH, Liem IH, Hoefnagel CA, Rutgers EJ, Kroon BB (1997) Validation of gamma probe detection of the sentinel node in melanoma. J Nucl Med 38:362±366 Kaudewitz P, Braun-Falco O, Ernst M, Landthaler M, Stolz W, Gerdes J (1989) Tumor cell growth fractions in human malignant melanomas and the correlation to histopathological tumor grading. Am J Pathol 134:1063±1068 Kirkwood JM (1999) Proceedings of the American Society of Clinical Oncology (ASCO) Meeting, 1999. Abstract 2072 Kirkwood JM, Straderman MH, Ernsthoff MS, Smith TJ, Borden EC, Blum RH (1996) Interferon alpha 2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group, trial EAST 1684 (rapid publication). J Clin Oncol 14:7±17 Kirkwood JM, Resnick GD, Cole BF (1997) Efficacy, safety, and risk-benefit analysis of adjuvant interferon alfa-2b in melanoma. Semin Oncol 24 [1 Suppl 4]:S16±23 Kirkwood JM, Ibrahim JG, Sondak VK, Ernstoff MS, Ross M (2002 a) Interferon alpha-2a for melanoma metastases. Lancet 359:978±979 Kirkwood JM, Bender C, Agarwala S, Tarhini A, Shipe-Spotloe J, Smelko B, Donelly S, Strover L (2002 b) Mechanisms and management of toxicities associated with highdose interferon alpha-2b therapy. J Clin Oncol 20(17): 3703±3718 Kirkwood JM, Richards T, Zarour HM, Sosman J, Ernsthoff M, Whiteside TL, Ibrahim J, Blum R, Wieand S, Mescari R (2002 c) Immunomodulatory effects of high-dose interferon alpha 2b in patients with high-risk resected melanoma: the E26690 laboratory corollary of intergroup adjuvant trial E 1690. Cancer 95(5):1101±1112 Kokoschka EM, Trautinger F, Knobler RM, Pohl-Markl H, Miksche M (1990) Long-term adjuvant therapy of highrisk malignant melanoma with interferon alpha 2b. J Invest Dermatol 95 [6 Suppl]:193S±197S Korabiowska M, Brinck U, Hoenig JF, Bartkowski SB, Mirecka J, Schauer A (1994) An application of MIB antibody to the retrospective study of melanomas of oral mucosa and facial skin. J Cancer Res Clin Oncol 69:365±368 Krag DN, Meijer SJ, Weaver DL, Loggie BW, Harlow SP, Tanabe KK, Laughlin EH, Alex JC (1995) Minimal access surgery for staging of malignant melanoma. Arch Surg 130:654±658 Kroon BB, Nieweg OE (2000) Management of malignant melanoma. Arch Chir Gynaecol 89:242±250 Krug B, Dietlein M, Groth W, Stutzer H, Psaras T, Gossmann A, Scheidhauer K, Schicha H, Lackner K (2000) Fluor-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in malignant melanoma. Diagnostic comparison with conventional imaging methods. Acta Radiol 41:446±452 Leong SPL, Steinmetz I, Habib FA, McMilian A, Gans JZ, Allen RE Jr, Morita ET, el-Kadi M, Epstein HD, Kashani-Sabet M, Sagebiel RW (1997) Optimal selective sentinel lymph node dissection in primary malignant melanoma. Arch Surg 132:666±672
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Chapter 25 Malignant Melanoma Reintgen D, Cruse CW, Wells K, Berman C, Fenske N, Glass F (1994) The orderly progression of melanoma nodal metastases. Ann Surg 220:759±767 Reintgen D, Cruse CW, Wells K, Berman C, Fenske N, Glass F, Schroer K, Heller R, Ross M, Lyman G (1996) The orderly progression of melanoma nodal metastases. Ann Surg Oncol 3:327±328 Reintgen D, Balch DM, Kirkwood J, Ross M (1997) Recent advances in the care of the patient with malignant melanoma. Ann Surg 225:1±15 Retsas S, Henry K, Mohammed MQ, MacRae K (2002) Prognostic factors of cutaneous melanoma and a new staging system proposed by the American Joint Committee on Cancer (AJCC): validation in a cohort of 1284 patients. Eur J Cancer 38(4):511±516 Rogers JM, Jung CW, Lewis G, Groman EV (1998) Use of USPIO-induced magnet susceptibility artifacts to identify sentinel lymph nodes and lymphatic drainage patterns. I. Dependence of artifact size with subcutaneous combidex ¸ dose in rats. Magn Reson Imaging 16:917±923 Ross MI, Reintgen D, Balch DM (1993) Selective lymphadenectomy: emerging role for lymphatic mapping and sentinel node biopsy in the management of early stage melanoma. Semin Surg Oncol 9:219±223 Ross MI (1996) Surgical management of stage I and II melanoma patients: approach to the regional lymph node basin. Semin Surg Oncol 12:394±401 Schneebaum S, Stadler J, Cohen M, Yaniv D, Baron J, Skornick Y (1998) Gamma probe-guided sentinel node biopsy ± optimal timing for injection. Eur J Surg Oncol 24:515±519 Schwimmer J, Essner R, Patel A, Jahan SA, Shepherd JE, Park K, Phelps ME, Czernin J, Gambhir SS (2000) A review of the literature for whole-body FDG-PET in the management of patients with melanoma. Q J Nucl Med 44:153±167 Shivers SC, Wang X, Li W, Joseph E, Messina J, Glass LF, DeConti R, Cruse CW, Berman C, Fenske NA, Lyman GH, Reintgen DS (1998) Molecular staging of malignant melanoma: correlation with clinical outcome. JAMA 28(280):1410±1415 Silverstein MJ, Gierson ED, Waisman JR, Senofsky GM, Colburn WJ, Gomagani P (1994) Axillary lymph node dissection for T1a breast carcinoma. Cancer 73:664±667 Sugranes G, Vidal-Sicart S, Piulachs J, Bombuy E, Pons F, Castel T, Herranz R, Visa J (2001) Gamma-detecting probe used intraoperative to locate the sentinel lymph node status in patients with malignant melanoma. Eur J Surg 167(8):581±586 Taback B, Fujiwara Y, Wang HJ, Foshag LJ, Morton DL, Hoon DS (2001) Prognostic significance of circulating microsatellite markers in the plasma of melanoma patients. Cancer Res 61:5723±5726 Temple CL, Scilley CG, Engel CJ, Shum DT, Lohmann RC, Mattar AG, Zabel PL (2000) Sentinel node biopsy in melanoma using technetium-99m rhenium colloid: the London experience. Ann Plast Surg 45(5):491±499 Thompson JF, McCarthy WH, Bosch CM, O'Brien CJ, Quinn MJ, Paramaesvara S, Crotty K, McCarthy SW, Uren RF, Howman-Giles R (1995) Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res 5:255±260
Thompson JF, Niewind P, Uren RF, Bosch CM, HowmanGiles R, Vrouenraets BC (1997) Single-dose isotope injection for both preoperative lymphoscintigraphy and intraoperative sentinel lymph node identification in melanoma patients. Melanoma Res 7:500±506 Thompson JF, Hunt JA, Culjak G, Kren RF, Howman-Giles R, Harman CR (2000) Popliteal lymph node metastasis from primary cutaneous melanoma. Eur J Surg Oncol 26:172±176 Thompson W, Gershenwald J, Lee J, Mansfield P, Balch C, Ross M (1996) Sentinel lymph node identification in melanoma patients using two techniques: dye vs. dye + radiolabelled colloid. Abstract presented to the Meeting of the Society of Surgical Oncology, Atlanta, 22 March 1996 Tilgen W (1995) Malignant melanoma: current therapeutic concepts. Onkologie 18:534±547 Tremblay F, Louffi A, Shibata H, Meteriossian S (2001) Sentinel lymph node biopsy for melanoma of the trunk and extremities: the McGill experience. Can J Surg 44(6):428±431 Tyler DS, Onaitis M, Kherani A, Hata A, Nicholson E, Keogan M, Fi S, Coleman E, Seigler HF (2000) Positron emission tomography scanning in malignant melanoma. Cancer 89:1019±1025 Uren RF, Howman-Giles RB, Shaw HM, Thompson JF, McCarthy WH (1993) Lymphoscintigraphy in high-risk melanoma of the trunk: predicting draining node groups, defining lymphatic channels and locating the sentinel node. J Nucl Med 34:1435±1440 Uren RF, Howman-Giles R, Thompson JF, Shaw HM, Quinn MJ, O'Brien CJ, McCarthy WH (1994) Lymphoscintigraphy to identify sentinel lymph nodes in patients with melanoma. Melanoma Res 4:395±399 Uren RF, Howman-Giles R, Thompson JF, Quinn MJ (1996) Direct lymphatic drainage from the skin of the forearm to a supraclavicular node. Clin Nucl Med 21:387±389 Uren RF, Howman-Giles R, Thompson JF, McCarthy WH (1998) Exclusive lymphatic drainage from a melanoma on the back to intraabdominal lymph nodes. Clin Nucl Med 23:71±73 Uren RF, Howman-Giles R, Thompson JF, Shaw HM, Roberts JM, Bernard E, McCarthy WH (1999) High-resolution ultrasound to diagnose melanoma metastases in patients with clinically palpable lymph nodes. Australes Radiol 43:148±152 Uren RF, Howman-Giles R, Thompson JF, McCarthy WH, Quinn MJ, Roberts JM, Shaw HM (2000) Interval nodes: the forgotten sentinel nodes in patients with melanoma. Arch Surg 135(10):1168±1172 Veen H van der, Hoekstra OS, Paul MA, Cuesta MA, Meijer S (1994) Gamma probe-guided sentinel node biopsy to select patients with melanoma for lymphadenectomy. Br J Surg 81:1769±1770 Veronesi U, Adamus J, Bandiera DC, Brennhovd IO, Caceres E, Cascinelli N, Claudio F, Ikonopisiv RL, Javoorskj VV, Kirov S, Kulakowski A, Lacoub J, Lejeune F, Meche Z, Morabito A, Rode I, Sergeev S, von Slooten E, Szcygiel K, Trapeznikov NN (1977) Inefficacy of immediate node dissection in stage I melanoma of the limbs. N Engl J Med 297:627±630 Vidal-Sicart S, Pons F, Piulachs J, Castel T, Palou J, Herranz R (1998) Mid-arm sentinel lymph nodes showing surprising drainage from a malignant melanoma in the forearm. Clin Nucl Med 23(5):273±274
References Vorpahl U, Jåger E, Schmidbauer U, Henneking K (1996) Value of inguinal lymph node excision in anorectal melanoma. Zentralbl Chir 121:483±486 Wagner JD, Schauwecker D, Davidson D, Coleman JJ 3rd, Saxman S, Hutchins G, Love C, Hayes JT (1999) Prospective study of fluorodeoxyglucose-positron emission tomography imaging of lymph node basins in melanoma patients undergoing sentinel node biopsy. J Clin Oncol 17:1508±1515 Wanebo HJ, Harpole D, Teates CD (1985) Radionuclide lymphoscintigraphy with technetium 99m antimony sulfide colloid to identify lymphatic drainage of cutaneous melanoma at ambiguous sites in the head, neck and trunk. Cancer 55:1403±1413 Weinstock MA (1993) Cutaneous melanoma. J Am Acad Dermatol 28(4):666±668 Weinstock MA (1993) Epidemiology and prognosis of anorectal melanoma. Gastroenterology 104:174±178
Whooley BP, Shaw P, Astrow AB, Toth IR, Wallack MK (1997) Long term survival after locally aggressive anorectal melanoma. Am Surg 64:245±251 Winter H, Bellmann KP, Kçchler I (1996) Prognoseverbesserung in der Melanomchirurgie ± Ergebnisse zehn Jahre nach Einfçhrung der Lymphabstromszintigraphie. In: Dçmmer R, Pahizzon R, Burg G (eds) Operative und konservative Dermato-Onkologie. Blackwell, Berlin, pp 132± 137 Winter H, Kçchler I, Aurisch R (1996) Prognoseverbesserung in der Melanomchirurgie durch lymphabstromgerechte Kontinuitåtsdissection. Erfahrungen 10 Jahre nach Einfçhrung der Lymphabstromszintigraphie. Acta Chir 31:282±290 World Health Organization: Support in form of illustrative slides from Derm Pathol Fndn USA. WHO, Geneva. See also: Heenan et al (1974, 1996)
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Chapter 26
Esophageal and Gastrointestinal Cancer A. Schauer, M. Schauer
Current Status of International Research Activity: an Overview The beneficial use of one of the existing sentinel lymph node (SLN)-detecting principles for locoregional staging of digestive tract tumors and improvement in tumor treatment is still questionable, because extensive experience of the SLN concept still does not exist in this field. The first scintigraphic investigations were carried out by Terui et al. as long ago as 1982 using 99mTc-rhenium sulfur colloid. The use of blue dye and/or 99mTc-nanocolloid, separately or in combination, for diagnosis or the systemic application of iron oxide colloids (ultrasmall particles of iron oxide = USPIO), which is still at an experimental stage of investigation, are possibilities. It must be stressed, however, that the number of publications on the sentinel node approach in gastrointestinal cancers has increased in recent years. It must also be seen in a positive light that prominent cancer centers are very much committed to improving existing locoregional cancer clearing concepts and developing new strategies (Siewert et al. 1986).
by-passing cannot be excluded. It is also not clear what locoregional network there is at any particular level along the course of the esophagus connecting paraesophageal lymphatics or nodes with parahilar and paratracheal lymph nodes. It seems that the answer to this question would be of interest, because alterations to operative lymph node clearance can have implications for R0 resection. With reference to all subtypes of esophageal cancers and to the difficult and hardly solved problem, we have to ask about the possibilities of support from the mature radiodiagnostic imaging systems. It is well known that ultrasound and computed tomography (CT) cannot really help to provide satisfactory solutions to the important problems bound up with SLN localization, early locoregional lymphatic spread, and even lymphatic involvement in advanced stages of esophageal cancer. In addition, it is clear a priori that even FDGPET cannot show up the SLN basins or any micrometastasis. Therefore, we can only ask for more accurate staging in the detection of fully developed regional lymph node metastases than is possible with other imaging systems. This chapter is intended to answer to the questions of whether and when FDG-PET is appropriate for the diagnosis of esophageal cancer.
Esophageal Cancer For cancers of the esophageal mucosa, there are two options: surgical treatment and radiotherapy. In T3 cases down-staging by combined radiochemotherapy is also performed, which can be followed by surgery in the patients who respond. The basic operations include esophagectomy with removal of the regional soft tissue containing paraesophageal lymph nodes. However, the wisdom of local en bloc resection can be questioned, because the possibility that lymph node involvement has developed in other basins as a result of
N-staging Concepts Deviating from the Common Sentinel Node Concept in Esophageal Cancers N. Avril, W. Weber, M. Schwaiger
In contrast to other cancer types of the gastrointestinal tract, it is virtually impossible to develop a ªsentinel node conceptº for esophageal cancers, because after infiltration into the deeper layers of the muscular wall, perpendicular spread along the
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muscular tube and outgrowth with metastasis into lymph nodes at different levels can occur. Because of this, it seems not to be sufficient just to develop a concept for finding the ªsentinel lymph nodeº (SLN) in direct relation to the primary; rather, it is necessary to devise concepts for early detection of regional lymphogenic metastases along the esophageal tube at the same time. In this context we have to ask about the efficiency of imaging concepts (CT, MRI, FDG-PET, Sinerem labeling, etc.). The results of FDG-PET, CT and endoscopic ultrasonography (EUS) are discussed below: Block et al. (1997) evaluated 58 patients with biopsy-proven esophageal cancer with FDG-PET and CT. In all but 2 patients increased FDG uptake was observed at the site of the primary tumor. FDG-PET identified metastases in 17 patients (12 of whom underwent confirmatory biopsy), whereas CT found metastases in only 5 patients. In 35 cases the patients underwent surgery, and histopathology identified lymph node metastases in 21 of these. The nodes were detected by FDG-PET in 11 patients and by CT in 6 patients. In detecting distant metastases in 10 patients whose disease was histologically proven, PET performed considerably better, with a sensitivity of approximately 70% and a specificity of more than 90% in the group as a whole and in the subset of patients with correlative CT data. Choi et al. (2000) also reported better detection of nodal involvement in squamous cell carcinoma of the esophagus by FDG-PET than by CT or endoscopic ultrasonography (EUS) (Flamen et al. 2000). Sixty-one consecutive patients with histologically proven primary esophageal carcinoma were studied prospectively with FDG-PET, 48 of these patients undergoing esophagectomy and lymph node dissection. At surgery, a total of 382 lymph node groups were dissected from the 48 patients, and 100 of these node groups from 32 patients proved to be malignant. In the identification of metastasis in individual groups, FDG-PET showed 57% sensitivity, 97% specificity, and 86% accuracy, whereas CT showed 18% sensitivity, 99% specificity, and 78% accuracy. For lymph node (N) staging, FDGPET was correct in 83% (40/48) of the patients, whereas CT and EUS were correct in 60% (29/48) and 58% (26/45), respectively. Therefore, FDG-PET was more accurate than CT or EUS for evaluating metastasis in individual lymph node groups and for lymph node staging in esophageal cancer. In
another study of 74 patients with carcinomas of the esophagus (n = 43) or gastroesophageal junction (n = 31), FDG-PET demonstrated increased metabolic activity in the primary tumor in 70 of 74 patients, resulting in a sensitivity of 95% (Flamen et al. 2000). False-negative PET images were found in 4 patients with T1 lesions. FDG-PET had a greater accuracy in diagnosing stage IV disease than did the combination of CT and EUS (82% vs 64%). FDG-PET showed additional diagnostic value in 16 (22%) of 74 patients by allowing up-staging in 11 (15%) and down-staging in 5 (7%) patients. For evaluation of locoregional lymph nodes, however, FDG-PET had a lower sensitivity than EUS (33% vs 81%), but a higher specificity (89% vs 67%). Meltzer et al. (2000) performed a retrospective evaluation of FDG-PET images from 47 patients referred for initial staging of esophageal cancer. In a subset of 37 of 47 cases, the PET findings were compared with CT findings and the utility of the imaging findings was evaluated using a high-sensitivity interpretation (assigning equivocal findings as positive) and a low-sensitivity interpretation. PET was less sensitive (41% in high-sensitivity mode, 35% in low-sensitivity mode) than CT (63± 87%) for diagnosing tumor involvement in locoregional lymph nodes, as determined by surgical assessment in 72% of patients. However, the specificity of PET-determined nodal sites was notably greater (up to approximately 90%) than that of sites determined by CT (14±43%).
Relative Value of FDG-PET ± Summary The contradictory results on the sensitivity of PET for identification of locoregional lymph node metastases can be at least partly explained by the extent of disease, e.g., the presence of micrometastases, which often cannot be detected by FDG-PET. Furthermore, tumor-involved lymph nodes in close proximity to the primary tumor are often difficult to distinguish from the primary tumor. However, the main advantage of PET in the initial staging of esophageal cancer is that by detecting distant disease not identified by conventional diagnostic procedures it facilitates the selection of patients for surgery. FDG-PET is not an appropriate first-line diagnostic procedure in esophageal cancer, and it
Adenocarcinoma of the Esophagogastric Junction, Including Typical ªCardia Carcinomaº
is not helpful in the detection of local invasion by the primary tumor; however, recurrent disease is easily diagnosed and differentiated from scar tissue. In addition, it has been suggested that FDGPET plays a valuable part in the follow-up of patients who undergo neoadjuvant chemotherapy and radiation therapy, by supporting early changes in treatment for nonresponsive tumors (Brçcher et al. 2001). Therefore, the management of patients with esophageal cancer can be improved with the use of FDG-PET.
Conclusions Based on the Current Status A. Schauer, M. Schauer
At present there is no practicable working formulation or established study program that makes early realization of a unique SLN concept for esophageal cancer seem likely. The following points might be of interest in the development of a new more scientifically based program: · A preliminary program should be developed to include the early stages of the esophageal cancer (c/pT1±2M0) diagnosed by clinical exclusions. · The program should also differentiate cancers with primaries localized at different levels above the cardia by using different prognostic markers. The program should be also adapted to take account of proven knowledge on the different local networks and assumed flows. · Anatomical lymphographic studies could support differences and changes in the lymphatic networks and nodal connections at different levels relative to the local topographic structures. · In view of the possibility of ªspilloverº from the real SLN(s) to other regional nodes in the lymphatic network, studies directed at determining exact timing are necessary. · Local peritumoral application techniques including the whole circumference of the cancer are necessary and require the development of special techniques to meet the need for a constant distance from the cancer margins (ultrasound guidance?) and injection on the opposite side to where cancer infiltration has taken place. · Animal experiments seem to be unavoidable for the development of standardized programs, to find how best to use blue dyes and/or 99mTc-na-
nocolloids: the dilutions necessary and the radioactive concentrations, the optimal angle for injection into the submucosa, etc. Reflection on the current state of knowledge and experience with tumors in other sites (e.g., prostate cancer) suggests that success may be possible but cannot be predicted. This conclusion also seems to be justified with reference to the development of improvements in the treatment of gastric or colorectal cancers.
Adenocarcinoma of the Esophagogastric Junction, Including Typical ªCardia Carcinomaº A. Schauer, M. Schauer
These cancers localized in the transitional zone of the esophagus, which is primarily lined with squamous epithelium, and the fundus±corpus region, which is lined with glandular structured mucosa, obviously have a different pathogenesis. Cardia insufficiency with reflux of the acid gastric juice and, with this, formation of permanent erosions and chronic ulceration lead to steadily increasing regeneration, ultimately culminating in the development of cancer. We have long called this kind of cancer development ªregeneration cancer.º It is clear that it is not the regeneration alone that triggers malignant transformation; rather, the massive shortening of the cell cycle allows a much higher proportion of carcinogenic hits to reach DNA molecules in sensitive phases of the cell cycle. At the site of the cardia the lymphatic flow is hardly predictable, because the permanent acid reflux induces sterile inflammation and fibrosis, with scar formation and altered lymphatic flow. With regard to distal esophageal cancers, which often show adenocarcinomatous differentiation, we must distinguish between different subentities. The cancers are summarized as adenocarcinomas of the esophagogastric junction, which is shortened to AEG cancers (Siewert and Lange 1990; Siewert and Stein 1998; Siewert et al. 1987, 1995, 1999, 2000). In the treatment of the different subtypes below, localization of and the surgical strategies for three different types (AEG 1±3) are briefly described and characterized (Fig. 1). It must be emphasized that there is no plausible program for new strategies. Therefore, handling
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Fig. 1. Subtypes of distal esophageal neoplastic lesions (AEG adenocarcinoma of the esophagogastric junction,
AEG 1 dependent on Barrett esophagus, AEG 2 and 3 with no dependence on Barrett metaplasia)
related to the individual case seems to be the option of choice, at least for the moment. The AEG 1±3 scheme developed by Siewert et al. (1987, 1995, 1999, 2000) can be used as a basis for new developments of SLN studies of cancers of the distal esophagus, the cardia and the fundus of the stomach. In such studies carcinoid of the fundus-corpus region could also be included, with somatostatinreceptor labeling used for detection of regional lymph node metastases. Siewert's concept has meanwhile become accepted in international discussion, especially in England, France, the United States, and some Asian countries (Triboulet et al. 2001).
ally considered for monobloc resection. However, in the case of ªearly cancerº (5±10%), if partial or subtotal gastrectomy were suggested as sufficient labeling of sentinel nodes could be helpful. At the moment there is no one scheme that is generally accepted as providing preoperative information about the involvement of lymph nodes; this would be especially valuable in cases with early metastasis. However, in attempts to guard against damage to the pancreatic parenchyma, dissection of peripancreatic lymph nodes was not regularly carried out at all centers participating in multicenter studies. It would therefore be quite helpful to have exact knowledge of the related local lymphatic spread in each case before lymphadenectomy is performed. This could be found by injecting 99m Tc-nanocolloids into the submucosa in the area surrounding the primary and searching for the regional nodes by means of a gamma probe. A second approach, which is focused not only on portrayal of the regional lymphatic network, but directly on regional tumor cell spread, and may therefore be useful in yielding preoperative knowledge of lymph node stage, could be to utilize monoclonal antibodies or their Fab' fragments directed not to intracytoplasmatic but to surface antigens.
Gastric Cancer
A. Schauer, M. Schauer Introduction For gastric cancer operations systematic schemes that are valuable in the evaluation of the lymph node status have been developed. In patients who undergo total gastrectomy, the perigastric lymph node groups and also the distal groups are gener-
Gastric Cancer
Fig. 2. Demonstration of the lymphatic network connecting the lymph node chains along both curvatures, but also connecting the nodes along both curvatures in a crosswise manner. This is obviously the most accurate analysis, because such networks can be seen macroscopically in cases with lymphangiosis carcinomatosa. In addition, this scheme also corresponds to the aberrant sentinel node localizations demonstrated by Tsioulias (2000) and Bilchik et al. (2001 a, b). If this scheme applies reliably in all cases, the abundant network of lymphatics, especially along the small curvature but also connecting the small and large curvatures, would be a reason for not performing partial gastrectomy even in patients with limited disease
It has been proposed that a high percentage of gastric cancers show positive immunohistochemical reactions to the transmembrane protein epidermal growth factor receptor (EGFR) and also to the c-erbB2 product p185. Senekowitsch et al. (1989) were successful in labeling EGFR-positive tumors in nude mice to a high degree with Fab' fragments of iodine-125-labeled antibodies directed to EGFR. Therefore, it should also be possible to label tumor cells by means of antibody fragments labeled with 99mTc or another radioactive marker administered preoperatively into the area surrounding gastric cancers and to measure the cancer spread via the lymphatics and in regional nodes intraoperatively with a gamma probe (see also the analysis prepared together with Minnich, later in this chapter). Waddington et al. (1991) tried intraoperative staging using radiolabeled monoclonal antibodies as long ago as in 1991, but obviously without success. It seems that this problem must be examined again under newly defined aspects and with more sensitive methods, including the use of antibody fragments and radioactive substances.
Fig. 3. In contrast to Fig. 2, this scheme shows roughly how it is apparently justifiable to divide up the lymphatic flow into different compartments (see division into three compartments as first devised by Siewert et al. 1986)
Lymphatic drainage from the stomach as analyzed in different departments of anatomy and published in textbooks differs in some important points. These are concerned less with the localization of the lymph nodes than much more with the network of the lymphatics. Whereas some authors demonstrate an impressive reticulated system of lymphatics (Fig. 2), others show connections of the nodal chains along the small curvature, but not across the surface of the stomach (Fig. 3). This means that transportation of cancer cells in the lymph is compatible with both schemes in the early stages, but may be different when the lymphatics are blocked by cancer cell accumulation. With reference to the two portrayals of the gastric lymphatic system it seems to be clear that partial gastrectomy can only be performed in the early stages of gastric cancer development, before extended lymphangiosis has taken place.
Classification of Stage-related Gastric Surgery J Macroscopic Diagnosis in First Diagnostic Endoscopic Procedures Differing macroscopic findings are already important factors in decisions on whether limited or total gastrectomy should be performed in patients with gastric cancers. Macroscopic features, in con-
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Chapter 26 Esophageal and Gastrointestinal Cancer
Fig. 4 a±c. Main macroscopic subtypes of ªearlyº gastric cancer. a Type I, exophytic (ªpolyp-likeº) gastric cancer, mostly highly differentiated adenocarcinoma, slightly protruding. Suitable for sentinel node labeling and, if possible, partial gastric resection. b Type II, flat types of differentiated adenocarcinomas or adenopapillary cancers with a smooth surface are suitable for regional sentinel node labeling. Tumors with high degrees of tumor cell dissociation are already visible in the biopsies (signet-ring cell cancers, anaplastic cancers, some with scirrhous growth patterns) and have
only restricted suitability for labeling procedures. c Type III, ulcerated gastric cancers, adenocarcinomas, flat, slightly eroded, some with solid (ªmedullaryº) growth patterns. The suitability of early stages (without regional fibrosis and sclerosing inflammation) for sentinel lymph node (SLN) labeling is limited. Under 50% of early gastric cancers can be classified as basic types, while combined types (mostly II and III) account for over 50%. Partial or subtotal resection is possible in all cases of types I±III that are suitable for SLN labeling and in combined types
nection with histopathological subtyping and grading, therefore have important implications for the further course. The main types of ªearlyº and ªadvancedº gastric cancers are described below.
veloped signet ring cell cancers (Figs. 7, 10) and scirrhous growing cancers (except for tiny local signet ring cell cancers), a sentinel node search is not helpful in N-staging. Figures 5±8 document the typical appearances and growth patterns.
Early Gastric Cancer. Three main subtypes of ªearly gastric cancerº can be distinguished. In approximately 50% of the cases combined types can occur. The three main types are schematically demonstrated in Fig. 4. It is clear that in view of the local limitation and the very limited invasion all types of early gastric cancer are suitable candidates for sentinel node search programs. Advanced Cancer. The endoscopic macroscopic aspect and the radiodiagnostic ascertainment of rigidity of the gastric wall are important features in preoperative planning strategies and should be considered in conjunction with reflections on the usefulness of an SLN search. Whereas in the case of cancers growing locally with an appearance reminiscent of a cauliflower and in that of locally growing ulcerated cancers a SLN search does seem to be helpful, in diffuse de-
J Main Histopathologically Defined Subtypes of Gastric Cancer and How They Relate to Application of the SLN Concept The main histologically defined subtypes of gastric cancer can be at least roughly coordinated with the macroscopically defined subtypes (Figs. 9±11). The idea that the macroscopic type and the extension of the cancer found on endoscopic evaluation and, in addition, the histopathological subtype are important factors in the planning of partial, subtotal, or total gastrectomy is plausible. In parallel with this, planning of the SLN search is also comparable to these features. The following illustrations recorded during histopathological investigation show the most important types. Figure 9 demonstrates a highly differentiated adenocarcinoma of the stomach, mostly growing in an exophytic (cauliflower-like) manner. In its
Gastric Cancer
Figs. 5±8. Main macroscopic subtypes of ªadvancedº gastric cancer Fig. 5. Exophytic (ªpolyp-likeº) subtype with ªfilling defectsº seen on radiodiagnosis
Fig. 8. Diffuse wall-infiltrating subtype with loss of motility on diagnostic radiography (partly ªmassive fibrous induration of the wallº). *For the different subtypes and the feasibility of limited gastrectomy see correlation-statements below. The extent of the resection depends on the localization of the primary, clinically and, if possible, pathohistologically confirmed T or pT category, and the cancer classification according to Lauren. The reader is also referred to the guidelines of the German Society of Surgery and the German Cancer Society (1999). The surgical strategies can be briefly summarized as follows: Type, localization, extent Intestinal type, antral localization, T1 and T2 (or pT1±2)
Subtotal *
Intestinal type, T2 or pT2 and 3 at other localization ± diffuse type at any localization T4 or pT4 category ± cancer infiltration of esophagogastric junction or regional ± pancreas or colon
Total
Extended
*
*
Fig. 6. Ulcerated (ªulcer-likeº) subtype with ulceration, deep in parts, seen on diagnostic radiography
Fig. 7. Signet ring cell cancer with diffuse wall-infiltrating subtype with loss of motility seen on diagnostic radiography (clinically observed as ªlinitis plasticaº)
early stages, this type is suitable for SLN labeling and intraoperative staging to facilitate the decision on whether partial or subtotal gastrectomy could be performed. Figures 7 and 10 illustrate the histo-
logical picture of a signet ring cell cancer of the stomach: multifocal development of this type is possible, and the cancer is often already advanced when diagnosed. For this reason, the value of searching for the SLN for the purpose of deciding whether partial gastrectomy is possible is doubtful. In individual cases peritumoral labeling can help in the search for the SLN(s). A third type (Fig. 11), undifferentiated (anaplastic) gastric cancer, can show a high degree of cancer cell dissociation. The cancer cells are loosely spread in the stroma. They can be delineated from inflammatory cells (lymphocytes, macrophages) by using anticytokeratin antibodies directed to cytokeratins 8 and 18. A sentinel node search with the aim of selecting patients for partial gastrectomy is of dubious value.
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Chapter 26 Esophageal and Gastrointestinal Cancer Fig. 9. Highly differentiated adenocarcinoma of the stomach. Note the small, less markedly polymorphic, cancer cell nuclei and the abundant well-developed cytoplasm of the cancer cells. This lesion has a mostly exophytic (cauliflower-like) growth pattern. In early stages such a lesion is suitable for SLN labeling and intraoperative staging for the purpose of deciding between partial and subtotal gastrectomy
Fig. 10. Histological picture of a signetring cell cancer of the stomach: multifocal development of this type is possible and the cancer is often already advanced on diagnosis. Therefore, in many cases it is doubtful whether an SLN search with the aim of partial gastrectomy is of any value. In special early cases (controls by multiple biopsies) peritumoral labeling can help make it possible to find the SLNs. Cancer cells are stained blue with Alcian blue and are ªfalling outº of the glandular structures of the mucosa into the interstitium
Fig. 11. Anaplastic gastric cancer with loosely spread, small, cytokeratin-positive (red stained cancer cells on right in the picture (scirrhous growth is also possible)
Gastric Cancer
J Summary of the Main Features of the Different Subtypes of Advanced Cancers and Recommendations for Their Treatment For ease of reference this summary is given in list form. · Exophytically growing, cauliflower-like gastric cancer. ± Histopathological investigation generally reveals adeno- (papillary) carcinoma. ± Radiologically a polypous filling defect is seen. ± This type is better suited than the others to treatment by partial gastrectomy, at least in early stages. · Ulcerated (ulcer-like) gastric cancer ± Histopathological investigation mostly reveals a solidly growing cancer, with less development of vascular stromal parts and early development of ulceration. ± Radiological techniques frequently allow differential diagnosis against chronic gastric ulcer. ± This type is less suited to treatment by partial gastrectomy, because it mostly has only a moderate to low grade of differentiation. · Gastric cancers with flat growth pattern ± Histopathological investigation reveals monocellular mucinous (signet-ring-cell) cancer. Numerous lymphocytes are seen between tumor cells (clinically apparent as ªlinitis plasticaº). ± Radiological examination reveals cancer growing horizontally; peristalsis is often reduced or absent. ± In cases with diffusely growing cancer this type is mostly unsuitable for partial gastrectomy. Only in very early (locally limited) stages does this seem to be possible, and then with close histological monitoring intraoperatively. · Gastric cancer (scirrhous) with a flat growth pattern ± Histopathological investigation discloses that cancer cells are arranged in a chain-like configuration with abundant collagen fiber formation. ± Radiological examination also reveals flat growth. Total loss of peristalsis is a frequent finding, because of abundant formation of fibrous stroma. ± This type is mostly unsuitable for treatment by partial gastrectomy. Only in very early
stages, and then with close histological monitoring intraoperatively, does it seem this might be possible, but there are no clinical methods (imaging systems) available that could confirm such early stages, in addition to which even full investigation of biopsy specimens does not allow total certainty that the cancer is genuinely in an early stage.
Rough Rules for Extent of Surgical Treatment in Early and Advanced Gastric Cancer J Treatment Strategies in Early Gastric Cancer Lymph node metastases develop in only 4±5% of cases of the ªmucosalº type (types I and II a = 37% of all subtypes), but develop in up to 20% of cases of the ªsubmucosalº types (types II b, II c and III = 63% of all subtypes). NB: It is not rare for early gastric cancers to develop from a few foci located close together (local multifocality). The local extension is more than 2 cm in diameter in most cases. In contrast, multicentricity of cancers develops when foci are further apart in 5±10% of cases. Caveat: ªEarlyº cancers can start invasive growth even in the earliest phases of cancer development, with · A high grade of invasiveness and · A high grade of cancer cell dissociation (see also Figs. 10, 11). These features are especially relevant in the case of cancers of the signet-ring cell type and small-cell anaplastic cancer with a scirrhous growth pattern. The following conclusions can be drawn from these facts. · In view of the low rate of regional lymph node involvement in types I and II a and when cancers with high-grade cancer cell dissociation (signet-ring-cell type, scirrhous growth pattern = 37%) are excluded, labeling with 99mTcnanocolloid and blue stain can help in the achievement of more precise partial gastrectomy and of R0 resection. This can also be inferred from the data published by Tsioulias et al. (2000) and Bilchik et al. (2001 a), at the John Wayne Cancer Center, which demonstrate that in gastrointestinal cancers not only local skip metastasis is possible, but whole basins can even be by-passed so that metastasis into completely unexpected nodes takes place.
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Chapter 26 Esophageal and Gastrointestinal Cancer
· In the submucosal groups of early cancer (types II b, II c, and III), injection of labeling solutions (patent blue or 99mTc-nanocolloid) into the peritumoral submucosa seems to be helpful in decisions on which cases can still be treated by subtotal resection and which would be better treated by total gastrectomy (signet-ring cell cancers, undifferentiated cancers, cancers with sentinel nodes outside expected basins) (see Tsioulias et al. 2000; Bilchik et al. 2001 a). · The results reported by Tsioulias et al. (2000) demonstrate that the sometimes extended lymphatic basins can be ªjumped overº by skip metastasis or by-passing of the regional nodes in all subtypes of gastrointestinal cancer. However, what the group demonstrates cannot be explained by simple ªspilling overº with passage of cancer cells through the real sentinel node or by-passing of the first node and settling of cancer cells in a lymph node located near to the sentinel node. According to the pictures shown, these cancer cells by-pass a whole basin with three or four groups of lymph nodes. This process can be termed ªextremely long-distance by-passingº in the hope of stimulating surgical teams to use newly developed methods of patent blue and/or 99m Tc nanocolloid labeling. This seems to be very important, as it should reduce the frequency of locoregional recurrences (Fig. 12).
Fig. 12. Distal antral gastric cancer (blue block) with a subcardial labeled SLN. Donated by Dr. Tsioulias, John Wayne Cancer Center, USA
Such locally distant metastatic involvement sometimes remains undetected and may often be responsible for recurrences, in some cases even when the operating team has thought it has achieved R0 resection. · Because these results are extremely important for future developments, the original photographs from the Tsioulias publication are presented. J Treatment Strategies in Advanced Gastric Cancer Cases Approximately 50% of advanced gastric cancer cases belong to the so-called intestinal type [macroscopic types (Borrmann) II and IV]. In mixed types the anaplastic parts should be taken as the relevant ones for subtyping, because these, mostly highly proliferating (MiBI investigations in biopsies), and more aggressive subclones are responsible for the cancer progression. A highly detailed, anatomically based listing of stomach-associated lymphatic basins (Fig. 13) is not very helpful in the development of surgical strategies, but it must be assumed that it is of fundamental importance to strategies for dividing these complexes into different main compartments for: partial, subtotal or total gastrectomy regimens. Therefore, the main compartments defined by Siewert et al. (1989) are briefly characterized below. · Compartment I includes all lymph nodes localized at the large and small curvature of the stomach (stations 1±6 according to the scheme of the Japanese Research Society for gastric cancer lymphatic drainage) (Fig. 14 a). · Compartment II includes lymphatic basins in the topographic region of the celiac trunk, extending from the hepatic arteries to the hilus of the spleen (Fig. 14 b). · Compartment III extends to the paraaortal and mesenteric lymphatic basins (Fig. 14 c). J Anatomical Localization of the Node Groups (Figs. 13, 14) Related to the three lymphatic compartments described above (I±III), which have been defined and exactly described by Siewert et al. (1986, 1990), peritumoral labeling of sharply delineated gastric cancers with intestinal gland to solid growth pattern and low-grade tumor cell dissociation in stages T1(pT1)±T2(pT2) assists in SLN detection with a specially adapted gamma probe device (see also the section by Wengenmair et al.).
Gastric Cancer Fig. 13. Lymphogenic drainage of the stomach as illustrated by the Japanese Society for Research on Gastric Cancer (1 paracardial, right, 2 paracardial, left, 3 small curvature, 4 large curvature, 4 a short gastric arteries, 4 b left gastro-omental artery, 4 d right gastroomental artery, 5 cranial of the pylorus, 6 caudal of the pylorus, 7 left gastric artery, 8 common hepatic artery, 9 celiac trunk, 10 hilus of the spleen, 11 splenic artery, 12 hepatoduodenal ligament, 13 behind the head of the pancreas, 14 root of the mesenteric artery, 15 a middle colic artery, 16 abdominal aorta, 110 paraesophageal/aboral third, 111 diaphragm)
In this context, the recently published results of Tsioulias et al. (2000), demonstrating the possibility of passing through or by-passing the expected lymph node basins, must be taken into account. This means that even in advanced gastric cancer cases labeling methods based on patent blue and/ or 99mTc-nanocolloids can help in making decisions on: · Whether subtotal or total gastrectomy should be the method of choice. · What lymph node groups are thought to be involved and should be monitored especially carefully by gamma probe, in surgical resective procedures, and in histological and immunohistochemical evaluations. But this serious and careful work can only be performed prospectively in a well-organized comprehensive cancer center with strong interdisciplinary cooperation and sound financial backing. This classification of the three lymph node compartments (I±III) as a basis for N-staging and SLN
search will hopefully be a basis for the development of new strategies in the near future. In conclusion, this basic knowledge, which is now accepted by many research groups, should be the starting point for new therapeutic approaches in surgery, with the SLN concept used for more accurate surgical treatment.
Radioimmunolabeling Strategies for Measurement of Depth of Cancer Infiltration and Detection of Positive Nodes For more than 10 years labeled monoclonal antibodies have been used to evaluate the depth of cancer infiltration in the stomach and colon walls and to detect cancer cell infiltration in regional lymph nodes. These efforts have had only limited success. However, positive results may be a valuable step towards moderation of locally used sentinel node concepts or towards combining the two strategies.
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Chapter 26 Esophageal and Gastrointestinal Cancer Fig. 14 a±c. Division of lymph nodes into three compartments (I±III) as a basis for N-staging and SLN search as detailed by Siewert et al. (1989). a Compartment I includes all lymph nodes along both curvatures. b Compartment II includes all lymph nodes along the celiac trunk and the hepatic and splenic arteries and at the hilus of the spleen. c Compartment III includes the para-aortic nodes and lymph nodes at the mesenteric root
Relevance of c-erb B1±3 Oncogene Overexpression for Suggestions About the Regional Lymph Node Status in Gastric Cancer Patients A. Schauer, M. Schauer, T. Minnich
With reference to the results obtained in breast cancer research programs, it might be suggested that within those positive for the c-erb B family (see Figs. 15±17), c-erb B2 (p185)-positive cases of gastric cancer in particular will be characterized by early hematogenous and lymphatic spread and, with this, fast cancer progression (Sugiyama et al. 1989; Jain et al. 1991; Yonemura et al. 1991, 1992; Lemoine et al. 1991; Apel 1992; David et al. 1992; Jaehne et al. 1992; Roh et al. 1992; Minnich et al. 1995). Yonemura et al. (1991) calculated that the risk of death from gastric cancer in c-erb B2 (p185)positive cases was five-fold that in p185-negative cases. Molecular biological explanations have been proposed: · The c-erb B1 oncoprotein (EGFR) is a 170-kDa phosphorylated glycoprotein (Cohen et al. 1992; Hunter 1984), and it is coded on chromosome 7 (7p11±p13) (Spçrr et al. 1984). · The c-erb B2 oncoprotein (p185) is a 185-kDa protein and is encoded on chromosome 17 (q11.2±q21) (Coussens et al. 1985). · The gene for the c-erb B3 receptor is localized on the long arm of chromosome 12 (q13). The oncoprotein has a molecular weight of 160 kDa (Plowman et al. 1990). The coexpression rate for c-erb B2 (p185)-positive cases with c-erb B1 (EGFR)-positive cases is approximately 58%. Of the c-erb-B1-negative cases, 90% are also c-erb-B2 negative. Positive p185 reactions already found in diagnostic biopsies mean
Relevance of c-erb B1±3 Oncogene Overexpression for Suggestions About the Regional Lymph Node Status Fig. 15. Undifferentiated gastric cancer showing strongly positive reaction for the epidermal growth factor receptor transmembrane protein (EGFR). The cancer cell membranes are intensively stained (IgG 1-mouse antibody from Merck, Darmstadt, Germany)
Fig. 16. Moderately differentiated adenocarcinoma of the stomach with a strongly positive reaction for the c-erb B2 (p185) transmembrane protein with antibody 9G6 directed to the extracellular domain
Fig. 17. Moderately differentiated adenocarcinoma of the stomach, with strongly positive reaction for c-erb B3 in parts with antibody, prepared by Gullick (Hammersmith, London, UK)
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Chapter 26 Esophageal and Gastrointestinal Cancer Table 1. Overexpression of c-erb B1 (EGFR) in 116 cases of gastric cancer by grade and stage (too few cases for statistical significance) Grade I
0%
Grade II
31%
Grade III
36%
Early cancer
18%
Advanced cancer
36%
Lymph nodes negative (N0)
9%
Lymph nodes positive, at least N1
22%
Table 2. Overexpression of c-erb B2 (p185) in 116 cases of gastric cancer (too few cases for statistical significance) Grade I
0%
Grade II
17%
Grade III
17%
Early cancer (pT1)
6%
pT2 (advanced cancer)
18%
Cases with negative lymph nodes
9%
Cases with positive lymph nodes
22%
that preoperative M-staging by radiological imaging systems is especially essential. Our group (Minnich et al. 1995) investigated 116 cases with gastric cancer for overexpression of c-erb B1±3 (singular and coexpression), and we related positive reactions to different prognostically relevant parameters as mutated p53 expression, prolif-
eration activity, degree of malignancy, and cancer stage (lymphogenic and hematogenous metastasis. The most important results are summarized in Tables 1 and 2. In contrast to the c-erb B1 (EGFR)- and c-erb B2 (p185)-related results, c-erb B3 overexpression is not correlated with unfavorable prognostic factors. In cases with hematogenous cancer progression the c-erb B2-overexpression rate increased from 16% to 22%. This increasing rate was not fully significant (P = 0.62). Our results (Minnich et al. 1995) and those published in the literature (Falk et al. 1989; Yonemura et al. 1991) allow the conclusion that the influence of c-erb B2 (p185) overexpression in particular correlates with nodal progressive behavior of the cancer (see Table 3). Ohguri et al. (1993) found reduced survival rates only in c-erb B2-positive, high-grade cancers. It can be concluded from these results that in association with positive reactions for p185 in gastric cancer biopsies, the SLN(s), or in addition secondary nodes of the basins, can be involved to a higher degree. Evidence of p185 positivity opens the opportunity for 99mTc-colloid and/or blue dye labeling in suitable cases according to the experience of Tsioulias et al. (2000) (see Chapter 6). Intraoperatively these nodes can be examined by use of the ultrarapid immunohistochemical investigation technique developed by Hæfler and Nåhrig (see Chapter 17). Access to the results of these investigations makes it easier to decide whether partial or total gastrectomy should be performed. Figures 15±17 show positive reactions in immunohistochemical stainings with antibodies directed to the c-erbB1-, c-erbB2- and c-erbB3-encoded transmembrane proteins. In contrast to overexpression of c-erb B2 (p185 protein), which was correlated with higher rates of
Table 3. Immunohistochemical analyses of c-erb B1, -B2 and -B3 by lymph node involvement (116 cases) N-stage
pN0
n
47
% pN+ % a
69
P = 0.75 a c-erb B1
P = 0.06 a c-erb B2
P = 0.95 a c-erb B3
Negative
Positive
Negative
32
15
43
4
40
7
68
32
91
9
85
15
45
24
54
15
59
10
65
35
78
22
85
15
P-values apply to overexpression related to lymph node involvement
Positive
Negative
Positive
Relevance of c-erb B1±3 Oncogene Overexpression for Suggestions About the Regional Lymph Node Status Fig. 18. Moderately differentiated adenocarcinoma of the stomach with strongly positive reaction using antibodies directed to c-myc nuclear protein (dark owing to use of the ABC technique)
Fig. 19. Undifferentiated adenocarcinoma of the stomach with total loss of gland formation. Staining for the proliferation-associated nuclear protein Ki67 using the antibody MiBI from Dianova, Hamburg, Germany (APAAP technique as described by Cordell et al. 1984)
lymph node involvement, c-myc positivity was not related to this behavior (Fig. 18). Anaplastic (undifferentiated) cancers showed quite different proliferation activity, ranging from 10±15% to 80±90% (Figs. 19, 20), and positivity for p53 was mostly correlated with higher degrees of malignancy (Fig. 21). Staging as an Essential Prelude to Limited Resection (Partial Gastrectomy) in Gastric Cancer Patients Whereas definition of pT stages has practically not changed since ªearlyº cancer stages were first differentiated from ªadvancedº cancer stages, the definition of N stages ± though practiced for a long period ± was not plausible.
This dilemma has been thoroughly reviewed in recent times, and a new proposal has been established by UICC members. However, this new approach is also not satisfactory, because all node positions are summarized as ªregional lymph nodesº as the key to N staging. In view of the results of Tsioulias et al. (2000), which show that SLN can be localized in the second or third lymph node station from the primary, the new UICC definition seems to be a compromise necessitated by the sometimes incalculable situation. Because the decision on whether partial or total gastrectomy should be performed depends basically on the pTNM system, this is reprinted in Table 4. With reference to the UICC classification, it seems clear that the ªabsolute limitº for partial
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Chapter 26 Esophageal and Gastrointestinal Cancer Fig. 20. Undifferentiated adenocarcinoma of the stomach stained for the proliferation-associated protein Ki67 using the antibody MiBI from Dianova, Hamburg. Note the extremely high rate of stained nuclei (~ 80%), corresponding to high proliferation activity of the cancer cells
Fig. 21. Undifferentiated adenocarcinoma of the stomach: loosely layered cancer cells mainly in the center of the picture; immunohistochemical staining for mutated p53 oncoprotein. Note the cancer cell nuclei stained dark red using the antibody D0±7 from DAKO, Hamburg, Germany
gastrectomy is intraoperatively histologically confirmed stage pT2pN0 (see Table 4), because the false-negative rate for N0 will be high when only one or two lymph nodes 3 cm from the primary (old N1 definition) are investigated. Therefore, important prerequisites must be fulfilled: · Labeling of the SLNs by analogy with Tsioulias et al.'s (2000) method to allow evaluation of more distant lymph nodes also during operation. · Intraoperative node evaluation by combined investigations: ± Frozen sections. ± Imprint cytology of the cutting surfaces.
± Ultrarapid immunohistochemical examination. Only when all three confirmatory techniques are used by the pathologists can far-reaching security in decision-making be obtained. These statements seem to be absolutely justified. They make it clear that such programs for limited gastrectomy can hardly be followed under clinical study conditions except with optimal interdisciplinary cooperation from surgeons and pathologists. As already pointed out, cases with linitis plastica or cancers with scirrhous growth pattern should not even be considered for partial gastrectomy.
Relevance of c-erb B1±3 Oncogene Overexpression for Suggestions About the Regional Lymph Node Status Table 4. TNM classification of gastric cancer according to the UICC (1997) Primary
Table 4 (continued) Stage III a
pT0
No primary detectable
pTis
Carcinoma in situ: intraepithelial cancer without infiltration of the lamina propria
pT1
The cancer infiltrates the lamina propria or submucosa
pT2
The cancer infiltrates the muscularis propria or subserosa
T2
N2
M0
T3
N1
M0
T4
N0
M0
Stage III b
T3
N2
M0
Stage IV
T1T2T3
N3
M0
T4
N1N2N3
M0
Any T
Any N
M1
3 pT3
pT4
The cancer penetrates the serosa (visceral peritoneum), but does not infiltrate the neighboring structures The cancer infiltrates the neighboring structures
Lymph node involvement pNx
Regional lymph nodes cannot be evaluated
pN0
No regional lymph node metastases found
3 pN1
Metastases in 1±6 regional lymph nodes
pN2
Metastases in 7±15 regional lymph nodes
pN3
Metastases in more than 15 regional lymph nodes
Distant metastases Mx
Distant metastases cannot be evaluated
M0
No distant metastases found
M1
Distant metastases certified
Principle of stage division Stage 0
Tis
N0
M0
Stage Ia
T1
N0
M0
Stage I b
T1
N1
M0
T2
N0
M0
T1
N2
M0
T2
N1
M0
T3
N0
M0
Stage II
Are Preoperative Sentinel Node Search and Detection a Valuable Part of N-staging in Gastric Cancer Cases? If total gastrectomy with extended lymphadenectomy is planned there is no point in a SLN search, because all compartments of nodes are resected. When partial gastrectomy is planned, however, a SLN search and inclusion in the surgical strategies is helpful in showing whether lymph nodes outside the expected basins can be involved in metastatic locoregional cancer progression. [(In this context see also Tsioulias et al. (2000).] Therefore, in future study programs sentinel node searches should be limited to cases in which there is a hope that limited surgical strategies may be enough (see on this point the description of subtypes of early cancer and advanced cancer and histopathologically defined subtypes (Figs. 9±11; pp. 374±376).
Strategies for Preoperative Confirmation of Regional Lymph Node Involvement and Intraoperative N-staging In order to find answers to the open questions about such strategies the following points must be analyzed: 1) Are the imaging systems helpful in N-staging? 2) Is preoperative labeling of cancer-infiltrated lymph nodes possible with an acceptable quality? 3) What is the value of intraoperative pT and pN staging using frozen sections and ultrarapid immunohistochemistry? 1: Imaging methods in staging of gastric cancer: no comprehensive knowledge is available based on
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Chapter 26 Esophageal and Gastrointestinal Cancer Table 5. Comparison of CT and PET in detection of metastases in the liver No. of cases
48
False positive because of inflammatory reaction
No liver metastasis
Liver metastasis
FDG-PET
CT
FDG-PET
CT
4/7
35
32
7/8
3/8
modern imaging methods (CT, MRI, EUS, FDGPET) (Table 5). In the assessment of gastric epithelial neoplasms the ascertainment of their benign or malignant nature, for instance in the case of an exophytic polypoid growth, will still remain the task of pathologists, in most cases a conditio sine qua non in the future, because imaging methods cannot facilitate decisions at the cellular level. Only limited information on infiltration depth and horizontal extension of the cancer can be obtained by means of imaging methods (ultrasonography, PET, etc.). But any statement can be made only with serious reservations, because gastric cancers with medium and low differentiation are mostly accompanied by a high degree of inflammatory reactions within the cancer-infiltrated area and additionally in the regional tissues. Therefore, the regional lymph nodes along the small and large gastric curvature also cannot be separately assessed in the imaging evaluations in many cases of gastric cancer. According to the investigations of McAteer, PET detected the location of the primary in all cases, including T1 tumors, but the regional lymph nodes were not identified separately. In conclusion, at present imaging methods give no adequate support in early stages of gastric cancer to specialists searching for the sentinels and also give no exact answer about regional cancer spread. The only hope with respect to the question of total vs limited gastrectomy is that the methods currently available (blue staining, 99mTc-labeling) seem to be successful and further of techniques especially adapted for different regions are in development. 2: Numerous investigations have been performed to test labeled antibodies with a view to their applicability for detecting locoregional lymph node metastases preoperatively (Table 6). A series of such screening investigations that have already been running for many years, predominantly in patients with colorectal cancers, has been collected
Lymph node metastasis
4/14 = 29%
and these are displayed in Table 7 (see section on colorectal cancers). 3: Intraoperative staging now sometimes seems to be regarded as essential before stage-adapted surgery. As there is no comprehensive concept that covers all parts of the gastrointestinal tract, intraoperative staging concerning the pT value (transmural biopsies or biopsies of the serosa, etc.) and regional lymph node investigation in frozen sections combined with imprint cytology of the cut surfaces of the nodes for N-staging are often the methods of choice so far. Development of the ultrarapid immunohistochemical staining technique for cytokeratin and/or chromogranin A-positive cells in the lymph nodes (see Chapter 17) could bring about considerable improvements in N staging (metastasis of cancer, carcinoids or mixed type-cancers). However, before the performance of these intraoperative procedures, preoperative investigations can already give information on the extent of the neoplastic processes. These newly developed radiodiagnostic and nuclear medical approaches must be incorporated into future comprehensive concepts. The actual status in nuclear medicine is reported separately by Avril et al., as detailed below, with notes on its implications for all parts of the gastrointestinal tract.
Colorectal Cancers As in many other cancer types, after ascertainment of the cancer diagnosis by investigation of biopsy material taken from the primary, before locoregional cancer clearance hematogenous metastasis into characteristic target organs must be excluded. Radioimaging methods such as CT and/or PET are helpful to exclude liver metastases. Therefore, the value of PET should be analyzed before any discussion on whether the SLN concept is appropriate as a means of attaining improvements to surgical strategies.
FDG-PET in Detection and Staging of Colorectal Cancer
FDG-PET in Detection and Staging of Colorectal Cancer
N. Avril, W. Weber, M. Schwaiger
an otherwise negative conventional work-up (n = 8). In these patients, FDG-PET results were correct in 8 out of 9 variances, yielding a positive additional diagnostic value in 62% of the patients.
Detection of Primaries and Metastases It is clear that detection of colorectal primaries is based almost exclusively on clinical endoscopy of the entire colon and pathological evaluation of biopsies taken from areas of suspected exophytic tumor growth or infiltrated areas. However, FDGPET imaging can provide support in cases of multifocal colorectal cancers or when less than the whole colon is accessible for sufficient inspection by endoscopic methods. The correct use of endoscopy and FDG-PET in selected cases seems to be the method of choice, because the limitation of diagnostic use of FDG-PET alone is the result of false-positive imaging of inflammatory lesions. Abdel-Nabi et al. (1998) investigated 48 cases of primary colorectal cancers, obtaining the results displayed in Table 5. Huebner et al. (2000) performed a meta-analysis of the literature on the use of FDG-PET for the detection of recurrent colorectal cancer. In 11 publications, sensitivity of 97%, with a 95% confidence level ranging from 95% to 99%, was found, together with a specificity of 76% (95% confidence level ranging from 64% to 88%). Furthermore, through pooling of the change-in-management data, an overall FDG-PET-directed change in management was calculated at 29%, with a 95% confidence level (range 25±34%). In 103 patients suspected of having recurrent colorectal adenocarcinoma, Flamen et al. (1999) found discrepancies between conventional staging procedures and FDG-PET in 40 (10%) of 412 regions. In these, FDG-PET gave additional diagnostic value in 14 out of 16 locoregional, 6 out of 7 hepatic, 7 out of 8 abdominal, and 8 out of 9 extraabdominal regions. In a patient-based analysis, conventional staging procedures categorized a subgroup of 60 patients as having resectable recurrent disease limited to the liver (n = 37) or to the locoregional region (n = 23). FDG-PET detected additional tumor sites in 9 patients, excluded disease in 3 patients, and offered additional diagnostic information in 20% of the patients. A second subgroup consisted of 13 patients with inconclusive conventional staging findings (n = 5) or with elevated plasma carcinoembryonic antigen levels and
Relative Value of FDG-PET in Detection of Recurrences These studies show that FDG-PET clearly impacts on the therapeutic management of patients with colorectal cancer, specifically in the follow-up period. If surgical resection of recurrent colorectal carcinoma is considered, anatomical imaging for localization of lesions will be required. However, the high sensitivity of FDG-PET for detecting intraand extrahepatic metastases suggests that in patients who have a negative FDG-PET scan additional imaging may not be necessary. For the staging of patients with suspected recurrent colorectal cancer, several studies have indicated that FDG-PET provides greater diagnostic accuracy for detecting hepatic metastases of colorectal cancer than CT (Lai et al. 1996; Ogunbiyi et al. 1997; Flanergan et al. 1998). However, in lesions with a diameter of less than 1 cm, sensitivity of FDG-PET was inferior to CT portography (Vitola et al. 1996). In 24 patients previously treated for colorectal carcinoma who had suspected recurrences in the liver, FDGPET displayed greater accuracy (93%) than CT or CT portography (both 76%). Although the sensitivity of FDG-PET (90%) was slightly lower than that of CT portography (97%), the specificity was much higher (100% versus 9%) when the postsurgical sites were included. As a result, FDG-PET findings led to changes in the surgical plans devised for 6 (25%) out of 24 patients. In conclusion, the actual status reflected in the literature is summarized below. · FDG-PET is not a suitable method for N staging of colorectal cancers. · For this task the increasingly refined blue staining and 99mTc methods are much more helpful and are already routinely used by a few clinical research groups. Nonetheless, · FDG-PET seems to offer high sensitivity and specificity for detection of initial and advanced stages not observed in endoscopic investigations, especially in cases with multifocal cancer development.
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· FDG-PET is a suitable method of confirming or excluding liver metastasis in primary staging procedures and in the follow-up (exclusion of recurrences).
Improvements in Locoregional Cancer Clearance Since the SLN Concept Was Developed A. Schauer, M. Schauer In recent decades, a good step forward has been made in locoregional cancer clearance, especially in the surgical treatment of rectal cancers, with en bloc removal of the regional lymph nodes along the course of the arterial vascular stem back to its origin and also including the small, retrorectal lymph nodes by sharp preparation along ventral side of the os sacrum. This improved locoregional surgical cancer clearance has increased 5-year survival rates by approximately 20%.
The surgical strategy of more precise lymph node removal can be gathered from Fig. 22. The regional lymph node groups included in monobloc removal are colored red.
N-staging of Colorectal Cancers For many years the lymph node staging concept for colorectal cancers published by Spieûl et al. (1990) has been generally accepted. It is applied according to strict guidelines in most clinics. The basics of N staging have not yet been optimally sorted out, because locally they are oriented only to the number of cancer-involved lymph nodes and only include statistically significant experiences, and not tumor-biological and locoregional topographical criteria, including the problem of node by-passing. The scheme is therefore a compromise, which cannot be improved except by elaboration of significant biologically oriented criteria. A scheme
Fig. 22. Lymphatic network and different N-positions. In current surgical strategies the lymphatic chain is removed up to the origin of the arterial supply and the retrorectal nodes are also removed. With enhanced knowledge gained with sentinel node labeling more precise clearance can be achieved. Nodes in the N1±2 positions are now routinely resected ªen blocº with rectosigmoidal parts. For quantitative resection, these parts can be labeled before operation. Anal cancers (squamous cell cancer, malignant melanoma, cloacogenic basal cell carcinoma) can have inguinal medial sentinel nodes
FDG-PET in Detection and Staging of Colorectal Cancer Fig. 23 a±c. Definition of stages N1±N3 in colorectal cancers according to Spieûl et al. (1990, 1993). [N1 metastatic involvement of 1±3 perirectal or pericolic lymph node(s) [examples: cancers of ascending and of descending colon), N2 metastatic involvement of 4 or more perirectal or pericolic lymph nodes (examples: cecal cancer and cancer of the sigmoid colon), N2 lymph node metastases along a nominated vascular stem (examples: cancer of ascending colon and rectal cancer)]
(Fig. 23 a±c) published earlier (Spieûl et al. 1990/ 1993) gives a helpful overview that could be useful in daily routine work; new knowledge can only be gained if we all work in accordance with this overview. With regard to N staging an important new feature was the confirmation that local recurrences of rectal cancers often develop from small retrorectal (presacral) lymph nodes. With a view to the investigations performed and the results obtained by Tsioulias et al. (2000), the N1 positions as demonstrated by Hermanek et al. (2002) must be accepted for the moment, but the actual question that needs an answer as soon as possible is that of the rate at which N1 can develop in small basins, documented as the SLN(s) that are distant from the expected N1 positions. The aberrant localization of sentinel nodes ± far distant from the supposed N1 position ± in gastrointestinal cancers and carcinoids can be judged only roughly at the moment. The preliminary aberrant sentinel node rates in Tsioulias' collective amounted to approximately 8%. In addition, Yamamoto et al. (1998) demonstrated `skip metastases' in 10% of their cases (452 cases of colon cancer), and in some essential points these must be evaluated in a different way from the astonishing results obtained in Tsioulias' work. In Kosaka's (1999) investigation of gastric cancer cases the skip metastasis rate amounted to 15%. In this context, it must be emphasized that use of the term `skip' metastasis means only that the first node (the SLN) is cancer free and a node in close proximity (the next station) is cancer involved. In contrast to this situation, in Tsioulias' cases the SLNs were unexpectedly far aberrant, having jumped over three or four consecutive lymph node groups in many cases. Exactly this is the point that is now providing the stimulus for work on new surgical strategies. Further experience can only be obtained in extensive prospective study programs (multicenter studies). The results obtained could then support the systematic SLN search not only in rectal cancers (as is already the case), but for all colon cancers (Fig. 24 a±c).
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Chapter 26 Esophageal and Gastrointestinal Cancer
Fig. 24 a±c. N1-positions documented by Hermanek et al. (2002). a T1N1 tumors of descending and sigmoid colon. When the possibility of labeling the SLN(s) is being considered the individual position of N1 must be regarded critically. Only more extensive labeling investigations can allow development of a more ªindividualº portrayal of facultative lymph node involvement. b T1-2, N2 (progressed) tumors of ascending and transverse colon. In order to obtain a complete overview of all positions of the primaries (ascending, transverse, descending,
and sigmoid colon), the same systematic investigations must be carried out for all primary cancer locations. c T1±2 tumor of descending colon. This picture documents paraaortal lymph node involvement (inoperability must be assumed). N2 positions are not well defined. Investigations as described by the Californian group could yield more information. These systematic investigations take time and can only be done in a shorter time when surgical clinics with high numbers of patients are trying to obtain new information
FDG-PET in Detection and Staging of Colorectal Cancer
Experience with SLN Labeling of Intestinal and Pancreatic Cancers at the John Wayne Cancer Center With a view to the usefulness of applying the SLN concept there has already been some progress in learning how to use it in the treatment of colorectal cancer with intraoperative mapping of SLNs (Joosten et al. 1999; Merri et al. 1999). Furthermore, Tsioulias (2000) and Bilchik (2001 a) (John Wayne Cancer Center) report that the SLN concept works successfully in the treatment of pancreatic, small bowel, and colon cancers (Figs. 25±27). The false-negative rate was 11%. In 23% of the patients up-staging was necessary when the result of the sentinel node investigation was known. These results help in decisions on whether or not adjuvant chemotherapy is necessary. Drainage of colon cancers in an aberrant way modifies the operation techniques. In the colon cancer series of 203 cases treated by Saha (2000), the SLNs were found in all but 5 cases. The confirmation or exclusion of metastases was accurate in 96% of cases in this series. In view of current experiences and the improvements already discussed, especially in the field of
Fig. 25. Cancer of the ascending colon, showing a sentinel node in a left-sided localization in the transverse colon
SLN search in the treatment protocols for colorectal cancers, we can be sure that further advances will be obtained in the near future.
Fig. 26. Cancer of the small intestine with SLN at the mesenteric root; the contrast solution has by-passed two or three lymph node stations
Fig. 27. Pancreatic cancer with SLN at the prehepatic ramification of the hepatic artery. The peripancreatic nodes are not labeled, which means there is also no sentinel node labeling
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Chapter 26 Esophageal and Gastrointestinal Cancer
Pilot Studies on Detection and Evaluation of SLNs in Colorectal Cancers In recent years pilot studies and interdisciplinary investigations have been started all over the world to evaluate the practicability and the therapeutic value of the SLN concept in colorectal cancer (CRC) treatment (Joosten et al. 1999; Lechner et al. 2000; Tsioulias et al. 2000; Waters et al. 2000; Bilchik et al. 2001b; Merrie et al. 2001; Ota and Lin 2001; Wong et al. 2001). The preliminary results obtained by the groups who have published their data in the international literature are still controversial (Table 6). Some have emphasized results they regard as quite positive and recommended the use of the SLN concept, while others have cast doubt on the usefulness of the SLN concept in locoregional cancer clearance; at present no definitive judgment is possible. Before we can come to any far-reaching conclusion,
we have to ask what the reasons for the diverging opinions are: · There is no consensus on whether to use the blue dye method, the 99mTc-nanocolloid method, or both. · In most studies only small numbers of cases were evaluated, and there have so far been no prospective studies. · Evaluation of the nodes by usage of HE staining and immunohistochemical analysis as well as RT-PCR is not fully clear. Therefore, it is a matter of urgency for prospective, well-programmed multicenter studies to be performed with the intention of reaching higher numbers of cases and obtaining life-tables. Regarding the evaluation of cancer involvement of regional lymph nodes, the combination of HE and immunohistochemical node evaluation in serial sections should have absolute priority, because evaluation by the RT-PCR method does not definitely corre-
Table 6. Sentinel node search in colorectal cancers Author/s
Year of publication
Labeling
No. of cases
SLN found
Predictive value of cancer negativity
HE negative, IHC positive (n) %
Result
Waters et al.
2000
Blue dye
22
20/22
100%
1
SLN search recommended
Lechner et al.
2000
Fab' fragment of CEA antibody
20 6 Rectum 14 Colon
7/20 Upstaging
Detection of atypical metastasis: retroperitoneal renal hilus, etc.
SLN search recommended
Bilchik et al.
2001
No. of cases of stage I/II 40
No. of nodes (SLN) detected 1±3
Average no. of nodes removed 15
SLN HE positive SLN additionally IHC positive Remaining patients RT-PCR +
10/40; 25%
SLN search recommended
Labeling blue dye
No. of cases 26: 18 male, 8 female
No. of SLN detected 2.8Ô1.6
No. of SLN to total no. of nodes SLN outside basin HE negative IHC positive
73/479
Wong et al.
2001
4/40; 10% 12 (46%)
± 4 (29%)
SLN search recommended
Joosten et al.
1999
Blue dye
No. of cases 50
Mapping 35/50; 70%
LN metastasis Blue dye Blue dye negative False negative
20/35 8/20 12 60%
SLN search recommended
Merrie et al.
2001
26
Labeling 99m Tc-nanocolloid
SLN found 23/26
Prediction of metastatic involvement False negative
55%
SLN search recommended
45%
Up-staging by Focused Analysis of SLNs in Cancers of the Gastrointestinal Tract
late with the presence of vital cancer cells. The preliminary important data obtained in some studies are listed in Table 6. When all known facts are summarized the following points seem to be of most interest: · Improvement in SLN detection. · Detection of aberrant metastases that have developed by ªskippingº or ªby-passingº nodes or node groups. · Increased security of locoregional cancer clearance with the aim of avoiding understaging of nodal involvement. · Reduction of the recurrence rates and increase in the healing rates.
Are Labeled Monoclonal Antibodies Helpful in Detection of Cancer Cell Infiltration into Sentinel Nodes In Vivo? In the last decade various efforts have been initiated to detect cancer cell infiltration by the use of labeled monoclonal antibodies, but the results obtained have not been fully convincing. Furthermore, no systematic comparative studies with the currently used labeling strategies using blue dye solution and/or 99mTc-nanocolloid are available. Because the strategies based on monoclonal antibodies binding to cancer cells can detect cancer infiltration of lymph nodes, this method detects sentinel node(s) with or without cancer cell infiltration (Table 7).
Up-staging by Focused Analysis of SLNs in Cancers of the Gastrointestinal Tract A. Schauer, M. Schauer
The extent of stomach resection in gastric cancer patients (partial or total gastrectomy) and, in consequence of this, the extent of locoregional lymphadenectomy are still subjects of some controversy. Concerning the extent of lymphadenectomy in CRCs a unique SLN concept has also not been developed up to now. Recently, however, Tsioulias et al. (2000) systematically tested the quality of the SLN concept and its applicability in gastric, intestinal, and pancreatic cancers in a series of 65 patients using the hypotheses:
· Lymphatic mapping and sentinel lymphadenectomy are feasible in gastrointestinal neoplasms. · The sentinel node (SN) status reflects the regional node status. · Focused analysis of the SN improves the accuracy of staging. The results obtained are based on the 65 cancer cases mentioned above [50 with colorectal neoplasms, 6 with gastric cancer, 5 with small bowel neoplasms (3 adenocarcinomas and 2 carcinoids) and 4 with pancreatic cancers]. In 62 cases (95%), the lymphatic mapping procedure identified at least one SLN. This 95% rate of SLN identification is higher than that initially reported rate for malignant melanomas, at 82% (Morton et al. 1992), or those given in the first reports on SLN identification in breast cancer (Guiliano et al. 1994). In 32 (89%) of the 36 cancers with nodal metastases there was at least one positive SLN, and in 15 cases (42%) metastases were found only in the SLNs. In 2 of 11 cases, cancer cells in the lymph nodes were found only by serial sectioning, and in 9 of them only on immunohistochemical stainings. The rate of false-negative cases ± when rectal cancers were excluded ± was 4% (2 of 54 cases) in the evaluation studies conducted by Tsioulias et al. (2000). In a surprising 8% (5 cases), aberrant metastases were localized and resected by the node mapping procedure. The results with reference to the localization of the different sites of the primaries are summarized in Table 8, which is a reproduction of the original table published by Tsioulias et al. (2000). Anatomically, these aberrant lymph nodes were not located within the routine operation field. Such facts have been known since earlier evaluations. According to Hermanek's investigations within the German gastric cancer studies, the rate of skip metastases was assessed as in the order of 3% (personal communication). However, in more recent investigations, SLN labeling procedures yielded skip metastasis rates of 15% for gastric cancer (51 cases) (Kosaka et al. 1999) and 10% for CRC cases (452 cases) (Yamamoto et al. 1998). It seems that immunohistochemically assisted examination of 20 or more regional lymph nodes is too cost intensive and stretches staffing establishments (technicians and pathologists) to the limit. Therefore, many pathologists and, in the study under scrutiny Tsioulias et al. (2000) too, ask whether it would be possible to assess more sensi-
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394
Chapter 26 Esophageal and Gastrointestinal Cancer Table 7. Applicability of labeled monoclonal antibodies in N-staging of gastrointestinal cancers (RIGS radioimmunoguided surgery system) Authors
Curtet et al.
Year
1990
No. of cases investigated
Monoclonal antibodies
Radionuclide
Results
Conclusions
10
CEA (ab'2)
111
In
Phantom investigation, small radioactive targets can be detected
Best results with 5mm-thick tungsten along collimator
Davidson et al.
1991
14 of cancer, 1 of adenoma
ICR2 directed to EMA
111
In
Uptake higher in EMA-expressing cancer than in nonEMA-expressing tumors (P = 0.019)
Kuhn et al.
1991
14
CEA MAB by infusion
111
In
Identification of intraabdominal lesions in 86%
Verification of complete resection possible
Dawson et al.
1991
52
Anti-CEA (A5B7)
±
Incorrect result 11.3% Correct prediction of Dukes stage
Provides additional information concerning extent. Technique has greater importance in second-look operation
Waddington et al.
1991
±
Tumor-associated antigen (MAB)
111
Tumors 10 ml in volume detected with NaI (TI) probe
Usefulness restricted by limited antibody specificity
Reuter et al.
1992
12
CEA-M0A
99m
SPET results positive in 8 of 15 cases
Measurement technique of IOSM adequate, specific enrichment of M0A too low
Arnold et al.
1992
36
Antitumorassociated glycoprotein antibody CC49
125
In RIGS 83% had positive antibody location In 34% staging changes In 30% chemotherapy based on RIGS
RIGS system provides immediate staging
Two- to fourfold increase in the no. of lymph nodes detectable
Useful role in detecting 2- to 5-mm nodes
60% primary detection P < 0.001 Recurrence in 82% P < 0.001
Recurrence detection positively valued
Abdel-Nabi et al.
1993
CEA
In
Tc or
131
I
I
1±2 mCi
111
In
4.1±5.3 mCi Di Carlo et al.
1994
32
B72.3 reacting with TAG72AG
125
I
Up-staging by Focused Analysis of SLNs in Cancers of the Gastrointestinal Tract Table 7 (continued) Authors
Moffat et al.
Burak et al.
Arnold et al.
Year
1995
1995
1996
No. of cases investigated
Monoclonal antibodies
Radionuclide
Results
Conclusions
12
Anticytokeratin 88BV59
99m
Tc
Sensitivity was 43%, 61%, 78%, 98%, and 91%, respectively, for CT, planar RIS, SPET, surgery, and OPS
99m Tc is a safe, effective radioimmune conjugate for colorectal cancer imaging
27
Earlier: CC49 and 72.3 anti-TAG; now: CC83
125
I
All 27 sites localized: 12 additional sites were RIGS-positive; occult tumor localizations found in 4 cases (15%)
CC83 Mab, used with RIGS is sensitive in detection of recurrent colorectal cancer
86
CC49
125
I
RIGS detected more tissue by involved in disease
More extensive localization of cancer can be detected
Table 8. Rates of sentinel node (SN) detection and metastasis (Tsioulias et al. 2000) Location
Tumor confirmed only in SN SNs detected (%)
Large bowel
SN-positive tumors
Hematoxylineosin positive
n
n
(%)
(%)
Multisection and immunohistochemistry positive n
Upstaging n
(%)
(%)
94
22
(44)
2
(3)
8
(17)
10
(20)
Stomach
100
6
(100)
1
(16)
1
(17)
2
(33)
Small bowel
100
2
(40)
0
(0)
1
(20)
1
(20)
Pancreas
100
2
(50)
1
(25)
1
(25)
2
(50)
95
32
(49)
4
(6)
11
(17)
15
(23)
Total
Table 9. Proportions of cases with positive sentinel nodes only, no other positive lymph nodes (Giuliano et al. 1995) T1 = 100%
T2 = 70%
T3 = 26%
T4 = 20%
tive non-SLNs for examination in sentinel nodenegative cases. When the investigations published by Tsioulias et al. (2000) were repeated by Wiese et al. (1999) in 75 cancer cases with 354 investigated nodes positive, nonsentinel nodes in SLN-negative cases were found in only 0.6%. The distribution of cases with only positive SLNs and no other positive regional lymph nodes by stage of primary in Tsioulias et al.'s (2000) publication, reflecting to the results of Giuliano's
group (1995) in breast cancer study-programs is summarized in Table 9. This means that in higher T-stages according to blockade of lymphatics cancer cells are also drained to other basins. The topographical evaluations in the different sites of primaries demonstrate that the SLN concept with documentation of aberrant locations of nodes involved early provide very impressive evidence that the SLN concept is a highly relevant factor in prospective improvements in the outcome of our patients with cancers in the gastrointestinal tract also. The high rate of locoregional recurrence demands serious improvement of locoregional tumor clearance supported by the sentinel node search. Improvements are also related secondarily to our adjuvant chemotherapy concepts.
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Chapter 26 Esophageal and Gastrointestinal Cancer
Adjuvant Therapy Regimens in CRC Depending on the Sentinel and General Lymph Node(s) Status A. Schauer, M. Schauer
In cases with pT1±2 cancers and negative nodes (exclusion of sentinel node involvement and skip metastasis) no adjuvant chemotherapy can be advised. In pT1±2 cases with positive node(s) opinions are divided. In Dukes stage B disease with only one positive node (limited to the SLN) no chemotherapy is recommended. In Dukes stage C cases with more than three positive nodes chemotherapy with 5-FU and leucovorin is advised (for dosages see Chapter 33). For these tumors it is essential to know the number of positive lymph nodes before attempting to decide on the therapy. The reliability of an intraoperatively frozen section ± which would allow immediate lymph node dissection ± is limited. As the morbidity of additional lymph node dissection is lower than that of a second surgical operation that might become necessary, the advantage of the sentinel-technique with typical localization for these tumors is probably limited. This is true for the chain N1±N3, but not for atypically localized nodes. It must therefore be emphasized that retrorectal, presacral lymph node clearance can be optimized using the gamma probe.
FDG-PET in the Diagnosis of Pancreatic Cancer N. Avril, W. Weber, M. Schwaiger
Diagnostic Efforts in Detection and Limitation of the Primaries Pancreatic cancer and chronic pancreatitis are often impossible to differentiate by conventional imaging modalities. The identification of pancreatic masses as benign or malignant by FDG-PET has been intensively studied (Bares et al. 1994; Stollfuss et al. 1995; Imdahl et al. 1999). It has been shown that the diagnostic accuracy of FDG-PET is better than that of CT, although most patients studied to date have had advanced disease. No data are currently available on the early diagnosis of pancreatic tumors. Furthermore, FDG imaging of pancreatic cancer is hampered by several factors that may limit its clin-
ical application. Hyperglycemia is common in patients with chronic pancreatitis, resulting in a markedly decreased sensitivity of FDG-PET for detecting malignant tumors, owing to a competitive interaction between FDG and glucose for uptake by the tumor. In a recently published study, the sensitivity in detecting pancreatic cancer decreased to 42% when the blood glucose level was higher than 130 mg/ 100 ml (Diederichs et al. 1998). Furthermore, foci of acute inflammation within pancreatic masses may cause false-positive results. These inflammatory reactions may not be detectable by routine clinical parameters (Shreve 1998). In 42 patients Sendler et al. (2000) compared the results of PET and of spiral CT and conventional ultrasonography (US) completed in the course of the routine diagnostic procedures prior to pancreatic surgery. When only the results with scores of IV and V were regarded as positive in the sense of representing definite malignancy, FDG-PET gave a sensitivity of 71% and a specificity of 64%. Quantification of regional tracer uptake contributed no significant diagnostic advantage in the differentiation between benign and malignant tumors. Spiral CT revealed a sensitivity of 74% and a specificity of 45.5%, and abdominal US, 56% and 50%, respectively. PET imaging had only fair diagnostic accuracy (69%) in characterization of enlarged pancreatic masses. More importantly, PET did not exclude malignant tumors. These results suggest that the number of invasive procedures is not significantly reduced by PET imaging. Patients with pancreatic carcinoma have a poor prognosis. Zimny et al. (2000) correlated the survival data of 52 patients with the standardized uptake value (SUV) for FDG determined by FDG-PET as a semiquantitative measure of glucose metabolism. The median survival in 26 patients with low SUV (< 6.1) was 9 months (95% confidence interval 6± 12 months), as against 5 months (95% confidence interval 4±6 months) in 26 patients with high SUV (> 6.1). According to these results, glucose metabolism of tumor tissue can be used to offer additional prognostic information in patients with pancreatic carcinoma. Detection of SLNs and Extended Lymphatic Spread In view of the often very fast locoregional tumor progression, including infiltration of soft tissue and lymphatic spread as well as early metastasis into the liver, a preoperative sentinel node search
References
using imaging systems is almost devoid of any value in ductal and acinic-pancreatic cancer. However, before any decision can be made on operability, imaging of tumor extent to determine whether there is any local invasion into the vascular system is very important. As a rule, the question of resectability according to Whipple in positive cases is answered almost exclusively by intraoperative staging with lymph node investigations in frozen sections supported by imprint cytology, and a decision in favor of this extensive operation can only be justified when no extrapancreatic cancer infiltration is found.
Diffuse Infiltrating Gastric Cancer (Mostly Scirrhous Tumor Type or Signet-Ring Cell Cancer) This tumor type is hardly suited for SLN investigation, because it is characterized by uncircumscribed horizontal tumor growth.
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Kodera Y, Yamamura Y, Shimizu Y, Torii A, Hirai T, Yasui K, Morimoto T, Kato T (1999) Adenocarcinoma of the gastroesophageal junction in Japan: relevance of Siewert's classification applied to 177 cases resected at a single institution. J Am Coll Surg 189(6):594±601 Kosaka T, Ueshige N, Sugaya J, Nakano Y, Akiyoma T, Tomita F, Saito H, Kita I, Takashima S (1999) Lymphatic routes of the stomachs demonstrated by gastric carcinomas with solitary lymph node metastasis. Surg Today 29:695±700 Kuhn JA, Corbisiero RM, Buras RR, Carroll RG, Wagman LD, Wilson LA, Yamauchi D, Smith MM, Kondo R, Beatty JD (1991) Intraoperative gamma detection probe with presurgical antibody imaging in colon cancer. Arch Surg 126(11):1398±1403 Lai DT, Fulham M, Stephen MS, Chu KM, Solomon M, Thompson JF, Sheldon DM, Storey DW (1996) The role of whole-body positron emission tomography with (18F)fluorodeoxyglucose in identifying operable colorectal cancer metastases to the liver. Arch Surg 131:703±707 Lechner P, Lind P, Snyder M, Haushofer H (2000) Probeguided surgery for colorectal cancer. Recent Results Cancer Res 157:273±280 Lemoine NR, Jain S, Silvestre F, Lopes C, Hughes MI, McLelland CM, Gullick E, Filipe WJ (1991) Amplification and overexpression of the EGFR and c-erb B2-protooncogenes in human cancer. Br J Cancer 64:79±83 McAteer D, Wallis F, Couper G, Norton M, Welch A, Bruce D, Park K, Nicolson M, Gilbert FJ, Sharp P (1999) Evaluation of 18F-FDG positron emission tomography in gastric and oesophageal carcinoma. Br J Radiol 72(858): 525±529 Meltzer CC, Luketich JD, Friedmann D, Charron M, Strollo D, Meehan M, Urso GK, Dachil MA, Townsend DW (2000) Whole-body FDG positron emission tomographic imaging for staging esophageal cancer comparison with computed tomography. Clin Nucl Med 25:882±887 Merrie AE, Phillips IV, Yun K, McCall JL (1999) The sentinel node in colon cancer. Eur J Nucl Med 26 [Suppl]: S263 Merrie AE, Van Rij AM, Phillips LV, Rossaak JI, Yun K, McCall JL (2001) Diagnostic use of the sentinel node in colon cancer. Dis Colon Rectum 44:410±417 Minnich T, Marx D, Rothe H, Rehberg S, Hoefer K, Schauer A (1995) Die c-erb B-Familie im Magencarcinom: Korrelation zu anderen prognostischen Faktoren. Verh Dtsch Ges Pathol 79:400 Moffat FL Jr, Vargas-Cuba RD, Serafini AN, Jabir AM, Sfakianakis GN, Sittler SY, Robinson DS, Crichton VZ, Subramanian R, Murray JH, Klein JL, Hanna MG, De Jager RL (1995) Preoperative scintigraphy and operative probe scintimetry of colorectal carcinoma using technetium99m-88BV59. J Nucl Med 36(5):738±745 Morton DL, Wen DR, Wong JH, Economow JS, Cagle LA, Storm K, Foshag LJ, Cochran AJ (1992) Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392±399 Nieweg OE, Tanis PJ, Rutgers EJT (2001) Summary of the Second International Sentinel Node Conference. Eur J Nucl Med 28:646±649
References Ogunbiyi OA, Flanagan FL, Dehdashti F, Siegel BA, Trask DD, Birnbaum EH, Fleshman JW, Read TE, Philpot GW, Kodner IJ (1997) Detection of recurrent and metastatic colorectal cancer: comparison of positron emission tomography and computed tomography. Ann Surg Oncol 4:613±620 Ohguri T, Sato Y, Koizumi W, Saigenji K, Kameya T (1993) An immunohistochemical study of c-erb B2 protein in gastric carcinomas and lymph node metastases: Is the cerb B2 protein really a prognostic indicator? Int J Cancer 53:75±79 Ota DM, Lin K (2001) Lymphatic mapping and sentinel node identification for colorectal cancer. Swiss Surg 7:252±255 Plowman GD, Whitney GS, Neubauer MG, Green JM, McDonald VL, Todaro GJ, Shoyab M (1990) Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proc Natl Acad Sci USA 87:4905± 4909 Reuter M, Montz R, Heer K de, Schåfer H, Klapdor R, Desler K, Schreiber HW (1992) Detection of colorectal carcinomas by intraoperative RIS in addition to preoperative RIS: surgical and immunohistochemical findings. Eur J Nucl Med 19(2):102±129 Roh JK, Paik S, Chung HC, Yang W, Kim HK, Choi IJ, Kim J, Koh E, Lee KS, Min JS, Yoon J, Kim BS (1992) Overexpression of erb B2-protein in gastric adenocarcinoma. Gan To Kagaku Ryoho 19(8 Suppl):1207±1219 Saha S, Wiese D, Badin J, Beutler T, Nora D, Ganatra BK, Desai D, Kaushal S, Nagaraju M, Arora M, Singh T (2000) Technical details of sentinel lymph node mapping in colorectal cancer and its impact on staging. Ann Surg Oncol 7(2):120±124 Sendler A, Avril N, Helmberger H, Stollfuss J, Weber W, Bengel F, Schwaiger M, Roder JD, Siewert JR (2000) Preoperative evaluation of pancreatic masses with positron emission tomography using 18F-fluorodeoxyglucose: diagnostic limitations. World J Surg 24:1121±1129 Shreve PD (1998) Focal fluorine-18 fluorodeoxyglucose accumulation in inflammatory pancreatic disease. Eur J Nucl Med 25:259±264 Siewert JR, Lange J (1990) Lymphadenektomie bei Magenund kolorektalem Karcinom. Dtsch Med Wochenschr 115:391±394 Siewert JR, Stein JH (1998) Classification of adenocarcinoma of the eosophagogastric junction. Br J Surg 85:1457± 1459 Siewert JR, Lange J, Bættcher K, Becker K, Stier A (1986) Lymphadenektomie beim Magencarcinom. Langenbeck's Arch 368:137±148 Siewert JR, Hoelscher AH, Becker K, Goessner W (1987) Cardia cancer: attempt at a therapeutically relevant classification. Chirurg 58:25±32 Siewert JR, Bættcher K, Stein HJ, Roder JD, Busch R (1995) Problem of proximal third gastric carcinoma. World J Surg 19(4):523±531 Siewert JR, Stein JH, Sendler A, Fink U (1999) Surgical resection for cancer of the cardia. Semin Surg Oncol 17:125±131 Siewert JR, Feith M, Werner M, Stein HJ (2000) Adenocarcinoma of the esophagogastric junction. Results of surgical therapy based on the anatomical topographic classification in 1002 consecutive patients. Ann Surg 282:353±361
Spiessl B, Beahrs OH, Hermanek P, Hçtter RVP, Scheibe O, Sobin LH, Wagner G (eds) (1990/1993) TNM atlas. Springer, Berlin Heidelberg New York Spçrr NK, Solomon E, Jansson M, Scheer D, Goodfellow PN, Bodmer WF, Vennstrom B (1984) Chromosomal localisation of the human homologues to the oncogene erb A and B. EMBO J 3:159±163 Stein JH, Feith M, Siewert JR (2000) Cancer of the esophagogastric junction. Surg Oncol 9:35±41 Stella M, De Nardi P, Paganelli G, Magnani P, Mangili F, Sassi I, Baratti D, Gini P, Zito F, Cristallo M, Facio F, DiCarlo V (1994) Avidin-biotin system in radioimmunoguided surgery for colorectal cancer. Advantages and limits. Dis Colon Rectum 37(4):335±343 Stollfuss JC, Glatting G, Friess H, Kocher F, Berger HG, Reske SN (1995) 2-(fluorine-18)-fluoro-2-deoxy-D-glucose PET in detection of pancreatic cancer: value of quantitative image interpretation. Radiology 195:339±344 Sugiyama K, Yonemura Y, Miyazaki I (1989) Immunohistochemical study of epidermal growth factor and epidermal growth factor receptor in gastric carcinoma. Cancer 63:1557±1561 Terui S, Kato H, Hirashima T, Lizuka T, Oyamada H (1982) An evaluation of the mediastinal lymphoscintigram for carcinoma of the esophagus studied with 99mTc rhenium sulfur colloid. Eur J Nucl Med 7:99±101 Triboulet JP, Fabre S, Castel B, Toursel H (2001) Adenocarcinomas of the distal esophagus and cardia: surgical management. Cancer Radiother 5 [Suppl 1]:90s±97s Tsioulias GJ, Wood TF, Morton DL, Bilchik AJ (2000) Lymphatic mapping and focused analysis of sentinel lymph nodes upstage gastrointestinal neoplasms. Arch Surg 135(8):926±932 Vitola JV, Delbeke D, Sandler MP, Campbell MG, Powers TA, Wright JK, Chapman WC, Pinson CW (1996) Positron emission tomography to stage suspected metastatic colorectal carcinoma to the liver. Am J Surg 171:21±26 Waddington WA, Davidson BR, Todd-Pokropek A, Boulos PB, Short MD (1991) Evaluation of a technique for the intraoperative detection of a radiolabelled monoclonal antibody against colorectal cancer. Eur J Nucl Med 18(12):964±972 Waters GS, Geisinger KR, Garske DD, Loggie BW, Levine EA (2000) Sentinel lymph node mapping for carcinoma of the colon: a pilot study. Am Surg 66:943±945 Wiese DA, Saha S, Badin J (1999) Sentinel node mapping in staging of colorectal carcinoma. Am J Clin Pathol 112:542 Wong JH, Steineman S, Calderia C, Bowles J, Namiki T (2002) Ex vivo sentinel node mapping in carcinoma of the colon and rectum. Ann Surg 233:515±521 Yamamoto Y, Takahashi K, Yasuno M, Sakoma T, Mori T (1998) Clinicopathological characteristics of skipping lymph node metastases in patients with colorectal cancer. Jpn J Clin Oncol 28:378±382 Yanagi M, Keller G, Mueller J, Walch A, Werner M, Stein JH, Siewert JR, Hæfler H (2000) Comparison of loss of heterozygosity and microsatellite instability in adenocarcinomas of the distal esophagus and proximal stomach. Virchows Arch 437:605±610
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Chapter 26 Esophageal and Gastrointestinal Cancer Yonemura Y, Ninomiya I, Yamaguchi A, Fushida S, Kimura H, Ohoyama S, Miyazaki I, Endou Y, Tanaka M, Sasaki T (1991) Evaluation of immunoreactivity of erb B2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res 51:1034±1038 Yonemura Y, Ninomiya I, Ohoyama S, Fushida S, Kimura H, Tsugawa K, Kamata T, Yamaguchi A, Miyazaki I, Endou Y, Tanaka M, Sasaki T (1992) Correlation of c-erb B2 protein and lymph node status in early gastric cancer. Oncology 49:363±367
Zimny M, Fass J, Bares R, Cremerius U, Sabrio, Buechin P, Schumpelick V, Bull U (2000) Fluorodeoxyglucose positron emission tomography and the prognosis of pancreatic carcinoma. Scand J Gastroenterol 35:883±888
Chapter 27
SLN Staging in Carcinoids and Neuroendocrine Tumors A. Schauer, M. Schauer, U. Ritzel
Origin, Development and Definitions Pertaining to the Neuroendocrine System The endocrine system has long been divided into two main components: the classic endocrine system, including the pituitary gland, the thyroid gland, the adrenals, the parathyroid glands, the pancreatic islets, the ovary or testes, and then the diffusely dispersed endocrine system located as single cells or cell clusters in various nonendocrine organs. The characteristics of these cells are well known. They can be identified by electron microscopy, by looking for endocrine and/or neuroendocrine granules, or more simply by exploiting the affinity of their secretory granules for silver (argyrophilia) in the Gomori or Grimelius staining methods. Special subtypes of these cells, especially in the small intestine, can reduce silver without exogenous agents. We call these cells argentaffin cells. Pearse, of London, developed a uniform concept, which is thought to include all peripheral neuroendocrine cell systems. This concept was based on the following points: · These cell types have their origin in the neural crest. · An important additional feature of at least some of them is amine precursor uptake and decarboxylation. Based on this, Pearse termed these cells ªamine precursor uptake and decarboxylating cellsº (APUD cells) and all cell types having this quality together, the APUD cell system. With reference to point 2, working with Hkanson and Aures, one of us (A. Schauer), using 14C-labeled dopa or histidine, was able to prove that enterochromaffin cells of rat antrum decarboxylate dopa and store the decarboxylation product, dopamine, whereas enterochromaffin-like cells of the parietal cell part of the stomach decarboxylate histidine to histamine and store this substance (Aures et al. 1968). Concerning point 1, we have performed immunohistochemical staining in approximately 100 em-
bryos or fetuses of different developmental stages, using monoclonal antibodies directed to different specific cell markers. These markers have included neuron-specific enolase, chromogranin A, S100 protein, synaptophysin and Ortho 932, and also such cell-specific substances as 5-hydroxytryptamine. We were never able to detect migration of labeled cells from the neural crest or the neural tube to the intestine, or migration within the intestinal wall, from the neural plexus (plexus submucosus and plexus myentericus) to the intestinal glandular body (Schauer, unpublished data). These results conflict strongly with Pearse's theory. It now seems to be clear that the neuroendocrine cells develop from local ªstem cellsº. Within the superfamily of neuroendocrine tumors the carcinoids can be delineated as a special category. These tumors develop mainly within the epithelial lining of the endoderm-derived mucosa structures, especially of the gastrointestinal and respiratory tracts. Their starting points are progenitor cells of the crypt zones or stem cell elements of the bronchial mucosa (for distribution of neuroendocrine tumors see Fig. 1). These cell elements leave the mucosal or glandular structures and drop down into the submucosa, from where they infiltrate the wall structures. The initial spread downward, without destruction of the pre-existing mucosal structures, has been named ªbourgeonnementº (Masson 1907). The tumor mass develops primarily in the submucosa, flattening the mucosal relief, and growing in a ªmushroom-likeº manner into the lumen.
Epidemiology of Carcinoids This subtype of neuroendocrine tumors is a rare entity. Therefore it is only rarely that a statistical evaluation is performed. The biological behavior depends heavily on the localization of the primary. Survival depends mainly on the tendency to early
27
402
Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors
Fig. 1. Sentinel lymph node localization in neuroendocrine and carcinoid tumors
hematogenous metastatic spread. An analysis of a high number of carcinoids recorded in the Netherlands' Data Collection has given a valuable statistical overview (Table 1).
colon (`midgut tumors,' 75% of total); and the distal colon or rectum (`hindgut tumors,' 10±15% of total). Fifty percent of midgut tumors develop in the appendix.
Distribution and Categories of Gastrointestinal Carcinoids. The neuroendocrine tumors developing from derivatives of the hepatopancreatic circle (so-called islet cell tumors) (see Fig. 1) will not be discussed in this section. Within the intestinal tract, carcinoid tumors can develop in the esophagus, stomach, and duodenum (`foregut tumors,' 10±15% of total); the jejunum, ileum, or colon and as far as the mid-transverse
Carcinoids Developing in the Bronchial System. These localizations are easily understood when we recall that during embryogenesis the tracheobronchial system splits off from the primary endoderm. Thus, it is understandable that carcinoids can also be localized in the bronchial system. Distribution of the Different Types of Neuroendocrine Tumors Developing from Neuroectodermal
Level of Malignancy of Carcinoids and Other Neuroendocrine Tumors (General Overview) Table 1. Epidemiology of carcinoids in The Netherlands ± data collected by Quaedvlieg et al. (2001) Total no. of carcinoids
Cases with available data
Frequency in population
Sex-related rates
Most frequent type < 35 years
2391
619
1.95/100 000
Age 15±25 M < F, F = Ô 1.5/ 100 000; Age 65±75 M > F, M = Ô 7.5± 9.5/100 000
Appendiceal carcinoid
Cellular Potential and Derivatives of the Hepatopancreatic Circle, Excluding Other Neuroendocrine Tumors. The different subtypes in this class are found in specific sites. · Along the sympathetic cord ± Malignant paraganglioma ± Pheochromocytoma · Skin or soft tissue ± Peripheral neuroendocrine tumor (PNET = Merkel cell tumor) · Thyroid gland ± Medullary thyroid cancer · Stomach, duodenum pancreas; main subtypes: ± Insulinoma (pancreas) ± Glucagonoma (pancreas) ± Gastrinoma (pancreas, duodenum, stomach).
Distant metastases Appendiceal carcinoid
Lung carcinoid
1.6%
5.5%
Distant metastases Other types 40%
Level of Malignancy of Carcinoids and Other Neuroendocrine Tumors (General Overview) From the start, it is necessary to bear in mind · That most such tumors can grow as local nodules or in a locally infiltrative manner. · That in malignant cases local lymphogenous metastatic spread is usual, but that as a rule all malignant types can also metastasize by the hematogenous route (Table 2). Hematogenous metastasis can be supposed when vascular invasions are detected histologically. As a preliminary remark we should point out that histopathological confirmation of malignancy based on cellularity is extremely difficult in some
Table 2. Percentages with hematogenous metastasis and malignant behavior of carcinoids and neuroendocrine tumors Carcinoids
Esophagus
Islet cell tumor type Frequency
Malignant behavior
Malignant behavior (%)
Low
Frequent
Insulinoma
5±10%
Stomach
2%
Gastrinoma 60%
Glucagonoma
70±90%; in literature 60%
Duodenum
5%
80%
Gastrinoma
60±90%
Ileum
28%
50%
Small intestine
33%
Rectum
20%
Vipoma
50%
Appendix
45%
Malignant paragangliomas
Regional and hematogenous metastasis frequent
Bronchus
1%
PNET, Merkel-cell tumors
Regional metastasis rare, hematogenous metastasis more frequent
Medullary thyroid cancer
Late metastasis, good prognosis possible
40% 1±2%
10%
403
404
Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors
of the tumors in this category. This is because many of the tumors have quite isomorphic tumor cell nuclei and only a low rate of mitosis. This means, for instance, that especially in the case of insulinomas, when frozen sections are used malignancy cannot be reliably established intraoperatively. In such cases it is necessary to evaluate the tumors in paraffin sections and to look for vascular invasions.
Methods of Confirming the Neuroendocrine Character and the Specific Subtype of these Tumors There are cumulative markers that can confirm the neuroendocrine character of neoplastic lesions: · S100 protein · Chromogranin A · Neuron-specific enolase Positive reactions are primarily essential for certification of the neuroendocrine character. Specific differentiating products can be labeled with antibodies against, for example, to indicate what the tumor entity under scrutiny is: · 5-Hydroxytryptamine (5HT) · Insulin · Glucagon · Gastrin · Pancreatic polypeptide (PP) · Gastrointestinal polypeptide (GIP) · Vasoactive intestinal polypeptide (VIP) · Somatostatin · ACTH · Calcitonin When these results are supported by serological measurements of the secreted biogenic amins and peptides, the tumor type can be verified. The putative level of malignancy can be derived from the type (see Tables 1, 2, 8). It is advisable also to investigate proliferation activity using the antibody MiBI (Ki67). Ploidy evaluations are not very helpful in attempts to ascertaining the degree of malignancy of the tumor, because some benign types are also aneuploid.
Is the SLN Concept Generally Applicable in the Case of Neuroendocrine Tumors? It does not appear possible to answer this question in a helpful way without bearing in mind the following points, which seem to be important: · Not uncommonly, neuroendocrine tumors have a low grade of malignancy and consequently a low metastatic potential. As a rule the patients affected have a long survival, often surviving for 10 years or more. · Neuroendocrine tumors generally spread slowly by way of locoregional lymphogenic metastasis. · The locoregional lymph nodes with the function of a single (group of) sentinel node(s) can be defined in most cases, but their topographical localization does not always favor their en bloc resection with the primary tumor (see also Chapter 26). · While most neuroendocrine tumors have lowgrade malignant potential, some of them are highly malignant. For instance, carcinoids of the lung can transform to high-grade metastatic cancer, and the development of small-cell lung cancer is even possible. Carcinoids of the stomach and ileum can also have a high malignant potential. In rare cases mixed types of carcinoids and adenocarcinoma, sometimes with high grades of malignancy, develop. When all these facts are considered together, it can be stated that it is basically possible to apply the SLN concept in neuroendocrine cancers. However, it must be borne in mind that the grade of malignancy varies very widely and that regional and hematogenous metastatic processes sometimes develop very slowly; hematogenous metastasis (liver, lung) sometimes takes place early in the course, even before locoregional spread has been confirmed clinically.
Early Experience with
111
In-pentetreotide
In investigations by Giammarile et al. (1995), after i.v. administration of 50±190 MBq of 111In-pentetreotide followed by a whole-body scan 1.5±4 h later, tomoscintigraphy or a dual bone, liver, or kidney scan was also performed to improve the anatomical definition. The lesions were visualized in the earliest phase of examination.
Is PET Helpful in Preoperative N-staging of Aggressive Neuroendocrine Tumors?
In 9 of their 49 cases an octreotide scan (OS) detected unsuspected sites of cancer infiltration, but in relation to octreotide-binding receptor proteins located in the tumor cell membranes not all sites detected by other image modalities were visualized. In their conclusion, the authors give a summary of their thoughts on the usefulness of OS in diagnosis, follow-up, and therapeutic management.
Clinical Significance of Blood Chromogranin
Table 4. Stage dependence of CgA positivity Stages I and II
Stage III
Stage IV
50%
60%
100%
In summary, CgA evaluation seems to be the best tumor marker currently available for NETs of the GEP type, lung carcinoids, and neuroblastomas.
Measurement in Neuroendocrine Tumors
Is PET Helpful in Preoperative N-staging of Aggressive Neuroendocrine Tumors?
Tumor marker measurement in neuroendocrine tumors (NETs) is a valuable source of preliminary information after clinical exploration and routine diagnosis followed by histocytopathological certification of the diagnosis but before surgical intervention, including sentinel node evaluation, is started. The tumor markers in current use are neuronspecific enolase (NSE) and chromogranin A (CgA); as in practically all marker tests, the clinical accuracy depends on histotype and extent of the disease (tumor mass). Compared with other markers, CgA now seems to be the best marker for most NETs as it is not dependent on their biological characteristics. Seregin et al. (2001) investigated 290 patients with 127 gastrointestinal (gastroenteropancreatic, GEP) tumors, with encouraging results. These are listed in Tables 3 and 4. Besides the high value in staging of GEPs, CgA evaluations are also useful in lung tumors, but their value is limited in medullary thyroid cancers (MTCs) and peripheral neuroendocrine tumors (pNETs) including Merkel cell tumors (MCCs). Stiranello et al. (2001) found chromogranin was a suitable marker in the blood of patients with neuroendocrine cancer, and even in cancer cases with neuroendocrine component.
The question raised in this heading is justified on two counts: · Because intraoperative determination of the level of malignancy, for example in the case of an insulinoma, is difficult when only frozen sections are available (pathologists cannot decide on the grade of malignancy on the basis of cellularity), PET investigations for evaluation of cancer spread (regional nodes and liver) in combination with knowledge of any hypoglycemic shock and lowered blood sugar levels can be helpful in preoperative diagnosis of the specific cancer, including cancer staging. · In addition, sentinel node detection procedures using blue dye methods and/or 99mTc-colloid labeling can be avoided when PET investigations, which need no local application of contrast agents, have already yielded data needed for staging. In special cases, then, PET can help to avoid unnecessary local injections, which can be followed, for instance, by pancreatic fistula development in the cases of labeled pancreatic neoplasias. Since it is known that neuroendocrine tumors often do not show increased glucose metabolism, +PET is of special interest when combined with CT and MRI results for N-staging.
N. Avril, W. Weber, M. Schwaiger
Table 3. Biomarker evaluation in neuroendocrine tumors (NETs). Data published by Seregni et al. (2001) No. of patients (total)
No. of patients with GEPs
Specificity
Sensitivity
CgA
NSE
CEA
HIAA
CgA
NSE
CEA
HIAA
290
127
86%
100%
91%
100%
68%
33%
15.4%
35%
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors
Preliminary Results in N-staging of Medullary Thyroid Cancer For curative treatment of medullary thyroid cancer, accurate determination of the extent of disease and early identification of any metastases is of critical importance. There is no single sensitive imaging modality available for localizing metastases. Therefore, several imaging modalities, e.g. sonography, CT, MRI, and scintigraphy using pentavalent 99mtechnetium-dimercaptosuccinic acid (DMSA), thallium-201, 111In-pentetreotide, radiolabeled anti-CEA antibodies or 123I-metaiodobenzylguanidine (MIBG), are performed in patients with elevated calcitonin levels. (This does not apply for tumors of the pancreas and upper gastrointestinal tract, which can occasionally express calcitonin). Few studies on PET imaging of MTC are available. Brandt-Mainz et al. (2000) investigated 20 patients with elevated calcitonin levels or sonographic abnormalities in the neck with FDG-PET, detecting tumors in 13 out of 17 patients. In 9 cases these were confirmed by histology and in 4, by CT. There were 5 patients with negative PET scans, in 1 of whom this was a true-negative result while in 4 false-negative results had been obtained. At all validated tumor localizations, FDG-PET detected 12 out of 14 tumor manifestations in the neck, 6 out of 7 mediastinal metastases, 2 pulmonary metastases, and 2 bone metastases. In 2 patients with elevated calcitonin levels, no diagnostic modality was able to detect the tumor location. The sensitivity of FDG-PET in the follow-up of MTC was 76%. In another study, PET was able to identify local recurrences in 6 patients in the presence of elevated calcitonin (Conti et al. 1999). In 4 out of 6 cases for whom follow-up data were obtainable, disease was confirmed either directly by surgery and/or indirectly through changes to or persistence unchanged of laboratory findings. The results suggest that PET may prove to be valuable as an adjunctive imaging test for identifying disease and influencing management in cases where conventional imaging fails to detect suspected disease. This is especially important for detecting metastases in patients for whom surgical resection can result in complete remission.
Preliminary Results in FDG-PET Staging of Neuroendocrine Tumors of the Gastrointestinal Tract Neuroendocrine tumors often are not accompanied by increased glucose metabolism. In a study conducted by Pasquali et al. (1998) the results of FDG-PET and CT in 16 patients with cytologically or histologically confirmed neuroendocrine tumors were compared. Eight patients had slow-growing and aggressive neuroendocrine tumors. FDG uptake was increased in the primary lesion in each of these 8 patients, and the tracer also demonstrated lymph nodes, liver metastases, or both in 5 of them. In 4 patients, additional tumor sites that had remained undetected on a CT scan were identified. Only a small amount of FDG uptake was found in 1 of the 8 cases of slow-growing neuroendocrine tumor. Adams et al. (1998 a) compared FDG-PET with 111 In-somatostatin receptor scintigraphy in 7 patients with metastasizing gastroenteropancreatic (GEP) tumors and 8 patients with MTCs. Two patients with poorly differentiated GEP tumors had increased FDG uptake but negative findings on 111 In-somatostatin receptor scintigraphy. In contrast, in 4 patients with well-differentiated GEP tumors, 22 lymph node metastases and 18 liver metastases were positive on 111In-somatostatin receptor scintigraphy but negative in FDG-PET. In 7 patients with recurrent MTCs and rapidly increasing CEA levels, PET demonstrated 1 pulmonary, 3 osseous, 20 mediastinal, 10 locoregional, and 4 hepatic metastases. Twenty-nine malignant lesions were confirmed by follow-up, and 9 lymph node metastases were surgically removed. In neuroendocrine tumors, therefore, FDG-PET imaging should be restricted to patients with aggressive and poorly differentiated tumors.
Is Determination of Somatostatin Receptor Subtypes (sstr 1±5) in Biopsies Helpful in Sentinel Node Search Strategies and Subsequent Therapy Planning? Different clinical research teams have tried to establish the expression rates of the known subtypes ± 1, 2, 2A, 3 and 5 ± of the somatostatin receptor family in malignant neuroendocrine tumors, and
Strategies to Discriminate Between Gastrointestinal, Pancreatic, and Pulmonary Carcinoids in Metastatic Tissues
also checked for any specificity that might be exploited in differentiating between such tumors and nonendocrine cancers (Catini et al. 2001; Papotti et al. 2001; de Herder and Lamberts 2002; Kulaksiz et al. 2002). The following preliminary results can be summarized: · The expression of the different subtypes in histologically investigated biopsies is significant for the overall expression in the whole of the cancer including its metastases. · The expression of a different subtype can be of fundamental importance in selection of the most efficient labeling substance for lymphoscintigraphy. In their investigations, Kulaksiz et al. (2002) demonstrated that all subtypes of somatostatin receptors (sstr 1±5) were highly expressed in the different neuroendocrine tumor subtypes, but the frequency and pattern of expression varied in the different types. The authors conclude that immunohistochemistry with subtype-specific antibodies can be used in clinical routine work to analyze sstr expression patterns for each patient before treatment and to facilitate well-directed individual medical therapy by administration of subtype-specific somatostatin analogues. de Herder et al. (2002) emphasized that octapeptides analogous to somatostatins bind only with sstr2 and sstr5. Most pancreatic endocrine tumors and carcinoids are supplied with sstr2. It is found in 90% of carcinoids and in 80% of endocrine pancreatic tumors. These tumors can be controlled by continuous administration of octapeptide-ss analogues. Casini et al. (2001) found in their series of cases that patients with a poor prognosis have a low expression of sstr2 and are therefore unresponsive to therapy with ss analogues. Although the majority of neuroendocrine tumors express sstr2, pancreas and prostate cancer, while they express sstr1, do not express sstr2 and are therefore unresponsive to treatment with octreotide, which binds preferentially to sstr2. In the investigations conducted by Papotti et al. (2001) in lung cancers and other NECs, the expression rate for sst receptor 2 was 68%, whereas it was only 24% and 20% for sst receptor subtypes 3 and 5, respectively. Also, some nonneuroendocrine cancers showed some weak reactivity.
Special Problems in Documentation of Early Lymphatic Spread of Neuroendocrine Cancers in the Upper Abdominal Region In many positions, the interpretation of enlarged lymph nodes seen on CT, MRI, and PET imaging is problematic, because inflammatory processes can mimic cancer involvement. However, in suspicious cases further investigations are indicated to clarify the findings. One option is more specific labeling of neuroendocrine primaries and their metastases by means of octreotides (as substitutes for somatostatin), which bind specifically to somatostatin receptor protein on the surface structures of neuroendocrine cancer cells. This binding process can be made visible by radioscintigraphic methods. At present, this nuclear medical strategy is the most specific one available for detection of lymphogenic and organ-related hematogenous metastatic processes of this tumor class sited some distance away from the primary (Giovannini et al. 1995; Banzo et al. 2001). The remaining, unsolved problems stem from the fact that primaries and regional lymph nodes are sometimes so close to each other that the nodes cannot be reliably distinguished by means of the imaging strategies. Figure 2 illustrates this problem in a neuroendocrine stomach cancer located at the corpusantrum transition and with a cancer-infiltrated lymph node a very short distance from the stomach wall.
Strategies to Discriminate Between Gastrointestinal, Pancreatic, and Pulmonary Carcinoids in Metastatic Tissues (Lymph Nodes, Liver) Cai et al. (2001) compared the expression rates of cytokeratins 7 and 20 and thyroid-transcription factor 1 (TTF1) in cases with pulmonary, gastrointestinal, and pancreatic carcinoids in an attempt to find how discrimination might be improved in metastatic carcinoid cases when only metastatic tissue is available for histopathological analysis. The results of these investigations are summarized in Table 5. The results allow the conclusion that the differential diagnosis of a lung metastasis from abdominal carcinoids against a primary pulmonary
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors Fig. 2. Carcinoid tumor localized at the corpus-antrum transition, infiltrating the stomach wall structures with a regional lymph node metastasis in the immediate vicinity; the two cannot be separated by imaging techniques
Table 5. Cytokeratins and TTF-1 as markers for discrimination of carcinoid subtypes according to Cai et al. (2001) Carcinoid subtype
CK7 positivity rate
P-values of ratios
CK20 positivity rate
P-values of ratios
TT-F1 positivity rate
P-values of relations
Lung carcinoids (LECs)
10/16 (63%)
< 0.001
0/16 0%
Relative to GIC and PEC (< 0.05)
11/16 69%
< 0.001
Gastrointestinal carcinoids (GICs)
5/46 (11%)
Pancreatic carcinoids (PETs)
6/12 (50%)
Relative to LEC and GIC (< 0.01)
24%
1/46 2%
33%
0/12 0%
carcinoid, in particular, can benefit from use of the immunohistochemical evaluable markers discussed (CK7, CK20 and TT F1).
Characteristics and Spectrum of Neuroendocrine (Carcinoid) Tumors of the Stomach With reference to application of the sentinel node concept, in many points this class of tumors simply cannot be considered in parallel with more common types of gastric cancer. The main differences are: · Localization of carcinoids mostly in the upper parts of the stomach, as against localization of
< 0.001
stomach cancers in the antral region in 60±70% of cases. · Different macroscopic growth pattern, i.e., smooth surface with growth reminiscent of the cap of a mushroom in carcinoids, as opposed to cauliflower-like structure in differentiated adenocarcinomas or diffuse wall infiltration in anaplastic gastric cancers. · Different biological behavior from gastric cancers, with mostly slower locoregional and hematogenous spread.
Histopathology and Immunohistochemical Confirmation of Gastric Carcinoids
Characteristics and Spectrum of Neuroendocrine (Carcinoid) Tumors of the Stomach Malignant carcinoid of the stomach is localized in the subcardial upper oxyntic (parietal) cell area. Cancer-infiltrated lymph nodes may be localized directly in the subphrenic paragastric soft tissue or in the transitional area before the esophagus. In node-positive cases transhiatic paraesophageal node excision as performed in AEG cancers (see Chapter 26) or thoracotomy with further node excision is essential. Therefore ± while we continue to have no more accurate means of preoperative N-staging ± accurate intraoperative node staging by pathologists will help us to avoid unnecessary thoracotomies and revision operations. The characteristic situation is presented in Fig. 3. The possible types of metastasis ± which
can be seen from the figure ± are paragastric and paraesophageal sub- and supraphrenic metastatic processes, all in N1 positions. We can be sure not only that skip metastasis may occur near the esophagogastric junction, but also that bypassing of more deeply located nodes may have a role (Fig. 3).
Lymphogenic Metastasis (Rough Overview) Stomach carcinoids have a much lower potential for spread along lymph node chains or development of lymphangiosis carcinomatosa. Therefore, new approaches to the more precise definition of the N-positions for carcinoids of the stomach are overdue. In these circumstances, it is of interest to detect the primary as early as possible and to try to obtain a preoperative nodal staging using sentinel node detection techniques: · Somatostatin receptor labeling · 99mTc administration around the primary (submucosa) so as to be forearmed preoperatively with the knowledge of whether or not additional hiatotomy or thoracotomy will be necessary. In conclusion, collected experience in gastric carcinoids suggests that the main routes for lymphatic metastasis follow compartments I and II, whereas compartment III seem to be less frequently involved.
Histopathology and Immunohistochemical Confirmation of Gastric Carcinoids
Fig. 3. Typical localization of a gastric carcinoid localized in the oxyntic cell area. Paragastric and more rarely paraesophageal sub- and supraphrenic lymph nodes can be involved in metastasis. Intraoperative node evaluation using ultrarapid immunohistochemical analysis (see section by Nåhrig et al. in this book, Chapter 17) can help to increase optimal locoregional cancer clearance
In gastric carcinoid tumors it is necessary to differentiate between: (a) microcarcinoidosis with development of tiny interstitial carcinoid foci and (b) extended infiltratively growing carcinoids. Figure 4 demonstrates the typical substrate of microcarcinoidosis, while a rare case of gastrointestinal neuroendocrine cancer expressing calcitonin in addition to other neuroendocrine activities is illustrated in Fig. 5. However, it is difficult to define and localize early regional lymphogenic spread. This must be seen under different aspects. Local lymphogenous spread is dependent at least to some degree on the particular subtype concerned.
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors Fig. 4. Examples of immunohistochemical confirmation of microcarcinoidosis of the stomach: chronic atrophic gastritis with intestinal metaplasia of the glandular body. Interstitially, invasively growing carcinoid tumor cell formations are seen. Immunohistochemical staining was positive for chromogranin A and synaptophysin
Fig. 5. Intestinal neuroendocrine tumor showing strongly positive reaction with antibodies directed to calcitonin (rare case)
Four groups of gastric carcinoid tumors can be defined: I. Carcinoid type I in cases with atrophic corpus gastritis II. Carcinoid type II in connection with multiple endocrine neoplasm (MEN) type I III. Carcinoid type III, with sporadic development IV. Neuroendocrine carcinoma These subtypes are characterized in Table 6. In the presence of partly Helicobacter pylori-positive, chronic atrophic gastritis with hypergastrinemia, multiple gastric carcinoid tumors can develop, possibly as the consequence of existing microcarcinoidosis (see also Bordi 1999). Case reports have been published (Brundler et al. 1999) in which the status of multiple carcinoids persisted
for years with no signs of progression. In such cases it may be advisable to reflect whether lymph node labeling with blue dye or 99mTc-nanocolloid, or even better, somatostatin receptor labeling with 111 In-octreotides and, depending on the results, surgical procedures are indicated.
Detection of Stomach Carcinoids by Means of Somatostatin Receptor Scintigraphy Differential Diagnosis Against Pancreatic Neuroendocrine Tumors (NEC). Gibril et al. (2000) found positive results in 19 (= 12%) of 162 cases with hypergastrinemia (Zollinger-Ellison, chronic atrophic gastritis) when these were all investigated
Clinical and Morphological Correlations of Gastric Carcinoids Table 6. Subtypes and biological behavior of carcinoids of the stomach (LN lymph node/s) Type I
Type II (associated with MEN 1)
Type III
Type IV neuroendocrine cancer
Localization
Oxyntic cell area
Oxyntic cell area
Mostly oxyntic cell area
Fundus, corpus and antrum
Frequency, cellular derivation
70±80% of all ECLcell carcinoids
6% of all ECL-cell carcinoids, mostly multiple
±25% of all stomach carcinoids, mostly multiple
Very rare, connected with MEN I
Dependencies
Chronic atrophic gastritis (CAG), autoimmune gastritis, hypergastrinemia
Strong link with Zollinger-Ellison syndrome (ZES)
Malignant potential
Helicobacter infection stimulates, low malignant potential
Sex dependence
70% Female
M:F=1:1
75% Male
66±70% Male
Age (mean values)
All decades after 2nd
Average 50 years
Average 55 years
Average 63 years
Extension
Mucosa, submucosa and muscularis 90%
Mostly < 1.5 cm, infiltration of submucosa in 91%
Mostly solitary, > 2 cm in 33%, infiltration of muscularis in 76%, serosal infiltration in 53%
Average diameter 4.2 cm, exophytic growth frequently deep infiltration and metastases
Proliferation activity necrosis
Mostly very low, mostly no necrosis
Regional LN metastases
Very rare
30%
75% hematogenous metastases, mostly in liver
Regional and hematogenous metastases, as in gastric cancer
Death rate
No reports of cases ending in death
Mostly favorable behavior, but rapid progress and transformation to neuroendocrine cancer possible
Death rate 27%, average survival 28 months
As in gastric cancer, average 7 months after diagnosis
Higher than in I and II. Increased proliferation, focal necroses in some cases
High mitotic activity, extensive necroses
using somatostatin receptor scintigraphy (SRS). The sensitivity of SRS in localizing gastric carcinoids was 75% and the specificity 95%. The positive and negative predictive values were 63% and 97%, respectively. In MEN I cases it must be realized that the localization of the neoplasm in the upper part of the abdomen is caused by a gastric carcinoid and not a pancreatic endocrine tumor.
Clinical and Morphological Correlations of Gastric Carcinoids Statistical Evaluation of 1094 Cases by Soga (1997). For application of the SLN concept in cases of gastric carcinoid a primary overview of the local progression and both regional and hematogenous spread is desirable and helpful in further decision making. Soga (1997) analyzed 1011 of the 1094 cases more precisely by means of the Gut-Pancreatic Endocrinoma Analyzing System, obtaining the results summarized in Table 7.
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors Table 7. Analysis of 1011 gastric carcinoids by locoregional, systemic, and clinical behavior No. of cases
Carcinoids < 20 mm
Rate of submucosal infiltration
Rate of metastasis in carcinoid < 20 mm
5HT activity overall
Carcinoid syndrome
1011
60.8%
53.8%
15.1%
22.3%
4%
Localization and Spectrum of Carcinoids of Small Intestine and Colon Carcinoids of the intestinal tract are seldom localized in duodenum and jejunum, but more frequently in the ileum and rectum. This makes it clear that the most frequent and also most important localizations of sentinel nodes are: · Lymph nodes localized around the caput of the pancreas for duodenal carcinoids. · Mesenteric lymph nodes for carcinoids of the jejunum. · Mesenteric lymph nodes are the first stations in lymphogenic spread from ileal carcinoids. · Perirectal nodes and retrorectal, often small, nodes can be the first stations in the metastatic process from rectal carcinoids.
Carcinoids of the Colon, Especially of the Rectum, and Search for Metastasis For these tumors the same principles for staging must be used as in investigations of rectal cancer. · Hematogenous metastasis into the liver must be excluded preoperatively, and lung metastasis must also be excluded, especially when tumors are located deep in the rectum. · The N1/2 position can be localized perirectally towards the vascular support or also retrorectally in the direction of the os sacrum. These topographical differences cause quite different preoperative assessments of the location of sentinel nodes. However, preoperative estimations are supported by the knowledge of frequency of lymph node metastases referred to the different localizations of the primaries. Based on many series, it can be stated that the frequency of lymph node involvement is · Lowest in rectal carcinoids · Higher in duodenal carcinoids · More than 40% in jejunal carcinoids · Very high, approximately 85%, in ileal carcinoids
Table 8. Lymph node and hematogenous metastases from carcinoids of small intestine and colon (Padberg et al. 2000) Regional lymph node (sentinel lymph node, SLN) metastasis Duodenal
2/7
28.6%
Jejunum
3/7
42.9%
Ileum
24/28
85.7%
Rectum
1/22
4.5%
Ileum
14/28
50%
Rectum
1/22
4.5%
Distant metastases
These values were elaborated by Padberg et al. (2000) and are summarized in Table 8.
Lymphatic Basins and SLN Positions Corresponding to Carcinoids Located in Small Intestine and Colon It is now known where the sentinel nodes corresponding to various types of tumors are likely to be found. · Duodenal carcinoids have their sentinel node(s) in the peripancreatic region. ± In early stages, when only local surgical treatment is planned, intraoperative lymph node investigations using frozen sections, imprint cytology and ultrarapid immunohistochemistry procedures according to Nåhrig and Hæfler (see Chapter 17) may be used. ± In cases with suspected N1 (sentinel node) involvement and planned duodenopancreatectomy using Whipple's operation principles, intraoperative histo- and cytopathological lymph node investigations may help to confirm whether this extensive surgery would be justified.
Treatment Strategies in Gastrointestinal Carcinoids
± In more advanced cases, when involvement of the N2 position needs to be excluded or confirmed, histopathological lymph node investigations of these nodes are important for postoperative decisions for or against adjuvant therapy regimens (blocking of the somatostatin receptors or administration of cytostatics in cases with lower degrees of differentiation and higher degrees of malignancy). · 1. Jejunal and, especially, ileal carcinoids show the highest degrees of regional lymph node involvement and hematogenous metastasis to the liver. Therefore, preoperative investigations of the liver (CT, sonography and scintigraphic methods) are very important. 2. Concerning involvement of the sentinel node(s), the lymph nodes along the course of the intestine and mesenteric nodes must be examined by somatostatin receptor scintigraphy and other methods preoperatively. From these facts it must be concluded that before surgical treatment of ileal carcinoids with the aim of R0 resection, intensive CT and nuclear medical investigations are necessary to exclude metastases to the liver and lung(s). With reference to local R0 resection, preoperative analysis by means of somatostatin receptor scintigraphy seems to be helpful insofar as it can give an overall view of the local spread.
Influence of Hematogenous Spread on Survival As mentioned above, the frequency of lymphogenous spread is higher in ileal carcinoids (85%) than in carcinoids in any other site. An extremely high frequency of hematogenous metastasis and low survival rates are also found with rectal carcinoids. This is clearly demonstrated in the Kaplan-Meier curves published by Padberg et al. (2000) and reproduced in Fig. 6 a, b.
Treatment Strategies in Gastrointestinal Carcinoids Ahlman 1999 has proposed ways of differentiating various subtypes of gastrointestinal carcinoid to allow individualized carcinoid treatment. Generally patients with distant metastases can undergo resection with curative intent or for symp-
Fig. 6 a, b. Survival of patients with a nonileal and b ileal carcinoids with and without metastases, according to Padberg et al. (2000)
tom palliation. Such treatment should be related to the growth rate (S-phase, MiBI evaluation etc.). In cases with midgut carcinoids and bilobar liver metastases interventional treatment (octreotide and/or interferon) seems to prolong survival and to reduce symptoms caused by hormonal activities (see also Tomasetti et al. 2000). In cases with a foregut carcinoid syndrome more problems can develop as a result of histamine release during interventional treatment, and these must be taken into account when the treatment is planned. Angeletti et al. (1999) treated 10 patients with GEP endocrine tumors with a daily dose of 500 lg octreotide. The results suggest that 1 year of octreotide treatment is effective in a long-term stabilization of tumoral progression in patients with metastatic GEP tumors. Debray et al. (2001) emphasize the necessity for further analysis of scintigraphic hot spots by radiological imaging modalities before treatment.
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors
Endocrine Tumors of the Pancreas and Duodenum As already pointed out, these tumors mainly develop within the pancreas, but gastrinoma, especially, can also develop in the stomach or duodenum. In the pancreas the tumors do not develop from the islet cells, but from the neuroendocrine cells of the ductal system. They grow within the parenchyma, and sometimes these tumors are small (approx. 7± 8 mm), but sometimes these tumors grow out of the pancreatic body. In such cases the tumors are ªbornº at the surface of the pancreatic body. Peritumoral labeling for a sentinel node search is not possible in the case of pancreatic endocrine tumors, in contrast to many other tumor types, because there is a danger of inducing pancreatitis or secretory fistula formation by activation of lipolytic and tryptic enzyme activities. In cases with endocrine tumors of the duodenum (gastrinomas) submucous injection of a small volume of labeling solution seems to be possible. In view of all these precautions, in the preoperative stage of diagnosis radioimaging and nuclear medical evaluation are the only techniques that might be helpful. Intraoperatively, palpation of the pancreatic body and regional lymph node basins are the most useful techniques in staging. Because most pancreatic tumors are localized in the body or in the tail of the pancreas, the first nodal station will be found in the supra- and infrapancreatic regions. For an overview of the rate of SLN involvement and further lymphogenic spread the overview given by Padberg et al. (2000) is informative. Figure 7 gives a short overview of subtypes of endocrine pancreatic tumors; their age and sex distribution are shown in Fig. 8, their ranges of increased serum hormone levels in Table 9, and their levels of malignancy in Fig. 9. The data summarized are valuable in clinical diagnosis and for the selection of surgical strategies designed to allow R0 resection. In inoperative cases conservative (palliative) treatment strategies can be considered. Figure 8 illustrates the age and sex distribution of 203 cases of pancreatic neuroendocrine tumors. Whereas there is a much higher rate of female than male patients in the third decade, in subsequent decades the sex distribution is approximately equal (Fig. 8).
Fig. 7. Frequencies of the different types in 365 endocrine pancreatic tumors. Absolute numbers above the columns (I insulinomas, GI glucagonomas, S somatostatinomas, PP PPomas (pancreatic polypeptide-secreting tumors), G gastrinomas, V vipomas, N nonsecretory active tumors, E tumors with ectopic hormone secretion)
Table 9. Hormone concentrations in serum in patients with endocrine pancreatic tumors (PP pancreatic polypeptide, PP-oma PP-secreting tumor, VIP vasoactive intestinal polypeptide, ACTH corticotropin = adrenocorticotropic hormone) Tumor type (n)
Hormone
Concentration (pmol/l) (Reference range)
Insulinomas
Insulin
280±1380
(108) Glucagonomas
(40±90) Glucagon
(23) PP-omas
(20±45) PP
(14) Gastrinomas
Gastrin
VIP
(2)
60±1300 (1±15)
ACTH
(8) Calcitoninomas
450±1320 (17±115)
(32) Corticotropinomas
600±24 000 (2±300)
(58) Vipomas
715±3700
23±1700 (3±15)
Calcitonin
>10700 (1.7)
Spectrum of Neuroendocrine Tumors of the Lung
Figs. 10±19. Neuroendocrine tumors of the pancreas and the gastrointestinal tract Fig. 8. Age and sex distribution of 203 endocrine pancreatic tumors (absolute numbers of cases)
Fig. 10. Endocrine tumor of the corpus region of the pancreas (ªborn outº of the organ)
Macroscopic, Histopathological and Immunohistochemical Subtyping of Pancreatic Endocrine Tumors
Fig. 9. Grade of malignancy of endocrine pancreatic tumors. Absolute numbers of cases 218/365 (60%); for numbers of benign and malignant tumors see figures beside the individual columns (I insulinomas, GI glucagonomas, S somatostatinomas, PP PPomas (pancreatic polypeptide-secreting tumors), G gastrinomas, V vipomas, N nonsecretory active tumors, E tumors with ectopic hormone secretion)
The evidence of malignancy of highly differentiated, isomorphic tumors of the pancreas cannot be reliable determined intraoperatively in frozen sections. Vascular invasion and lymph node metastasis are helpful criteria for confirming that a tumor is malignant. Figures 10±19 illustrate cases seen in daily routine practice, and the macro- and microscopic and immunohistochemical characteristics used for subtyping are noted.
Spectrum of Neuroendocrine Tumors of the Lung The increased serum concentrations of various hormones in the different pancreatic neuroendocrine tumors help in specifying the tumor. Because the rates of malignant transformations are quite different in the different subtypes the increased serum values are also helpful in the assessment of the grade of malignancy already in the preoperative stage (Table 9). The localizations of insulinomas are mostly assessed by intraoperative palpation combined with ultrasonography (Chatziioannou et al. 2001).
The different subtypes of neuroendocrine tumors of the lung were reviewed in 1997 by Hæfler, working from publications by Arrigoni et al. (1972), Gould et al. (1983), Travis et al. (1991), Bonato et al. (1992), and Capella et al. (1995). In the last paper mentioned, the whole spectrum of malignancies that may occur in the different subtypes was described, extending from benign through low-grade to high-grade malignant cancers. In order to develop readers' appreciation of the necessity for regional lymph node staging intraoperatively to enable ªR0 resection,º some aspects of the review by Capella et al. are discussed in this chapter.
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors Fig. 11. Top view of a gastrinoma of the pancreas: moderate polymorphism of the nuclei, moderate mitotic activity. Malignant behavior must be assumed
Fig. 12. Gastinoma of the pancreas: higher magnification. Note close connection of the tumor cells to the capillary system
Fig. 13. Insulinoma: note the close relation of the tumor cells to the well-developed capillary system (HE)
Spectrum of Neuroendocrine Tumors of the Lung Fig. 14. Insulinoma. The cytoplasm of the tumor cell is intensively packed with insulin granules. Mitotic activity is nearly absent. No vascular invasions can be seen (immunohistochemical staining for insulin)
Fig. 15. Insulinoma (primary). Immunohistochemical staining for insulin
According to Capella et al. (1995), neuroendocrine tumors of the lung can be divided in the following ways: · Benign or low-grade malignant, highly differentiated neuroendocrine tumors [typical (classical) carcinoid]. · Low-grade malignant neuroendocrine cancer (atypical carcinoid). · High-grade malignant, small-cell or intermediate-cell neuroendocrine cancer (partly large-cell neuroendocrine carcinoma) (Table 10). About group in this system, Hæfler adds the remark: ªIf metastases are already detectable the tumor should be classified as highly differentiated neuroendocrine carcinoma.º This classification, which needs close interdisciplinary cooperation between clinicians and pathologists, already goes some way to answering the questions of:
· How important the classification based on the listed subtypes is for preoperative planning and also with respect to operability. · How important evaluation of the degree of malignancy of the primary is with respect to sentinel node detection and, if preoperatively already possible, whether the node(s) is/are already tumor infiltrated. These two important questions will be answered in the next section. To come to a clear-cut judgment, in the following overview the main features of the three different subgroups are listed. The most important question to be answered is that discussed in the next section.
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors Fig. 16 a, b. Insulinoma: the tumor shows low proliferative activity (nuclei intensively stained red) [staining for proliferation-associated nuclear protein using the antibody MiBI (Ki 67)]
Is Preoperative Sentinel Node Imaging Helpful in Increasing the Cure Rates in Neuroendocrine Lung Tumors? This question must be discussed with reference to the three different subgroups in view of the different degrees of malignancy and, with these, the rates of locoregional and hematogenous spread. Type I: In the case of highly differentiated neuroendocrine tumors it must be assumed that the density of somatostatin receptors present is high. Therefore, it should be possible to label primaries and regional lymph node metastases with a high degree of efficiency. In our opinion, labeling is useful even when malignancy is absent or only of a low grade, as it can make it possible to achieve R0 resection operatively in nearly all cases. Besides
radioimmunolabeling using the ªsomatostatin receptor-binding conceptº, by analogy with lung cancer other procedures should also be discussed (see Chapter 24). Type II: Although this tumor class can be divided into two further subgroups, one with an excellent prognosis and one with a 50% death rate within 5 years, in both groups lymph node staging by means of somatostatin receptor imaging may help to increase the rate of R0 resection. In cases with loss of differentiation and enhanced proliferation, besides receptor imaging 99mTc-labeling or the Sinerem labeling-method also may support tracing of the sentinel nodes (99mTc needs to be applied into the marginal areas of the tumor, Sinerem can be given systemically). Type III: In these more or less anaplastic cases with extensive loss of differentiation use of the so-
Spectrum of Neuroendocrine Tumors of the Lung Fig. 17 a, b. Glucagonoma (immunohistochemical staining for glucagon)
Fig. 18. Vipoma [immunohistochemical staining for vasoactive intestinal peptide (ViP)]
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors Fig. 19. Gastrinoma (immunohistochemical staining for gastrin)
Table 10. Important histopathological and biological features relating to different degrees of malignancy (HPF high-power field) Benign or low-grade (I) of malignancy
Highly differentiated neuroendocrine carcinoma (atypical carcinoid (II))
Highly malignant and destructive neuroendocrine cancer (III)
Extension < 3 cm
Extension ±9 cm
Diffuse invasive growth pattern
No influence of growth pattern
Histological features
Small cell, intermediary cellular mostly with mass-necrosis large cell type (DD: large cell lung cancer)
Pattern
Higher degree of polymorphism
Rate of mitoses 10 per HPF
Adenoid
Hyperchromasia at single cells
Rate of MiBI-positive cells 27% (2.7±47) per HPF
Solid trabecular
Necrosis
DD: large cell nonneuroendocrine cancer (at least two neuromarkers, e.g., NSE, synaptophysin chromogranin, Phe5, PGPa5, Leu 7c positive in neuroendocrine cancers)
Paraganglioid
Rate of mitoses 3±10
5-year survival >15%
Spindle-cell shaped
MiBI average 5.1% Two subgroups according to Hæfler: A: MiBI 0.3±3.4, prognosis excellent B: MiBI > 7.3 Death rate 50%
Rate of mitoses 0±3/HPF MiB average < 1.1, average 0.6 5-Year survival 90±98%
5-Year survival rates (A+B): N0 = 85±90% N1 = 37%
Peripheral Neuroendocrine Cancers Located Subepidermally or Deeper
matostatin receptor labeling seems to be questionable, because supposedly loss of differentiation results in loss of receptor equipment. In these cases lymph node staging has to be handled in the same way as in carcinomas of the bronchial system (see Chapter 24).
Neuroendocrine Tumors of the Retroperitoneum and the Prevertebral Thoracic and Cervical Region This group embraces the pheochromocytomas and the malignant paragangliomas (Figs. 20±22). Pheochromocytomas mostly show a benign behavior, malignancies seldom being seen. In view of the close connection of cancer cells to the capillary system belonging to the neoplasm in such cases, hematogenous metastases into the lungs and into the liver are more relevant than regional lymph node involvement. Therefore, it is not necessary to reflect in detail about regional lymph nodes along the large vessels (aorta, vena cava inferior) in the retroperitoneum that might be involved. The same reflection may be emphasized for malignant paragangliomas, developing along the sympathetic prevertebral system. The main features of these tumor types are illustrated in Fig. 23.
Peripheral Neuroendocrine Cancers Located Subepidermally or Deeper The peripheral neuroendocrine tumor (PNET) is also referred to as the ªMerkel cell tumorº after the first person to report it. As far as the primary is concerned, the following experiences must be dealt with: · This tumor is mostly excised by surgeons or dermatologists without basic reflection on any further procedures necessary. · Histopathologically this tumor often presents an unspecific epithelial ªround-cell pictureº quite similar to that of a lymphoma. Therefore, misinterpretations are not uncommon in histopathological diagnosis. Consequently, even in the first step of the investigations, histopathologists should also use the lymphoma markers (common leukocyte antigen) and
Figs. 20±23. Neuroendocrine tumors of the retroperitoneum and prevertebral thoracic and cervical region Fig. 20. Macroscopic picture of a suprarenally located pheochromocytoma, which can be malignant. It is necessary to check the regional lymph nodes and exclude lung and liver metastases
neuromarkers mentioned above (S100 protein, chromogranin, synaptophysin, etc.) (Fig. 24), so as to obtain clear-cut discrimination between these two categories. Using S100 protein as a marker, care must be taken to avoid confusion with malignant melanoma (HMB45 must be used in addition in doubtful cases). The epithelial character of the tumor can be confirmed by staining for cytokeratins using antibodies directed to cytokeratins 5 and 6. To find out about both the malignant potential and the nuclear grade, investigations of proliferative activity, using the antibody MiBI (Ki 67), are helpful. Approximate information about the proliferative compartment gives a basis for preoperative assessments concerning hematogenous metastasis to the lungs, the brain, and the liver. In this context radiological imaging techniques are the most helpful methods. Before regional lymph node staging is performed on the basis of the SLN concept, it is necessary to consider whether the primary should be diagnosed before the operation in puncture biopsy material, or by examination of the extirpated primary. Then all histopathological and immunohistochemical investigations needed for typing, grading and evaluation of the proliferative activity can be performed to a good standard.
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors Fig. 21. Histopathological picture of a pheochromocytoma: moderate polymorphous cell populations with abundant development of cytoplasm (AFIP)
Fig. 22. Pheochromocytoma: demonstration of the catecholamine-containing cytoplasmic granules by chromate staining
Fig. 23. Malignant paraganglioma (immunohistochemical staining with antibodies directed to chromogranin A)
Search for Metastases in Neuroendocrine Tumors Before Surgical Treatment Fig. 24. Merkel-cell tumor. Note the lymphoma-like cellularity and the high rate of mitoses (:). Immunohistochemical staining for chromogranin A
When total extirpation of the primary without previous investigations is planned, 99mTc may be injected into the area surrounding the tumor to trace the sites of the sentinel nodes, as in melanoma investigations.
Neuroendocrine Cells in Carcinomas In a series of carcinomas with different origins, endocrine cells can be found as subpopulations. It is well known that in such cases these cell populations do not only accompany the tumor growth, but are also found in metastases of the cancers. This means that they are an integral part of these cancers. The endocrine cells can be part of the following cancers: for instance, ovarian cancers developing from cystomas or teratomas with malignant components can reach large diameters. The neuroendocrine components can be verified in such cases by investigations of the serum and urine, looking for corresponding neuroendocrine markers and, in biopsy material, by immunohistochemical investigations. The most important types of such lesions are listed in Table 11. Knowledge of the existence of the above specific subtypes of cancers that can develop in organs with and without pre-existent neuroendocrine cell populations is not especially valuable in the selection of surgical treatments and adjuvant therapy regimens. In addition, in connection with concepts that can be used in detection of sentinel nodes, as a rule, the cell populations with mostly low density are not helpful in detection of metastases by somatostatin receptor scintigraphic search. However,
knowledge of these subtypes is of interest for the pathologist as this can help to avoid misdiagnosing them as low differentiation carcinoids or neuroendocrine tumors, especially in lung, colon, and pancreas. In general, in most cases the SLN search must be handled as in more common types of carcinoma in the sites mentioned.
Search for Metastases in Neuroendocrine Tumors Before Surgical Treatment Clinically it is our experience that in tumor lesions with certain characteristic localizations, e.g., proximal parts of the stomach, duodenum, pancreas, ileum, and rectum, neuroendocrine tumor types must be taken into account. This is essential for the development of surgical and adjuvant treatment strategies. Therefore, at least two points seem to be important for staging procedures of this tumor class: · Compared with skin tumors (melanomas) and breast cancer, the preoperative SLN search is much more difficult in neuroendocrine tumor categories. ± These difficulties result from the very close locations of primaries and their SLNs, which means they are superimposed in gamma probe and radiological images. · The exclusion or confirmation of hematogenous metastasis by means of an octreotide scintigraphic evaluation helps preoperatively in planning patient-adapted treatment strategies. A few cases demonstrate this tumor staging by scintigraphic analysis of the spread of somatostatin receptor-positive cancer formation.
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors Table 11. Investigations performed to check for neuroendocrine components in cancers originating in various organs Origin of the cancer
Pre-existent neuroendocrine cells
Pathohistology-based diagnosis
Ovary
±
Cystadenoma mucinosum and mucinous
±
Cystadenocarcinoma
Testis
±
Benign and malignant teratoma
Lungs
+
Different carcinoma types (adeno-, squamous-cell, large-cell cancer)
Stomach
+
Adenocarcinoma
Colon
+
Adenoma and adenocarcinoma
Appendix
+
Adenocarcinoid
Gall bladder
±
Adenocarcinoma
Pancreas
+
Adenocarcinoma
Prostatic gland
+
Adenocarcinoma
Mamma
+
Adenocarcinoma (ductal cancers with solid and glandular growth pattern)
Case reports Case 1. Case 1 demonstrates a somatostatin receptor-positive, sharply delineated, tumor in the thymic region of the ventral mediastinum in a 69year-old man without further cancer formations in the lungs, and in mediastinal, parahilar, paratracheal or cervical lymph node regions. Histopathologically, this tumor expressed neuroendocrine markers (chromogranin A, etc.) and could be defined as carcinoid of the thymus (see Fig. 25).
Case 2. In case 2 octreotide labeling of a somatostatin receptor-positive neuroendocrine tumor of the pancreatic ªheadº with multiple, partly big liver metastases in a 65-year-old woman did not allow either detection or exclusion of regional lymph node metastases in the marginal areas of the pancreatic body (Fig. 26). Case 3. In an 82-year-old woman with an ileum carcinoid and multiple liver metastases, large somatostatin receptor-positive lymph nodules are Fig. 25. Indium-111-octreotide scintigraphy in a 69-year-old male patient with a primary carcinoid in the thymus, showing the primary lesion in the mediastinum. No signs of lymph node or hematogenous metastases Fig. 26. Indium-111-octreotide scintigraphy in a 65-year-old female patient with carcinoid of the pancreas and many receptor-positive liver metastases
25
26
Adjuvant Therapy Regimens in the Treatment of Neuroendocrine Tumors Related to the Sentinel Fig. 27. Indium111-octreotide scintigraphy in an 82year-old female patient with a carcinoid of the terminal ileum and liver metastases
seen in the mesenteric areas. A sentinel node cannot be located, because of advanced extensive lymphatic spread (Fig. 27).
Developments in Detection of Neuroendocrine Cancers and their Metastases in SLNs using 111 In-labeled and 123I or 131I Compounds The Rotterdam report of 1993 included an overview of diagnosis and therapy. Krenning et al. (1993) reported on their scintigraphic evaluations in the search for neuroendocrine primaries and their locoregional spread including the regional SLNs. The Rotterdam group used 111In-DTPA-D-Phe1 and 123I-Tyr 3-labeled octreotide for their studies. One of the important points emphasized by the authors is that in the search for primaries or their metastases false-positive reactions can develop in inflammatory processes, granuloma-like lesions rich in mononuclear cells or autoimmune processes. As a rule, however, radiolabeled octreotide is very helpful in confirmation and localization of neuroendocrine primaries and their metastases. The authors conclude from their results that besides the successful binding of the somatostatinanalogue octreotide, peptides, such as bombesin, substance P, or fragments of monoclonal antibodies, may also be useful in the detection of neuroendocrine tumors and their metastases. In the later comparative studies by Hoefnagel (1994) using 111In-pentetreotide and 123I- or 131I-me-
taiodobenzylguanidine (MIBG) as indicators, it was found that both radionuclides used with the compounds mentioned are sensitive indicators of neural crest tumors. The specificity in diagnosis and also the indications for therapy are different. In contrast to MIBG, 111In-pentetreotide is not specific for detection of neuroendocrine tumors and their metastatic spread, because positive scintigraphic results are also obtained in other tumors, in granulomas, and in autoimmune diseases. On the basis of these experiences recorded by his own group, Hoefnagel (1994) suggested that 131I-MIBG was not effective only in diagnosis but also in therapeutic efforts for several neural crest tumors, but the biodistribution of 111In-pentetreotide does not allow the use of this compound for radionuclide therapy.
Adjuvant Therapy Regimens in the Treatment of Neuroendocrine Tumors Related to the Sentinel and General Lymph Nodes Status In comparative studies of Ohrvall et al. (1997) using [111In-diethylenetriamine pentaacetic acid (DTPA)D-Phe1]-octreotide the detection rate of abdominal endocrine tumors using the Octreoscan (Mallinckrodt Medical Petten, The Netherlands) combined with single photon emission computed tomography (SPECT) on the one hand and a newly developed hand-held gamma detector probe (H-probe 2) for localization of the tumors on the other hand, has been evaluated. Twenty-one patients with endocrine pancreatic or midgut carcinoid tumors were given 100±200 MBq of the radionuclide. The cases underwent preoperative SPECT examination with subsequent surgery after 24±48 h. Intraoperatively, radioactivity in the tumors and in normal tissue was measured using the H-probe 2, which was connected to a portable personal computer. Resected tissues containing the carcinoid tumors were examined ex vivo with a gamma camera. Biopsies of all tumors were subsequently investigated in a cell counter and also in routine histology. In 34 of 60 cases, abdominal tumors were detected by SPECT, but this technique failed to visualize tumors smaller than 9 mm. Shielding of the manual probe allowed intraoperative examination despite the substantial radiation energy of 111In. It must be emphasized that the H probe 2 detected 91% of the investigated tumors, with inclusion of all those > 5 mm. Gamma camera analysis
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors
detected 68% of the tumors in the resected tissue parts. These results suggest that the intraoperative H probe 2 examination has improved the detection of small endocrine tumor lesions. According to these facts, investigations for detection of regional sentinel nodes and also more distal nodes should be performed to improve locoregional tumor clearance. Adams et al. (1998 b), in localization studies of sentinel and regional lymph nodes of colorectal cancers, emphasized the improved assessment of tumor spread and, as a result of this, changes in surgical management. Inspired by these advances, they conducted a prospective study to determine whether intraoperative radiodetection can reveal microscopic and occult disease of neuroendocrine tumors, namely medullary thyroid carcinomas (MTCs) and gastroenteropancreatic (GEP) tumors. Double nuclide scintigraphy was performed in ten cases with MTC tumor recurrence. Intraoperative radiodetection was performed 24 h after administration of [111In-DTPA-D-Phe1]-pentetreotide or 4 h after injection of 99mTc-DMSA using a hand-held gamma probe. Intraoperative gamma counting revealed 70 somatostatin receptor-positive lesions of GEP tumors. In contrast, the preoperative detection rates as percentages of the cancers detected intraoperatively were only: 74% by receptor imaging 44% by palpation of the surgeon 43% by routine imaging procedures. In 10 patients with MTC recurrences the surgeon found 30 tumor lesions using the gamma probe; in 3 foci false-positive reactions caused by lymphadenitis were found. The use of double nuclide scintigraphy investigations made it possible to confirm the nature of 67% of all lesions detected intraoperatively by the hand-held gamma probe (in 7 of 20 patients in whom octreoscan was used and in 13 of 20 in whom 99mTc-DMSA was used), while surgical palpation confirmed them in 60% and conventional imaging methods (CT, sonography) in 50%. The authors are convinced that intraoperative use of the hand-held gamma probe allows the detection of very small tumor foci (also including small lymph nodes, and especially SLNs) providing they are larger than 5 mm in the largest diameter and that it is more sensitive in cancer detection than external scintigraphy and conventional imaging. These statements, which are based on reproducible results, can help us to reach higher rates of optimal locoregional tumor clearance.
Targeting in Medullary Thyroid Cancer In a two-step radioimmuno-targeting technique, Peltier et al. (1993) used a bispecific anti-CEA (anti-In-DTPA monoclonal antibody and an 111Inlabeled DTPA dimer (di-DTPA-TL) in eight patients with MTC. Immunoscintigraphy was performed 5 h and 24 h after the injection of 111In-diDTPA-TL. In five patients radioimmunoguided surgery (RIGS) was performed using a hand-held gamma probe (sodium iodide). A biodistribution study was performed 48 h (four patients) or 24 h (one patient) after injection of 111In-di-DTPA-TL. Mean tumor uptake (% ID/ kg in tumor) was 39 (range 2.75±139). In these five patients immunoscintigraphy visualized all known and detected, formerly unknown, foci not detected by ultrasound sonography and computer tomography. Immunoscintigraphy performed in four cases for detection of a recurrence disclosed unknown locations in the mediastinum and neck in two of these cases. There were no false-positive results. In three of five cases RIGS detected tumor foci not detected by the surgeons. Two small microscopically detectable lesions in scar fields were missed by immunoscintigraphy. The investigations proved that bispecific anti-CEA/anti-In-DTPA-mediated targeting of 111In-di DTPAA-TL provided elevated tumor uptake and tumor-to-normal tissue ratios. The conclusion drawn from these results is that radioimmunodetection of small MTC lesions is possible even in cases in which morphological imaging techniques give no positive results. This targeting method seems to be important for the detection of tumor-infiltrated SLNs and helps in the achievement of R0 resection and, with this, reduction of locoregional recurrences of MTC.
The SLN Approach in Neuroblastomas Neuroblastomas characteristically affect children and are extremely rare in adults. The tumors are localized along the sympathetic cord. Their main localization is at the level of the adrenal glands, but they can also be found in the retrothoracic area up to the cervical region (near to the ganglion stellatum) (Fig. 28).
The SLN Approach in Neuroblastomas
Abdominal localizations below the region of adrenals to the pelvis are possible, and in rare cases neuroblastomas may even develop in the regions of upper parts of the thigh. Because the most frequent localization is the retroperitoneal area, all childhood cancers with this localization must be taken into consideration.
Figs. 28±31. Neuroblastomas are among the most important tumors in childhood. This series of figures illustrates the main morphological features of this tumor Fig. 28. The most frequent localizations of this neoplasm. Note the high frequency at the level of the kidneys. Neuroblastomas may also, however, occur in the dorsal parts of the mediastinum and also in the cervical and in pelvic regions
These are: · Nephroblastoma (Wilms, Birch-Hirschfeld) · Rhabdomyosarcoma · Lymphomas · Ewing sarcoma · Small-cell osteosarcoma When undifferentiated, all these tumors have quite similar histological appearances (Figs. 29, 30). This category of neoplasms was subsumed some decades ago as the so-called blue-nucleated tumors of childhood (ªblaukernige kindliche Tumorenº). Now, however, following the progress meanwhile achieved in immunohistochemistry, these tumors can be exactly classified as shown in Table 12. Clinically, patients with neuroblastoma excrete increased levels of vanillylmandelic acid and degradation products of dopamine in the urine. Investigations concerning · Localization of the primary of neuroblastomas · Localization of metastases in lymph nodes must be carried out intraoperatively. Martelli et al. (1998) used meta-iodobenzylguanidine (MIBG) radiolabeled with iodine-123 and -125 alternately. This is the newest study and in-
Fig. 29. Histological overview of a neuroblastoma. Note extensive spontaneous tumor necrosis (red to orange)
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Chapter 27 SLN Staging in Carcinoids and Neuroendocrine Tumors Fig. 30. Fine-needle aspiration cytology (FNAC) of a neuroblastoma. The neuroblastoma cell nuclei are round, compact and intensively stained (characteristic for the so-called blue nucleated embryonal tumors of childhood). They are arranged in pseudorosettes with fine-fibrous neuropil in the center. The fibers can be intensively stained with antibodies directed to neurofilaments
Table 12. Classification of neuroblastomas Tumor type
Specific/characteristic positive immunohistochemical reaction
Neuroblastoma
S100 protein Neurofilaments (Fig. 30) NSE
Nephroblastoma
Cytokeratin Vimentin Mono- and double expression of both intermediary filaments
Rhabdomyosarcoma
Vimentin Desmin Actin
Lymphomas
Common leukocyte antigen) B-cell markers: CD20 (L26), CD22 (4KB5); T-cell markers: CD3 (UCHL1), CD43
Ewing sarcoma
High glycogen content in cytoplasm, cytogenetics confirmed operatively
Small-cell osteosarcoma
Osteonectin
volved 58 children. All patients with positive reactions in MIBG scintiscans were enrolled on the study program. Positive case selection was oriented on the tumor-to-background ratio, those with a ratio in excess of 2 : 1 at the time of operation being selected. The sensitivity and specificity of the detection method with either 123I- or 124I-labeled MIBG were determined, the measurements being based on cor-
relation of probe findings and pathological analysis of 288 resected specimens. Intraoperative detection of tumor tissue was helpful in 65% of the cases. Labeling allowed: · Better definition of the tumor margins · Detection of locoregional lymph nodes that were involved, including the SLNs. Furthermore, it was easier to detect small, nonpalpable tumors in which it was more difficult to attaining good results by surgery, and in relapsed cases the localization of the recurrent tumor foci could be determined. This point, as well as the search for SLNs is especially significant, because surgeons have difficulties in detecting tumor cell foci in postsurgical scar areas. Nonetheless, they must be expected to do this in the 35% of cases in which the radioimmuno-supported search is not successful. In Martelli et al.'s study the tumors for which the radioimmunoassay-supported search remained unsuccessful were well-localized tumors, thoracic neuroblastomas, highly differentiated tumors (ganglioneuromas) (Fig. 31), and tumors with extensive necrosis and fibrosis. As regards comparison between iodine-123 and iodine-125, the sensitivity was nearly the same, at 91% and 92%, respectively, but the specificity was much higher for iodine-125: 85% as opposed to only 55% with iodine-123 (P < 0.005). The conclusion of the authors, based on these impressive results is clear: They recommend the use of iodine-125 and emphasize that the method helps to improve the quality of macroscopic resection (increased frequency of R0) in locoregional widespread neuroblastomas
References Fig. 31. Maturation of a neuroblastoma to a ganglioneuroblastoma. Full maturation to a ganglioneuroma with loss of metastatic potency is also possible
also with concern to the regional nodes including the sentinel nodes. The method is also helpful in cases with difficult access to the primaries and in cases with relapse.
Strategies in Neuroblastoma in General and in Dependence on the Lymph Node Status Spontaneous regression of neuroblastoma, often with extensive necrosis and apoptosis, is very common (Fig. 29). In addition, chemo- and radiosensitivity are very high. Regional lymphatic spread can be suspected or verified, but hematogenous metastasis into the lungs is also an important consideration, so that chemotherapy is given in practically all cases, regardless of the SLN status. Since this category of tumor develops almost exclusively in early childhood, special knowledge of its treatment is necessary. (For information on the treatment schemes see Chapter 33.)
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Ohrvall U, Westlin JE, Nilsson S, Juhlin C, Rastard J, Lundquist H, Akerstrom G (1997) Intraoperative gamma detection reveals abdominal endocrine tumors more efficiently than somatostatin receptor scintigraphy. Cancer 80(12) [Suppl]:2490±2494 Padberg BC, Stådtler C, Schræder S (2000) Morphologie, DNA-Zytophotometrie und Prognose gastrointestinaler neuroendokriner Tumoren (Karzinoide). Eine klinischpathologische Untersuchung an 95 Patienten. Pathologe 21:73±81 Papotti M, Croce S, Bello M, Bongiovanni M, Allia E, Schindler M, Mussolati G (2001) Expression of somatostatin receptor types 2, 3 and 5 in biopsies and surgical specimens of human lung tumors. Correlation with preoperative octreotide scintigraphy. Virchows Arch 439: 787±797 Pasquali C, Rubello D, Sperti C, Gasparoni P, Lissi G, Chierichetti F, Ferlin G, Pedrazzoli S (1998) Neuroendocrine tumor imaging: can 18F-fluorodeoxyglucose positron emission tomography detect tumors with poor prognosis and aggressive behaviour? World J Surg 22:588±592 Peltier P, Curtet C, Chatal JF, le Doussal JM, Daniel G, Aillet G, Gruaz-Guyon A, Barbet J, Delaage M (1993) Radioimmunodetection of medullary thyroid cancer using a bispecific anti-CEA, anti-indium-DTPA antibody and an indium-111-labeled DTPA dimer. J Nucl Med 34:1267± 1273 Quaedvlieg PF, Visser O, Lamers CB, Janssen-Heijen ML, Taal BG (2001) Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiology study with 2391 patients. Ann Oncol 12:1295± 1300 Schauer A, Aures D, Hkanson R, Clark WG (1968) Zellulåre Lokalisation und physiologische Bedeutung von Aminosåuredecarboxylasen. Verh Dtsch Ges Pathol 52: 356±361 Seregni E, Ferrari L, Bajetta E, Martinetti A, Bombardieri E (2001) Clinical significance of blood chromogranin A measurement in neuroendocrine tumors. Ann Oncol 12 [Suppl 23]:S69±S72 Soga J (1997) Gastric carcinoids: a statistical evaluation of 1094 cases collected from the literature. Surg Today 27: 892±901 Stivanello M, Berruti A, Torta M, Termine A, Tampellini M, Gorzegno G, Angeli A, Dogliotti L (2001) Circulating chromogranin A in the assessment of patients with neuroendocrine tumors. A single institution experience. Ann Oncol 12 [Suppl 2]:S73±S77 Tomassetti P, Migliori M, Caletti GC, Fusaroli P, Corinaldesi R, Gullo L (2000) Treatment of type II gastric carcinoid tumors with somatostatin analogues. N Engl J Med 343: 551±554 Travis W, Linnoila R, Tsokos M, Hitchcock C, Cutler G, Niemann L, Chrousos G, Pass H, Doppman J (1991) Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. Am J Surg Pathol 15(6):529±533
Chapter 28
The Sentinel Node Concept in Cancers of the Female Genitalia
Introduction
Table 1. Sentinel node mapping in genitourinary cancer. (according to Wawroschek et al. 2001)
Few series have been published in the last few years that could be used as a basis for assessing the value of a sentinel lymph node (SLN) concept for surgical treatment strategies in urogenital cancers. An overview relating to different tissues and organs is presented in Table 1.
Vulvar Cancer Invasive vulvar cancers are now routinely treated by vulvectomy along with bilateral en bloc femoroinguinal lymphadenectomy. Since this is an extensive operation, it seems essential to test whether the SLN concept is practicable (Hacker et al. 1981; Podratz et al. 1982; Iversen et al. 1983; Barton et al. 1992; Cavanagh 1997; Makar et al. 2001). Both patent blue dye for labeling of the lymphatics and the SLN(s) and 99mTc-nanocolloid labeling with scintigraphic and intraoperative guidance with the gamma probe can be practiced. Injection of the dye around the tumor lesion helps us to find · Whether sentinel nodes (SN) are labeled on only one side, corresponding to the location of the cancer · Whether the inguinal nodes on both sides may be involved in metastatic spread. The injection of patent blue has the advantage of clearly implicating the lymphatics and showing when extension of the operative resection is indicated, while double labeling with 99mTc-colloids in addition has the advantage that it also makes it possible to resect ªskipº or ªbypassº metastases in the initial surgery.
a
Cancer site
Sentinel node mapping
Reference
Kidney
No data now available
±
Bladder
No data now available
±
Ovary
No data now available
±
Uterus (endometrium)
Blue dyea labeling
Burke et al. (1996) Echt et al. (1999)
Cervix
Blue dye labeling
Echt et al. (1999)
Vulva
Blue dye labeling Blue + dye plus 99m Tc-nanocolloid scintigraphy
Levenback et al. (1995) Ansink and van der Velden (2000) Echt et al. (1999)
Testicle
No dye labeling and no data now available
±
Prostate
Scintigraphy
Wawroschek et al. (1999/2001)
Penis
Blue dye labeling and Scintigraphy Scintigraphy
Horenblas et al. (2000)
Blue dye = lymphazurin, patent blue
Wawroschek et al. (2000)
28
432
Chapter 28 The Sentinel Node Concept in Cancers of the Female Genitalia Table 2. Results in sentinel node (SLN) detection in vulvar cancer with the aid of patent blue (collected by Wawroschek et al. 2001) (FNR false-negative rate, NPV node-positive verification) Reference
Patients (n)
Levenback et al. (1995)
21
De Hullu et al. (1998) Ansink et al. (1999) (Multicenter Study) Terada et al. (2000) Total a
SN detection %
SN positive %
%
Rate
%
29
66
19/29
1
5/29
0
0/5
100
14/14
10
18
56
10/18
10
1/10
0
0/1
100
9/9
51
93
56
52/93
1
9/52
18
2/11
12
92
11/122
25
3/11
0
0/3
152
60
92/152
18
18/102
9a
91
Groin (n)
Rate
FNR %
NPV Rate
%
Rate
95.3
100
41/43
9/9
One patient had two tumors
Tables 2±4 show percentage SLN detection by means of patent blue dye and of lymphoscintigraphy together with a gamma probe; the data displayed are based on a comparison of the results of different research groups carried out by Wawroschek et al. (1999, 2000, 2001). It can be clearly seen that detection rates of 100% were recorded in all groups when scintigraphy and gamma probes were used (Table 4), whereas the blue dye method yielded much lower rates (Table 2). In the early investigations of Levenback et al. (1995), SLN excision seemed to be helpful and important. Among 21 cases treated, SN were detect-
able in 17. In no case with negative SLN were any non-SN positive. Unusual locations of the SLN were found. In 1 case the SLN was located below the fascia cribriformis, and in 1 patient with cancer of the clitoris lymphatic channels were passing under the symphysis pubis to the pelvic nodes. These cases confirm that vulvar cancer is also a condition in which labeling of the SLNs helps toward more accurate operation regimens and better informed decision making on adjuvant therapeutic measures. Since 1995 Levenback et al. (2001) have extended their experience by continuing their investigations in 52 patients. Over half (67%) of the pa-
Table 3. Improvement in successful SLN detection rates since 1995 Vulvar cancers (n)
SLN detection rate since 1995
Localization Lateral
Midline
52
88%
22/25
24/2
SLN successfully detected in groins
Hampering rate, excision vs punch biopsy
Lateral vs medial localization
Improvement since 1995
57/76 groins 75%
11/24 vs 8/ 51 (P = 0.007)
22/25 groins
P = 0.034
35/51 groins (P = 0.067)
P = 0.034
Vulvar Cancer Table 4. Results of SN detection in vulvar cancer by lymphoscintigraphy and gamma probe (according to Wawroschek et al. 2001) Reference
Groin (n)
SN detection
SN positive
FNR
%
%
%
Rate
%
Rate
Rate
Rate
NPV
DeCesare et al. (1997)
10
20
100
20/20
20
4/20
0
0/4
100
16/16
De Hullu et al. (1998)
10
18
100
18/18
11
2/18
0
0/2
100
16/16
Terada et al. (2000)
9a
12
100
12/12
25
3/12
0
0/3
100
9/9
De Cicco et al. (2000)
3
55
100
55/55
15
8/55
0
0/8
100
47/4
66
105
100
105/105
16
17/105
Total a
Patient (n)
One patient had two tumors
tients had squamous cell cancers, while the rest had melanomas or adenocarcinomas of the vulva. The SLN identification rate rose to 88% (from only 66% in 1995) when the blue dye technique was used. Overall the data displayed in Table 3 were obtained. Wawroschek et al. updated the available results using results of lymphoscintigraphy and the intraoperative observations with the gamma probe in four centers. Very high detection rates of SLN were reached (105/105 = 100% patients collected by four groups). These results are summarized in Table 4. New experiences have recently been published by Molpus et al. (2001) and Slintz et al. (2002).
Both these groups also recommend supporting surgical treatment of vulvar cancer by the modern techniques of searching for SLN(s) by using the blue dye and/or 99mTc-microcolloid techniques. The results are summarized in Table 5. Tavares et al. (2001) compared the detection rates of SLNs in breast cancer, malignant melanomas, and vulvar cancers. The authors used 99mTcphytate administered by subdermal injection 18± 24 h before surgical treatment. Blue dye has been used in addition, with the aim of improving visual localization. SLN detection in vulvar cancers (cases without pretreatment) was very high (Table 6).
Table 5. SN detection in vulvar cancers: positive rates and micrometastases Reference
No. of cases
SN labeling
SN detection rate
SLN positivity in HE staining
Micrometastases < 2 mm HE + IHC serial sections
Molpus et al. (2001)
11
Blue dye + 99m Tc-colloid
11/10 91%
5%
2%
Slintz et al. (2002)
26
99m
20 unilateral 6 bilateral 100%
9 = 34.6%
Tc-microcolloid
FNR
Conclusion
Individual search, using both methods necessary 0%
Performance of SLN concept recommended
433
434
Chapter 28 The Sentinel Node Concept in Cancers of the Female Genitalia Table 6. SLN detection rates: comparison in breast cancer, melanoma and vulvar cancer Breast cancer cases
Malignant melanoma cases
Vulvar cancer cases
38/41 = 93%
18/19 = 95%
15/15 = 100%
Acceptance of the SLN Concept in Vulvar Cancer Treatment? An evaluation of patients' and gynecologists' opinions on the acceptance of minimally invasive SN dissection versus complete inguino-femoral lymphadenectomy in vulvar cancer patients has been carried out by De Hullu et al. (2001). In spite of high complication rates (one or repeated episodes of infection at the operation site, severe constant pain and lymphedema, etc.), 66% of the patients preferred complete inguino-femoral lymphadenectomy over acceptance of a 5% false-negative rate consequent on SLN evaluation and restriction to further node removal only in SN-positive cases. In contrast, 80% of gynecologists were willing to accept false-negative rates of 5±20% and to regard the SLN concept as a promising diagnostic tool. It seems that the high degree of patient tolerance in spite of the high frequency and severity of complications is fostered by the fear of locoregional cancer recurrence. Conversely, gynecologists find the high complication rates and the consequences of complications depressing. They hope that local recurrences, which are quite rare, can be overcome as experience of searching for SLNs grows. In summary, this questionnaire yielded responses that were promising for future developments, but obviously it came too early, before the accumulation of experience reported by patients also.
Cervical Cancer Cervical cancer, in most cases showing squamous cell differentiation, develops in the circumference of the endocervical mucosa, mostly in the transitional zone of squamous epithelium to the endocervical glandular differentiated zone.
In most cases the stages of cancer development are clearly preprogrammed and can be followed in series of Papanicolaou smears taken from the patients at intervals, in which Papanicolaou III (moderate dysplasia) becomes transformed to Papanicolaou IVa (severe dysplasia) and subsequently to Papanicolaou IVb (carcinoma in situ) and finally to Papanicolaou V (invasive cancer). In a high percentage of cases the whole dysplastic or atypical lesion develops more or less in the whole circumference (all 12 segments according to Rosai's scheme). However, the transition to early stromal invasion sometimes starts in one or a few segments. From there, the invasive process invades the cervical tissue and can break through into the parametrial tissue structures. These experiences suggest that: · SLNs should not be looked for until after Pap V is confirmed or, in cases with Pap IVa or IVb or V, when invasive cancer is found. · SLN labeling also seems to be appropriate in early cases with palpable or sonographically or otherwise confirmed invasion of the cervix uteri. · Unilaterally localized SLN can be expected especially in cases with early invasive cancers in the lateral parts of the cervix (sectors 2±4 or 7±9). In cases with invasive processes that have developed ventrally or dorsally bilateral SLN labeling can be expected more frequently. The same is true in exophytically growing cancers affecting more or less the whole of the circumference, in which the cancer can be clearly seen by means of a speculum. In confirmed or strongly suspected invasive processes, before SLN labeling, radioimaging (CT, MRI, PET) can give approximative information about the pelvic lymph node status. In addition, in isolated cases minimally invasive pelvic exploration can give preoperative information before or after SLN labeling.
Ovarian Cancer
Problems in Local Administration of Labeling Solutions Difficulties may be encountered with local administration of the labeling solutions in the case of cervical cancer: · Injections of the labeling solutions into the cervical tissue must take account of the location of the invasive process [segment(s)], the depth of invasion, and endophytic and exophytic cancer growth, etc. · The injection fluid can only be administered peritumorally, and care must be taken to avoid intratumoral injection. · Old cervical lesions that have healed with extensive scarring, e.g. after childbirth, must also be taken into account, because in these conditions the primary lymphatic stream can be bypassed. · It already seems to be clear that combined use of lymphoscintigraphy and blue dye results in the highest SLN detection rates. Altogether, new strategies for labeling can be based on existing experiences with the administration of labeling solutions. These might be implemented by subtumoral injection into the cervix, and, in the case of more deeply infiltrating cancers, via the fornix into supracervical parametrial soft tissue parts. So far, there have been no systematic investigations on the optimal sites for injection. It is well known that the cervical tissue has a high fiber density. This makes the transport of injected fluids very slow. However, it could be that the transport
of labeling fluids increases when prostaglandins are injected at low doses together with the labeling fluid. In recent years a few preliminary evaluations of the appropriateness of SLN labeling in cervix cancers have been published (Verheijen et al. 2000; Lantzsch et al. 2001; Levenback et al. 2002). These initial results are summarized in Tables 7 and 8. They confirm that SLNs can be localized unilaterally and bilaterally. The combination of the blue dye and radioactive labeling methods is superior to the blue dye technique alone. This suggestion is supported by the results of Verheijen et al. (2000), who detected the SLN(s) in 80% of cases by administration of 99m Tc-colloidal albumin, but in no more than 4 out of 10 cases when they used blue dye only.
Ovarian Cancer Ovarian cancers in the stricter sense (malignant germ cell tumors and teratomas excluded) develop: · Directly from the parenchyma of the ovary (in early stages these are sometimes small cancers of 1±2 cm) · In a multiple-step carcinogenesis via a borderline lesion from serous papillary or mucinous ovarian cystomas · Extraovarially, directly from the peritoneum (residual rests of the coelom epithelium?), when they are named extraovarian ovarian cancer In approximately 50% of cases that are already advanced both ovaries show tumor development. It
Table 7. Uni- and bilateral sentinel lymph node labeling in cervical cancer using
99m
Tc nanocolloids (Lantzsch et al. 2001)
No. of cases
Labeling method
Labeling possible
Unilateral labeling
Bilateral labeling
SLN positive
14
99m Tc-nanocolloid
13/14
8/13
5/33
1
Table 8. Sentinel node detection rates in cervix cancer using blue dye and tion (Levenback et al. 2002; see also Ramirez and Levenback 2001)
99m
Tc-labeled colloids separately or in combina-
No. of patients
SLN detection rate
SLN bilateral
Blue and hot
Blue only
Hot only
Metastatic disease
Sensitivity
Negative predictive value
39
33/39 (=85%)
21/39 (55%)
49%
27%
24%
8/39 (21%)
87.5%
97%
435
436
Chapter 28 The Sentinel Node Concept in Cancers of the Female Genitalia
was initially assumed that there would be lymphogenic spread to the contralateral side at least in cases without massive lymphangiosis carcinomatosa, but this seems not to have an important role. In most such cases initial bilateral simultaneous or phase-shifted development of cancer in both ovaries must be assumed. Often early peritoneal seeding develops, and this sometimes rapid progress can be only partially stopped by administration of cytostatics or, in c-erbB2-positive cases, of herceptin. In these very heterogeneous conditions, in many cases involving early fulminant peritoneal spread with ultrarapid cancer progression, the development of a SLN search concept is neither encouraging nor helpful. Therefore in the next section only the general staging possibilities allowed by PET are described and discussed and are compared with the options offered by CT.
Role of FDG-PET in Diagnosis and Staging of Ovarian Cancer Detection of sometimes small ovarian primaries, a high rate of early bilateral primaries, early peritoneal metastatic spread, and ªavoidanceº of regional LN metastasis in cases with already advanced peritoneal carcinosis mean that the value of searching for SLNs is much reduced. The same is true of surgical regional lymphadenectomy in cases with incipient or advanced peritoneal carcinosis. Therefore, our evaluations of the use of FDGPET have to concentrate almost exclusively on the detection of ovarian and extraovarian primaries (extraovarian ovarian cancers) in their early stages. The results of some groups who analyzed the value of PET in primary tumor diagnosis are summarized in Table 9.
Table 9. Evaluation of significance of FDG-PET in diagnosis of ovarian primaries Reference
n
Positive predictive value
Negative predictive value
Hçbner et al. (1993)
53
86%
76%
Ræmer et al. (1997)
19
Schræder et al. (1999)
40 (30 malignant)
Fenchel et al. (1999)
85 asymptomatic patients
96%
75%
Sensitivity/ specificity (%)
Recurrence detection rates
54/83
4/5
90%
40%
50/78
Table 10. Misinterpretations of FDG-PET imaging in ovarian cancer diagnosis Reference
n
Rate of misinterpretation
Ræmer et al. (1997)
19
4
Fenchel et al. (1999)
85
24
Type of lesion Inflammatory reactions or endometriosis or follicular cysts 2 Borderline lesions 1 Well-differentiated Ca (FIGO 1) 4/30 Not of coelomic origin 3 Inflammatory reactions 1 Teratoma 1 Benign schwannoma 1 Dermoid cyst 1 Thecoma 4 Benign cystic tumors 2 Corpus luteum cysts 3 Endometrial cysts 1 Sactosalpinx
References
Nonovarian cancer lesions that can lead to misinterpretations in primary diagnoses based on PET are summarized in Table 10.
Conclusions These studies demonstrate that FDG-PET cannot reliably differentiate between benign and malignant ovarian tumors and that its sensitivity in detecting borderline tumors and early-stage ovarian cancer is limited. However, PET may still be useful in the management of patients with ovarian neoplasms by identifying occult foci of metabolically active tumor that do not appear in morphological studies. In addition, the high sensitivity of PET for malignant tumors may be useful in the detection of recurrent ovarian cancer (Hçbner et al. 1993). FDG-PET has also been found to be helpful in the diagnosis of residual disease after chemotherapy (Schræder et al. 1999). In these applications, sensitivity and specificity appear to be greater than those of CT. In addition, it must be clearly stated that neither FDG-PET nor any other imaging methods are helpful in systematic early detection of lymph node metastasis, and especially of cancer-infiltrated SLNs.
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Chapter 28 The Sentinel Node Concept in Cancers of the Female Genitalia Podratz KC, Symmonds RE, Taylor F (1982) Carcinoma of the vulva: analysis of treatment failures. Am J Obstet Gynecol 143:340±351 Ramirez PT, Levenback C (2001) Sentinel nodes in gynecologic malignancies. Curr Opin Oncol 13:403±407 Ræmer W, Avril N, Dose J, Ziegler S, Kuhn W, Herz M, Jånicke F, Schwaiger M (1997) Metabolic characterization of ovarian tumors with positron-emission tomography and F-18 fluorodeoxyglucose. Ræfo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 166:62±68 Schræder W, Zimny M, Rudlowski C, Bull U, Rath W (1999) The role of 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG PET) in diagnosis of ovarian cancer. Int J Gynecol Cancer 9:117±122 Sliutz G, Reinthaller A, Lantzsch T, Mende T, Sinzinger H, Kains C, Koelbl H (2002) Lymphatic mapping of sentinel nodes in early vulvar cancer. Gynecol Oncol 84:449±452 Tavares MG, Sapienza MT, Galeb NA Jr, Belfort FA, Costa RR, Osorio CA, Goes JC, Endo IS, Soares J Jr, Lewin S, Marone MM (2001) The use of 99mTc-phytate for sentinel node mapping in melanoma, breast cancer and vulvar cancer: a study of 100 cases. Eur J Nucl Med 28:1597±1604
Terada KY, Coel MN, Ko P, Wong JH (1998) Combined use of intraoperative lymphatic mapping and lymphoscintigraphy in the management of squamous cell cancer of the vulva. Gynecol Oncol 70:65±69 Terada KY, Shimizu DM, Wong JH (2000) Sentinel node dissection and ultrastaging in squamous cell cancer of the vulva. Gynecol Oncol 76:40±44 Verheijen RH, Pijpers R, Diest PJ van, Burger CW, Buist MR, Kenemans P (2000) Sentinel node detection in cervical cancer. Obstet Gynecol 96(1):135±138 Wawroschek F, Vogt H, Weckermann D, Wagner T, Harzmann R (1999) The sentinel lymph node concept in prostate cancer ± first results of gamma probe guided sentinel lymph node identification. Eur Urol 36:595±600 Wawroschek F, Vogt H, Bachter D, Weckermann D, Hamm M, Harzmann R (2000) First experience of gamma probe guided sentinel lymph node surgery in penile cancer. Urol Res 28:246±249 Wawroschek F, Vogt H, Weckermann D, Wagner T, Hamm M, Harzmann R (2001) Radioisotope guided pelvic lymph node dissection of prostate cancer. J Urol 166(5): 1715±1719
Chapter 29
Cancers of the Male Genitalia
Sentinel Lymph Node Identification in Penile Cancers In the tumor types specific to the male, correlations between sentinel node labeling and biopsy and their significance must be discussed as part of a strategy concept in the treatment of penile cancer. The rates recorded for this tumor type in the western world are not extremely high, but neither are they very low. Experience with large numbers has been reported from India, where penile cancer has a high frequency. The clinical features taken into consideration in the assessment of regional lymph node involvement are confusing. The following facts document the inadequacy of physical examination and radioimaging for confirmation or exclusion of regional lymph node involvement (Mukamel 1987; Abi Aad and de Kernion 1992). The early change from the temporary use of lymphangiography to sentinel node evaluation for investigating the lymphatic spread of this tumor types was reported by Cabanas (1977). He treated penile cancer patients without the dissection of inguinal, femoral, and iliacal lymph nodes when the sentinel node was tumor free. The 5-year survival rate of his patients was 90%. Cabanas (1992) repeated and modified his recommendations without far-reaching changes. His principles were: Primarily, bilateral sentinel lymph node (SLN) biopsy should be performed. In cases with positive nodes inguino-femoral dissection should be carried out. In node-negative cases no further surgical treatment is indicated, but the patient needs to be observed closely, with examinations monthly for 1 year and then every 2 months for 3 years. He repeated this scheme again in 2000. Ravi et al. reported as long ago as in 1991 on 52 patients with invasive penile cancers who were treated by ªpickingº of inguinal lymph nodes. In 5 patients (9.6%) the nodes were positive. (ªPickingº is similar to berry-picking in the case of thyroid
29
cancer, meaning here revision of all lymph nodes that are enlarged, including the SLN.) However, in 7 of 47 cases with negative results the patients developed inguinal recurrences, 3 of which were distant metastases. The 5-year survival rates of patients with inguinal nodes that were positive and negative on picking were 100% and 82%, respectively. In conclusion: the ªinguinal pickº technique is helpful in node-positive cases, but does not guarantee the absence of regional metastases. Similarly, Akduman et al. (2001) investigated 5 cases with microscopic involvement of a single lymph node only (confirmed by full-groin dissection), and gamma probe identification was 100% accurate. None of the patients with negative sentinel nodes had a recurrence. Recently Senthil-Kumar et al. (1998) developed an acceptable program for lymph node staging. They stated that clinical node examination alone is inadequate in selecting cases for bloc dissection. Fineneedle biopsy seems to be accurate and specific in cases with palpable nodes. In cases with impalpable nodes a preliminary medial inguinal node (MIN) biopsy followed by sentinel node biopsy in MIN biopsy-negative cases will allow accurate selection of all patients with metastases in the inguinal nodes. If intraoperative staging is possible bloc dissection can be carried out at the same time. Pizzocaro et al. (1997) also recommended fineneedle aspiration cytology (FNAC) combined with imaging investigations to obtain a better overview for surgical intervention. Recently Valdes et al. (2001), working in Amsterdam, published their data, which are derived from a larger number of investigated cases than any other group has examined (Table 1). In their group of 74 patients there were only 2 with falsenegative SLNs. These data seem to offer help for further developments. In rare cases malignant melanoma may develop in the penile skin or mucosa of the glans or in the
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Chapter 29 Cancers of the Male Genitalia Table 1. Sentinel lymph node (SLN) visualization in penile cancer patients, bilaterality of SLN, synchronous and asynchronous drainage a No. of patients (n)
Labeling
SLN visualization rate
Bilaterality
Left groin only
Right groin
Synchronous drainage
Asynchronous drainage
Positive nodes b
74
99m
72/74 97%
58/72 81%
9/72 13%
6%
22/58 38%
62%
16 22%
Tc-nanocolloid 64.8 MBq 0.3±0.4 ml
a
Additional results: 161 sentinel nodes removed in total Pitfalls: in 4 patients false-positive results were obtained because of skin contamination; at follow-up, 2 patients with negative SLNs were found to have recurrences
b
male urethra (Begun et al. 1984). In these melanoma cases the diagnostic and treatment strategies discussed for malignant melanomas in general, and in some cases, those discussed specifically for penile cancers, must be carefully considered to find the best method of individual treatment. Nonetheless, there are also a few publications that express negative opinions of inguinal node evaluation. Perinetti et al. (1980) reported a case in which 6 months after inguinal lymph node examination with a negative result an unresectable node recurrence was found to have developed. In additional investigations by Pettaway (1999), among 20 patients with negative SLN, 5 had developed metastases after 3±21 months. On the basis of these depressing results the authors suggest that routine node dissection can no longer be recommended. The last two publications discussed are depressing. However, on the basis of the facts presented, it seems to be impossible to come to a definitive assessment of the value of nodal staging on the basis of evaluation of these statements alone. The positive results recorded by the other investigators cited are much more persuasive according to the data presented in detail.
Treatment Strategies in Premalignant and Occult Malignant Lesions Besides the mostly benign warty lesions, such premalignant lesions as giant condylomas, bowenoid papulosis, and erythroplasia of Queyrat and Bowen's disease have a role (Horenblas 2001 a, b; Horenblas et al. 2000 a, b; von Krogh and Horenblas 2000 a, b).
These premalignant lesions can be excised by laser surgery (van Bezooijen et al. 2001). It is necessary that these lesions be histopathologically investigated in serial sections to exclude early stromal invasion. In the collective of Bezooijen et al. (2001), in 3 of 19 patients (19%) recurrences occurred. During the 25-month follow-up period, 5 patients had true carcinomata in situ (26%) and 1 developed invasive cancer. It is clear that whenever stromal invasion is detected the search for the regional sentinel nodes must be started.
Labeling the SLNs in Penile Cancers by Application of 99mTc-Nanocolloid In Germany the Augsburg group led by Prof. Dr. P. Heidenreich and his coworkers (H. Vogt, J. Kopp, and H. Wengenmair in the Department of Nuclear Medicine, Prof. Dr. R. Harzmann and Dr. F. Wawroschek in the Department of Urology, and Dr. T. Wagner in the Department of Pathology) is highly experienced in SLN-labeling strategies, using different subtypes of gamma probes and the investigation of removed nodes by serial sectioning and the use of immunohistochemistry for single-cancer cell detection. The characteristic pictures discussed at this point were kindly put at our disposal by Dr. F. Wawroschek, Augsburg, Germany and illustrate the performance levels of the various labeling procedures in cases with penile cancer. In Fig. 1, the injection technique used in a case of penile cancer at the glans is demonstrated. The labeled nanocolloid solution is injected strictly peritumorally, using a small tuberculin syringe
Labeling the SLNs in Penile Cancers by Application of
99m
Tc-Nanocolloid
spillover, in accordance with the small particle diameter used for the investigations. Corresponding to these figures showing exact imaging of the SLN(s), Fig. 4 shows identification of the SLN(s) in the inguinal region using the gamma probe, before its removal for histopathological and immunohistochemical examination.
Fig. 1. One of the injection sites that can be used to administer the labeling solution into the peritumoral subepithelial soft tissue parts. Note how the penis is held firmly in the left hand to ensure a stable position while the injection is given
with a suitably fine needle. For a safe injection technique, the penis is fixed in place by hand with the peripenile soft tissue gathered up. Figures 2 and 3 illustrate unilateral labeling of a lymph node in the groin in a case with penile cancer. The scintigraphic results 13 min and 2 h after injection are demonstrated. This picture is of basic importance for the surgical preparation along the lymphatic flow to the labeled node(s). Figure 3 shows that the secondary pelvic nodes are also already slightly labeled approximately 30 min after injection. This might be explained as a result of
SLN detection can be difficult in tissues with a dense structure: a) When the primary is too close to the regional lymph nodes. b) When the basin is too extensive and vascular and nerve structures pass through it. c) When the gamma probe used is not fine enough to reach the labeled lymph node(s). a) This situation is unimportant, because the labeled area around the primary can be drawn aside. b) When this applies there are problems. The putative SLN must be carefully loosened from the surrounding areas to make elevation from the base possible. Measurement by the gamma probe is improved by this. c) This is not too serious, because it is possible to use more slender probes. The surgical preparation of an inguinal node with gentle elevation of the node covered by soft tissue is demonstrated in Fig. 4, and a blue-dye-labeled node can be seen in Fig. 5.
Fig. 2 a, b. Unilateral labeling of a solitary enlarged lymph node in the groin. a Note the labeling at the corpus of the penis and along the course of the inguinal ligament, reaching one intensively labeled and enlarged inguinal lymph node within 13 min. b Only one lymph node in the inguinal region is labeled. Note very weak labeling of two pelvic lymph nodes after weak spillover of the labeling fluid, 2 h after injection
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Chapter 29 Cancers of the Male Genitalia
Fig. 3. Labeling of inguinal sentinel lymph node(s) (SLN(s) in a case with penile cancer). The picture clearly demonstrates an inguinal SLN in a patient with penile cancer (black arrow). In addition, the secondary nodes (outlined arrows) are also labeled after 34 min
Testicular Cancers This category of cancers is subdivided into seminomatous and nonseminomatous subtypes and combined types, meaning seminomatous and nonseminomatous entities together. Cancers developing in the testes can often be detected early, because with tumor growth the tension on the capsule of the testis is accompanied by pain reactions.
The lymphatic metastatic process involves the retroperitoneal lymph nodes. Seminomas can also primarily develop in the retroperitoneum along the so-called Keimbahn (ªgerm trailº) or in the mediastinum. The tumor biology is similar in all primary locations (testis, retroperitoneum, mediastinum) (Osada et al. 1998; Bokemeyer et al. 2001). This applies especially to chemosensitivity. As a rule, testicular tumors show high degrees of chemosensitivity. This property is sometimes exploited to achieve down-staging, which gives a better starting position for surgical treatment. However, in the last few decades this high degree of chemosensitivity has led to obvious indifference to the surgical aim of attaining R0 resection. As a result, it has become very rare for strategies designed to improve lymph node removal to be developed with the aim of achieving R0 resection as the primary result.
Main Macroscopic and Microscopic Features of Malignant Testicular Tumors Malignant teratomas have cystic parts in a high proportion of cases. This special feature helps in preoperative evaluations based on ultrasound investigation (Fig. 6). In contrast, seminomas generally show a homogeneous medullary structure (Fig. 7). This homogeneous picture is recognized in the microscopic
Fig. 4. A SLN being pulled up above the level of the epidermis with forceps for direct measurement with the gamma probe. The probe is coated with a plastic ªstockingº to keep it clean and free of infectious material
Main Macroscopic and Microscopic Features of Malignant Testicular Tumors Fig. 5. Exposure of an inguinal lymph node double-labeled by blue stain injection and 99mTc-nanocolloid injection. Gamma probe is being approached to it for SLN identification
Figs. 6±8. Malignant testicular tumors Fig. 6. Malignant teratoma of the testis. Lymphatic spread has a subordinate role compared with hematogenous spread into the lungs
growth pattern. The cancer cells grow in a pattern reminiscent of a lawn (Fig. 7). They mostly have round nuclei with pale karyoplasm and prominent nucleoli (Fig. 8), and characteristic loosely layered lymphocytes and sarcoidosis-like granulomas can be found in the interstitium. Such granulomas can sometimes also be detected in the organs, where they are obviously induced by substances released from the tumor. Surgeons and pathologists must be careful not to misinterpret these small foci as metastases. The international literature does not so far include any publications on labeling with blue dyes
or radionuclides with the aim of detecting sentinel nodes in the presence of such tumors. In orientation on testicular cancer development partly of multifocal origin within the testis, it would be only possible to administer labeling substances into the region of vascular supply. But there is a real danger of injecting the labeling fluid intravenously into the local vascular plexus. When all the known facts (high chemosensitivity) and all existing problems are considered together, there seems to be no chance at present of developing proposals for sentinel node labeling procedures that could be useful in daily routine.
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Biological Prognostic Factors: Implications for Risk-adjusted Therapy Regimens
Fig. 7. Seminoma of the testis. Lymphatic spread into iliacal and retroperitoneal paraaortic and paracaval lymph nodes is possible. Therefore, a search for sentinel node(s) and/or metastases into the nodes could be helpful for therapy planning
Some nonseminomatous germ cell tumors (NSGCT), and to a lesser degree also seminomatous germ cell tumors (SGCT), show early metastasis to the lungs and from there to the liver. Therefore, besides the scientific interest in locoregional lymphatic spread, research has also been steadily concentrated on collecting new information on tumor-associated factors that are important for vascular invasion and thus for a potential tendency to systemic spread. Heidenreich et al. (1999) analyzed cases of clinical stage I NSGCT with the intention of finding out about the prospective value of investigating different markers that are frequently associated with rapid cancer progress. In particular, they evaluated the importance of MIBI (Ki67), mutated p53, bcl2 expression, cathepsin D and E-cadherin, using a semiquantitative scoring system. In addition, they assessed the percentage of embryonal carcinoma parts (% EC) and the presence of vascular invasion (VI). Investigation of 149 clinical stage I NSGCT cases revealed the following:
Fig. 8. Histology of seminoma. Notice the round nuclei with prominent nucleoli and pale cytoplasm
Can Radiotherapy or Chemotherapy be at Least Partly Replaced by More Accurate Stage-related Surgical Treatment?
· % EC (P < 0.001) and VI (P < 0.0001) were the most independent risk factors associated with pathological stage II disease. · % EC and VI combined allowed correct prediction of the final pathological stage in 88% of the patients. · Less than 45% EC and absence of VI identified pathological stage I disease correctly in 91.5%. · In contrast, more than 80% EC and presence of VI predicted pathological stage II correctly in 88% of the patients. We can conclude from Heidenreich's results that the percentage of EC and the presence or absence of VI seem to be reliable indicators making it possible to distinguish between patients at high and at low risk for occult retroperitoneal disease. In stage I patients, p53, bcl2, MIBI, cathepsin D and E-cadherin did not appear to have any prognostic value in clinical stage I NSGCT patients. Fujikawa et al. (2000) evaluated the mean nuclear volume (MNV) in 57 seminoma patients. Multivariate logistic regression analysis revealed that in their series, compared with the analysis of beta HCG, AFP, ALP, and LDH, MNV was the only variable predicting lymph node metastasis (P = 0.0315). In stage I patients the estimated MNV was the only variable that was significantly correlated with progression-free survival (P = 0.0118).
Initial, Meanwhile Obviously Abandoned, Approach to Retroperitoneal (Sentinel) Node Labeling in Testicular Cancer Systematic labeling with consecutive radioimaging of inguinal and retroperitoneal lymph nodes has been carried out only very rarely in patients with testicular tumors. Mechev and Sakalo (1994) have investigated the largest number of cases. They recruited 181 patients with germ-cell tumors of the testis, 80 patients with no evidence of retroperitoneal lymph node metastases, and 101 patients with metastasis in the regional lymph nodes. Eighty patients underwent transperitoneal lymphadenectomy. It was therefore possible to compare the results of histological and of lymphoscintigraphic investigation. In the lymphoscintigraphic investigations the following results were obtained:
sensitivity 83%, specificity 90.9%, significance 86.2%. The authors conclude from their results that lymphoscintigraphy helps to confirm sites, extension, and topographical distribution of lymph node metastases, which makes it a valuable tool that is helpful in decision-making about adjuvant therapeutic regimens (radiotherapy, chemotherapy, etc.).
Can Radiotherapy or Chemotherapy be at Least Partly Replaced by More Accurate Stage-related Surgical Treatment? Seminomas account for approximately 50% of germ cell tumors, the other 50% being nonseminomatous tumors, which also include cancers with trophoblastic parts. Because seminomas, in contrast to NSGCTs, spread preferentially by the lymphogenic route, this category would presumably be most suitable for primary lymphatic control. At the moment it seems that there is no need to establish a sentinel node concept, because radio- and chemotherapy programs seem to be optimal. The treatment protocols applied are roughly as follows: Stage I
surveillance or retroperitoneal radiotherapy (28 Gy). Stage II a disease with limited retroperitoneal lymph node metastasis: treatment by retroperitoneal radiotherapy, or alternatively systemic chemotherapy with carboplatin. Stage II b, III disease with bulky retroperitoneal lymph node involvement or distant metastases: systemic chemotherapy including cisplatin and etoposide as the standard approach. After exclusively paraaortic radiation, even with follow-up periods in excess of 5 years, the incidence of pelvic lymph node relapses remained below 4% (Sedelmayer et al. 1999). However, radiotherapy, especially with the late vascular changes it causes through ªcreepingº endothelial proliferation, and the systemic toxicity caused by the drugs used in chemotherapy are not without effect on longterm results. Therefore, more precise lymph node evaluations of the retroperitoneum resulting from
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improvements to radioimaging and radio- and radioimmunolabeling or Sinerem, etc. must be reflected in the aspects of new methodical strategies in advanced stages of development. New positive results could then help make it possible to modify or avoid unnecessary treatments and to restrict radio- and/or chemotherapy to more strictly selected collectives. The discouraging features discussed above must be contrasted with the demonstration of positive regional lymph nodes by FDG-PET and/or CT. However, these imaging methods only give positive results when cancer infiltration is sufficiently extensive. The results and experiences of the last few years are summarized by Avril et al. in the next section.
Is FDG-PET Helpful in N-staging of Germ Cell Tumors (SGCT and NSGCT)? N. Avril, W. Weber, M. Schwaiger
Does FDG-PET have Advantages in Determining the Extension and Delineating Malignant Parts within Primaries? As stated above, germ cell tumors are divided into seminomatous (SGCT) and nonseminomatous (NSGCT) subtypes and in addition mixed types including both these categories. With this in mind, FDG uptake and metabolism in the different components and comparison with results of CT are of special interest. Wilson et al. (1995) examined 21 patients with metastasized SGCT or NSGCT by FDG-PET. While metastases of both types of germ cell tumors showed metabolic activity, the FDG uptake in necrotic and fibrotic tissue, but also in the mature teratoma, was comparable to that in normal tissue. Three patients who responded to therapy showed a decline in metabolic activity in their tumors, while 2 nonresponders did not show any change.
Value of FDG-PET and Comparison with Results of CT in Staging Procedures In a study of 54 patients (27 with SGCT and 27 with NSGCT), Mçller-Mattheis et al. (1998) compared PET with abdominal CT, tumor markers, and histopathological findings obtained following
primary or postchemotherapy retroperitoneal lymphadenectomy. In 21 patients with stage I SGCT, the results of the PET scan were identical with the results of the CT. As the patients had received radiation therapy and the results were not histopathologically validated, the value of PET in this group remained unclear. In 2 of the 7 patients with stage I NSGCT, metastases that had not been seen on CT were detected by PET, while in 4 of the 7 patients micrometastases remained undetected by PET. In 3 of the 4 patients who underwent surgery for a pure seminoma in stage II B or II C, PET correctly identified tumor-free lymph nodes following chemotherapy. In one case the histological examination of a mass that persisted even after chemotherapy revealed a ganglioneuroma, even though the PET scan had been negative.
Value of FDG-PET in Detection of Cancer-infiltrated SLNs and in General Retroperitoneal Lymph Node Staging Hain et al. (2000) proved in their study that when used for primary staging, FDG-PET can detect metastases that are missed by conventional diagnostic methods. In another recent study, Albers et al. (1999) reported correct retroperitoneal staging using PET in 34 out of 37 cases, compared with 29 out of 37 using CT. Seven out of 10 distant metastases were detected by PET, while CT identified only 4 metastases. The PET scans did not produce any false-positive results, although neither malignant lesions less than 5 mm in size nor mature teratomas (regardless of size) were detected. Cremerius et al. (1999) examined 50 patients and obtained comparable results.
Is PET Helpful in Detection of Residual Tumor after Chemotherapy? All studies have documented that PET is unsuitable for detecting residual tumor parts, because there is a high degree of overlap with resorptive inflammatory reactions after the completion of chemotherapy regimens. The use of PET after chemotherapy even for tumors in late stages is the subject of some controversy (Cremerius et al. 1998; Ganjoo et al. 1999).
References
Prospective Views This review shows that SLN detection in operative and conservative treatment is now an international focus of research interest. Several research projects are based on interdisciplinary radiological, nuclear medical, and histopathological and immunohistochemical approaches. Even for some neoplasms, such as breast cancer and malignant melanoma, which have already been the subjects of many studies, there are still open problems and definitive answers to important questions are still lacking. Whereas localization of the sentinel node(s) can be determined in a high proportion of cases, it is still not possible to say definitively on the basis of imaging results whether incipient metastatic involvement is present preoperatively. Some sophisticated approaches that may be successful in the near future are based on PET, iron oxide nanocolloid application, and the use of labeled monoclonal antibodies or their fragments directed at the surface structures of cancer cells. Another problem is the delineation of the lymphatic stream, especially in head and neck tumors and tumors of different categories draining into the nodes of the inguinal region. These problems arise when the primaries are located in different compartments and organ structures and the lymphatics do not follow a linear course but form networks, some of them intensive. Therefore, we must always think in three dimensions. Consideration of the progress made as the result of research into breast cancer and malignant melanoma makes it clear that future developments will point the way for increased R0 resection. This progress and the ongoing investigations worldwide with highly specialized techniques lead us to hope that there will be further successful developments.
References Albers P, Bender H, Yilmaz H et al (1999) Positron emission tomography in the clinical staging of patients with stage I and II testicular germ cell tumors. Urology 53:808±811 Begun FP, Grossman HB, Diokno AC, Sogani PC (1984) Malignant melanoma of the penis and male urethra. J Urol 132:123±125 Bezooijen BP van, Horenblas S, Meinhardt W, Newling DW (2001) Laser therapy for carcinoma in situ of the penis. J Urol 166:1670±1671
Bokemeyer C, Droz JP, Horwich A, Gerl A, Fossa SD, Beyer J, Pont J, Schmoll HJ, Kanz L, Einhorn L, Nichols CR, Hartmann JT (2001) Extragonadal seminoma: an international multicenter analysis of prognostic factors and long term treatment outcome. Cancer 91(7):1394±1401 Cabanas CA (1992) Anatomy and biopsy of sentinel lymph nodes. Urol Clin North Am 19:267 Cabanas RM (1977) An approach for the treatment of penile carcinoma. Cancer 39:456±466 Cremerius U, Effert PJ, Adam G, Sabri O, Zimny M, Wagenknecht G, Jakse G, Buell U (1998) FDG PET for detection and therapy control of metastatic germ cell tumor. J Nucl Med 39:815±822 Cremerius U, Wildberger JE, Borchers H, Zimny M, Jakse G, Gunther RW, Buell U (1999) Does positron emission tomography using 18-fluoro-2-deoxyglucose improve clinical staging of testicular cancer? ± Results of a study in 50 patients. Urology 54:900±904 Fujikawa K, Matsui Y, Oka H, Fukazawa S, Sasaki M, Takeuchi H (2000) Prognosis of primary testicular seminoma: a report on 57 new cases. Cancer Res 60(8):2152±2154 Ganjoo KN, Chan RJ, Sharma M, Einhorn LH (1999) Positron emission tomography scans in the evaluation of postchemotherapy residual masses in patients with seminoma. J Clin Oncol 17:3457±3460 Hain SF, O'Doherty MJ, Timothy AR, Leslie MD, Partridge SE, Hud RA (2000) Fluorodeoxyglucose PET in the initial staging of germ cell tumours. Eur J Nucl Med 27:590± 594 Heidenreich A, Sesterhenn IA, Mostofi FK, Moul JW, Engelmann UH (1999) Histopathologic and biological prognostic factors of clinical stage I non seminomatous germ cell tumors. Implications for risk-adjusted therapy. Urologe A 38(2):168±178 Horenblas S (2001 a) Lymphadenectomy for squamous cell carcinoma of the penis. 1. Diagnosis of lymph node metastasis. BJU Int 88:467±472 Horenblas S (2001 b) Lymphadenectomy for squamous cell carcinoma of the penis. 2. The role and technique of lymph node dissection. BJU Int 88:473±483 Horenblas S, Jansen L, Meinhardt W, Hoefnagel CA, De Jong D, Nieweg OE (2000 a) Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 163:100±104 Horenblas S, Krogh G von, Cubilla AL, Dillner J, Meijer CJ, Hedlund PO (2000 b) Squamous cell carcinoma of the penis: premalignant lesions. Scand J Urol Nephrol Suppl 205:187±188 Krogh G von, Horenblas S (2000 a) Diagnosis and clinical presentation of premalignant lesions of the penis. Scand J Urol Nephrol Suppl 205:201±214 Krogh G von, Horenblas S (2000 b) The management and prevention of premalignant penile lesions. Scand J Urol Nephrol Suppl 205:220±229 Mechev DS, Sakalo VS (1994) Radionuclide diagnosis of regional metastases in patients with testicular tumours. Int Urol Nephrol 26(3):337±344 Mçller-Mattheis V, Reinhardt M, Gerharz CD, Fçrst G, Vosberg H, Mçller-Gårtner HW, Ackermann R (1998) Positron emission tomography with [18F]-2-fluoro-2-deoxyD-glucose (18FDG-PET) in diagnosis of retroperitoneal lymph node metastases of testicular tumors. Urologe A 37:609±620
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Chapter 29 Cancers of the Male Genitalia Osada H, Jojima K, Yamate N (1998) Primary mediastinal seminoma. Efficacy of chemoradiotherapy alone. Jpn J Thorac Cardiovasc Surg 46(9):810±814 Perinetti EP, Crane DB, Catalona WJ (1980) Unreliability of sentinel lymph node biopsy for staging penile carcinoma. J Urol 124:734 Pettaway CA, Pisters LL, Dinney CP, Jularbal F, Swanson DA, Eschenbach AC von, Avala A (1995) Sentinel lymph node dissection for penile carcinoma: the M. D. Anderson Cancer Center experience. J Urol 154:1999±2003 Pizzocaro G, Piva L, Bandieramonte G, Tana S (1997) Upto-date management of carcinoma of the penis. Eur Urol 32:5±15 Ravi R, Shrivastava BR, Mallikarjuna VS (1991) Inguinal pick in invasive penile carcinoma: can it stage node negative patients? Arch Esp Urol 44(9):1123±1126
Sedlmeyer F, Joos H, Deutschmann H, Rrahim H, Merz F, Kogelnik HD (1999) Long-term tumor control and fertility after para-aortic limited radiotherapy of stage I seminoma. Strahlenther Onkol 175(7):320±324 Senthil-Kumar MP, Ananthakrishnan N, Prema V (1998) Predicting regional lymph node metastasis in carcinoma of the penis: a comparison between fine-needle aspiration cytology, sentinel lymph node biopsy and medial inguinal lymph node biopsy. Br J Urol 81:453±457 Valdes Olmos RA, Tanis PJ, Hoefnagel CA, Jansen L, Nieweg OE, Meinhardt W, Horenblas S (2001) Penile lymphoscintigraphy for sentinel node identification. Eur J Nucl Med 28:581±585 Wilson CB, Young HE, Ott RJ et al (1995) Imaging metastatic testicular germ cell tumours with 18FDG positron emission tomography: prospects for detection and management. Eur J Nucl Med 22:508±513
Chapter 30
Prostate Cancer: an Overview
30
Is Sentinel Node Detection Helpful in the Curative Treatment of Prostate Cancer?
General Remarks Prostate cancer accounts for 21% of all neoplasms in the male population in Germany (Schçssler et al. 1993) and has similar rates of incidence in most countries in the Western world. This cancer type has long been mentally connected with ªold men's diseases,º and the level of commitment to research aimed at the development of new diagnostic and therapeutic approaches to it has therefore been relatively low. Now, however, with increasing survival rates even in older age groups, interest in improving its diagnosis and treatment is growing. With new trends in N-staging (see Wawroschek et al. 1999, 2000) in mind, it will be much more difficult to develop convincing strategies for detection of sentinel lymph node(s) (SLN), and it is also more difficult to dissect them, whether in isolation or together with secondary nodes within the pelvis, in the course of prostate cancer treatment than in the procedures used in breast cancer or malignant melanoma treatment. The difficulties are connected mainly with problems in administering contrast agents for sentinel node detection and orientation in the local topography of the lymphatic network structures of the pelvis. In addition, the problem is rendered more difficult because not only the lymph nodes must be dissected, but also the network of lymphatics in continuity with the prostate gland, which can contain cancer cells or cancer cell clusters. Invasive and noninvasive imaging techniques have been flawed by unacceptably high false-positive and false-negative rates in most approaches (Loening et al. 1977; Wilson et al. 1977; McCarthy and Pollak 1991; Schçssler et al. 1993). In view to this fact and since we have no uniform and highly developed concept for detection of sentinel node(s) that is actually practiced by the majority of our urologists at present, systematic iliac and ob-
turator lymph node dissection is currently generally referred to as the ªgold standardº when positive nodes are suspected, followed by prostatectomy in the case of confirmed prostate cancer. As a rule of thumb, it is generally accepted and well documented that cancer-positive aortic nodes are connected with positive pelvic nodes and that at least in these cases it must be accepted that the condition is incurable. As much as 20 years ago three different options for prostate cancer treatment in stage D1 were tested (radical prostatectomy, extended radiotherapy, and hormone therapy). The median survival in all groups was 39.5 months. None of the three treatment strategies was superior in prolonging life (Kramer et al. 1981), and there was no convincing breakthrough improving on this situation up to the 1990s. New approaches to antiandrogen- and radiochemotherapy see Chapter 33.
Serum Values of Prostate-specific Antigen and Prostate Acid Phosphatase as Indicators for Cancer, Metastatic Spread and Cancer Recurrence Bluestein et al. (1994) follow from their investigations on 1632 patients that prostate-specific antigen (PSA) is the best predictor of pelvic lymph node metastases (P < 0.0001).
Definition of the Degrees of Malignancy in Gleason's Grading (Scoring) System This section starts with a detailed analysis of the grading strategy (characteristic features of the subgroups). The predictive power is enhanced by considering the Gleason grading (scoring) (P < 0.001) and
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Chapter 30 Prostate Cancer: an Overview Table 1. Gleason grading system for prostatic adenocarcinoma: histologic patterns Pattern
Peripheral borders
Stromal invasion
Appearance of glands
Size of glands
Architecture of glands
Cytoplasm
1*
Circumscribed expansive growth
Minimal
Simple, round, monotonously replicated
Medium, regular
Closely packed
Similar to that in benign epithelium
2*
Less circumscribed; early infiltration
Mild, with definite separation of glands by stroma
Simple, round, some variability in shape
Medium, less regular
Loosely packed rounded masses
Similar to that in benign epithelium
3A
Infiltration
Marked
Angular, with variation in shape
Medium to large
Variable packed irregular masses
More basophilic than in patterns 1 and 2
3B
Infiltration
Marked
Angular, with variation in shape
Small
Variable packed irregular masses
More basophilic than in patterns 1 and 2
3C
Smooth, rounded
Marked
Papillary and cribriform
Irregular
Round to elongated masses
More basophilic than in patterns 1 and 2
4A
Ragged infiltration
Marked
Microacinar, papillary, and cribriform
Irregular
Fused, with chains and cords
Dark
4B
Ragged infiltration
Marked
Microacinar, papillary, and cribriform
Irregular
Fused, with chains and cords
Clear (hypernephroid)
5A
Smooth, rounded
Marked
Comedocarcinoma
Irregular
Round to elongated masses
Variable
5B
Ragged infiltration
Difficulty in identifying glands' lumens
Irregular
Fused sheets and masses
Variable
Marked
* In foci suspicious for cancer (pattern 1 and 2) positive reaction using the antibody P5O4S immunostaining helps to certify cancer diagnosis
the local clinical stage of the primary together (P < 0.001). The basic patterns leading to the Gleason scores are described in Table 1. The main criteria for delineation of the subgrades are comprehensively summarized in Fig. 1 according to the original publications about Gleason's scoring system. The subentities are still more precisely characterized by own drawings (Fig. 2).
Recently the WHO published the fascicle ªTumors of the Urinary System and Male Genital Organsº. The criteria of Gleason patterns and scoring of prostate cancers are summarized in the following overview. The criteria of the main patterns are compatible with the original description, presented in Table 1.
WHO-Classification 2004 Gleason pattern 1 1+1 = 2 = Gleason score
Well circumscribed nodule of closely packed glands, no infiltration (local in situ condition).
Gleason pattern 2 2+2 = 4 = Gleason score
Round or oval glands, loosely arranged, not as uniform as in pattern 1. Facultative minimal invasion, glands of intermediate size, with less variation than in Gleason pattern 3.
Correlations with Molecular Biological and Clinical Parameters
Gleason pattern 3 3+3 = 6 = Gleason score
Most common pattern: Higher degree of infiltration distance of glands more variable, more often malignant glands between preexistent. Often angular and small glands besides large ones. Cribriform pattern is rare and difficult to distinguish from cribriform high grade PIN.
Gleason pattern 4 4+4 = 8 = Gleason score
Glands fused, cribriform, may be poorly defined, partly not separated by stroma, edges of fused glands scalopped, thin strands of connective tissue, loss of lumina in cribriform parts. Hypernephromatoid pattern, a rare variant.
Gleason pattern 5 5+5 = 10 = Gleason score
Almost complete loss of glandular lumina, growth in solid sheets and strands or as single cells. Comedonecroses may be present.
If the tumor has only one pattern, Gleason score is obtained by doubling the pattern number (see scheme). If there exist two different pattern, the two pattern numbers are summed up, e.g. 3 plus 4 = 7 = Gleason score. If there is found a tertiary pattern, prognosis worsens additionally.
Correlations with Molecular Biological and Clinical Parameters
Fig. 1. Prostate cancer scoring according to Gleason. See Table 1 for details of the patterns
In order to give an impression of the histopathological differences of high, moderate, and low differentiation cancers, Figs. 3±7 show the characteristic histopathological features of each.
Investigations carried out by Conrad et al. (1998) in 345 cases showed that the amount and distribution of undifferentiated Gleason grades (pattern 4 and 5) cancer in the biopsies were the best predictors of the lymphatic spread, followed by serum PSA. In classification and regression analyses, nearly 80% of the patients who had Gleason score 4 or 5 disease in 3 or fewer biopsies and did not have a predominance of high-grade cancer in any biopsy can be classified as low-risk patients. Positive nodes were found in this group in only 2.2% (95% confidence interval, 0.8±4.7%). The authors conclude that the sextant biopsy principle enhances the predictive accuracy of algorithms, which define the probability of lymphatic spread. However, use of PSA and prostate acid phosphatase (PAP) values does have some limitations: · Oesterling et al. (1988) concluded from their studies that preoperative levels of PSA are not sufficiently reliable for the prediction of the pathological stage in patients with early cancer. But they confirmed the findings of other laboratories, demonstrating that PSA is a sensitive tumor marker for the detection of residual disease after radical prostatectomy and subsequent recurrence of the cancer in long-term follow-up studies.
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Chapter 30 Prostate Cancer: an Overview Fig. 2 a, b. Analysis of the Gleason patterns and cytology of prostate cancer based on growth pattern and cytological criteria derived from the top-view drawing presented in original publications 1
Circumscribed, highly differentiated
Less circumscribed, early invasive
Glands medium to large, partly angular
Small, partly angular and ramified glands
Papillary and cribriform pattern, irregular, round to elongated cancer cell formations, cytoplasm more basophil than in patterns 1 and 2
a
· Primarily in high-grade cases, or in the course of dedifferentiation, the PSA values can be low or decrease in spite of persisting or recurrent cancer (Partin et al. 1990). Conversely, unpredictable contributions from prostate parts with benign prostate hyperplasia components or foci with inflammation leading to increased release of PSA can moderate the PSA level, causing increased serum values.
These facts must be given due consideration by urologists, both during primary treatment and also in the follow-up of their patients, but with a view to the SLN concept and the performance of the necessary clinical studies the results are of special interest. It was found that PSA and PAP correspond to histopathologically detected metastatic lymph node involvement.
Correlations with Molecular Biological and Clinical Parameters Fig. 2 b Microacinar, papillary, cribriform patterns, irregular with chains and cords, cytoplasm dark
Microacinar, papillary, cribriform patterns, fused with chains, cytoplasm clear, hypernephroid
Comedocarcinoma, round to elongated cancer cell formations, cytoplasm variable
Soliud fused sheets, difficulty to identify glands
b
In the course of our daily routine work the P-values of correlations of PSA and PAP in uni- and multivariate analysis are of special interest (Table 2). In multivariate analysis the serum PSA level was the most powerful independent prognosticator followed by the T category, tissue PAP and tissue PSA. But there are limitations to the detection of early cancer development, as already mentioned above.
Table 2. Relationship of levels of prostate-specific antigen (PSA) and prostate acid phosphatase (PAP) in cancer tissue values to histopathological grade, DNA ploidy and T-category. The following values were found N category to serum PSA level
P < 0.001
to histological grade
P < 0.001
to tissue PSA
P < 0.001
to tissue PAP
P < 0.004
to T category
P < 0.005
to DNA ploidy
P < 0.002
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454
Chapter 30 Prostate Cancer: an Overview Figs. 3±7. Degrees of malignancy of prostate cancer: main types Fig. 3. Highly differentiated prostate cancer corresponding to Gleason pattern 2, corresponding to Gleason score 2+2 = 4. Note the fairly isomorphic glandular structures
Fig. 4. Well-differentiated prostate cancer with fairly isomorphic cancer cell nuclei, corresponding to Gleason score 3+3 = 6 low rate of mitoses, only focal branching of the glands
Fig. 5. Moderately differentiated prostate cancer with more pronounced variation of the glands. Gleason pattern 4, corresponding to Gleason score 4+4 = 8
Relation Between Dysplasia and Cancer Fig. 6. Anaplastic prostate cancer with high grade of polymorphism and high rates of mitosis. Gleason score 10
Fig. 7. Anaplastic prostate cancer with high grade of tumor cell dissociation and nerve sheath invasion. Gleason score 10
Importance of Tumor Volume to Clinical Significance in Treatment of Prostate Cancer
are probably unlikely to reach clinical significance because the doubling time of this cancer is too long.
Minimal Lesions
Relation Between Dysplasia and Cancer
Stamey et al. (1993) tried to calculate the probability of having a diagnosis of prostate cancer within a man's life. The prostates of 139 consecutive bladder cancer patients who had undergone cystoprostatectomy were examined. Prostate cancer was found in 55 patients (40%), larger cancers being detected only in 8%. The cancers ranged in volume from 0.5 to 6.1 ml. These results allowed the conclusion that prostate cancers smaller than 0.5 ml
In addition, McNeal (1993), also from Stanford University, investigated prostates with dysplastic changes of glands in the biopsy material. In 48% of these he found foci fulfilling the criteria for prostate cancer, and in 3 of the 107 cases investigated grade 4 cancer (low degree of differentiation) was found. Among patients in whom microcarcinomas were diagnosed, dysplasia was found in other parts in 81%.
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Chapter 30 Prostate Cancer: an Overview
Gleason Score (Grading) in Ultrasound-guided Biopsies Related to Results in Prostatectomy Specimens In their comparative studies of ultrasound-guided biopsies and prostatectomy specimens conducted in 289 cases, Gregori et al. (2001) obtained the following results summarized in Tables 3 and 4. It is very interesting that with whole-prostate evaluation (specimen investigations) as reference, upstaging is necessary in about 40%, that among cases with unilateral positive biopsies bilateral cancer infiltration is found in about 65%, and that among cases with bilateral positive biopsies intracapsular cancer infiltration is found in about 66%.
Table 3. Predictive value of Gleason score, up- and downgrading (according to Gregori et al. 2001) Recorded no. of patients
Identical Gleason score in the biopsies
Up-grading vs down-grading related to histologically investigated specimens
289
126 (43%)
118 (40.8%) vs 43 (14.8%)
Table 4. Specimen-related histopathological results in cases with uni- and bilateral positive biopsies (according to Gregori et al. 2001) Unilateral positive biopsy vs cancer on one side
Bilateral disease
Organ confined
Capsule penetration
193 (66.7%)
127 (65.8%)
142 (73.5%)
41 (26.4%)
46 (33.1) Bilateral positive biopsy (n)
Intracapsular cancer vs specimen confined
Overall positive margins
96
64 (66.6%)
14%
32 (33.3%)
Posterolateral capsular penetration
Apical capsular penetration
52/83 (61.4%)
28/83 (33.7%)
These data may also help in decision making when a catalogue of the indications for sentinel node evaluation is developed. Carlson et al. (1998) also examined the correlations between Gleason scores in biopsy specimens and the diagnoses made in prostatectomy specimens. They investigated 106 cases and obtained the results summarized in Table 5. The positive predictive values of the different Gleason scores are displayed in Table 6.
Division of Grade II (WHO) Cancers into Favorable and Unfavorable Subgroups Supported by Gleason Grading Lilleby et al. (2001) tried to differentiate more precisely between favorable and unfavorable subtypes of grade II cancers graded by means of the WHO criteria compared with the Gleason-graded subgroups. The review of specimens from 178 patients yielded the numbers of cases in the different groups shown in Table 7. Separating patients with a Gleason score of 7 (score 3 + 4 vs 4 + 3) led to a two-tiered Gleason grouping (88 patients in the favorable group and 90 in the unfavorable group). The authors concluded that equal allocation of patients to subgroups based on the Gleason system helps the clinician to overcome the dilemma of overrepresentation of grade II patients, which does occur with the WHO grading. Subgrouping grade II cancers by means of the Gleason grading system appears to make separation more of a possibility, for instance with a view to an additional sentinel node search and referral to radiotherapy. Altay et al. (2001) found that high Gleason scores together with elevated PSA levels (> 10 ng/ ml) involved a high risk of extraprostatic cancer extension, in some cases with seminal vesicle involvement (P < 0.05).
Grading Errors in Gleason Grading Evaluations Compared with a Database King and Long (2000) investigated the question of grading errors. A pooled database from ten series (n = 2687) served as a baseline for comparison aimed at checking the accuracy of Gleason score
Simultaneous Lymphogenous and Hematogenous Metastatic Spread? Table 5. Accuracy of Gleason biopsy grading No. of patients
Correlation of biopsy with radical prostatectomy
Correlation within one grade
All patients correlated within 2 grades
Under-grading
Over grading
106
72 (68%)
103 (97%)
106 (100%)
26 (25%)
8 (8%)
Table 6. Predictive values Percentage of positive predictive values
Well differentiated
Moderately differentiated
Moderately to poorly differentiated
Poorly differentiated
Gleason
2±4
5±6 70%
7
8±10
5 66%
6 67%
7 71%
Table 7. Distribution of prostate cancer cases (n = 178) within the Gleason grading scheme and rate of grade 2 cancers in this collective (WHO grading) Total no. of cases
Gleason < 7 (n)
Gleason 7 (n)
Gleason 8±10 (n)
Grade II WHO (n)
178
44
58
76
130
Table 8. Deviations of grading prostate cancer cases using the Gleason scale from the database Within 1 point in 93%
P = 0.029
Compared with database in 78%
P = 0.029
Upgrading of biopsies in 35%
P = 0.19
Compared with database in 43%
P = 0.19
Gleason 7 exact match in 78%
P = 0.07
Gleason 7 database in 20%
P = 0.07
grading. With the biopsy technique used an exact Gleason score match was achieved in 57% of the cases, a mean of 42% (P = 0.055) compared with the pooled database (PD). Table 8 shows the P-values for deviation from the database. King and Long's conclusion was that: ªSampling effects may contribute significantly to grading errors in prostate needle biopsies.º Koksal et al. (2000) found that Gleason grading error compared with the grading of prostatectomy specimen grading was highest in highly differentiated cancers. This can be easily understood on the basis of primary multifocality clonal selections. Allsbrook et al. (2001) evaluated the interobserver reproducibility of the Gleason grading: constant undergrading was observed in the Gleason scores, at the following rates:
· Scores of 5 and 6 · Score of 7 · Scores of 8±10
in 47% in 47% in 25%
Underestimation of the growth pattern was also observed: · Pattern 2 in 32% · Pattern 3 in 39% · Pattern 5 in 30% The authors recommend training programs and courses to improve the quality in grading-practice and to reduce interobserver differences.
Simultaneous Lymphogenous and Hematogenous Metastatic Spread? The fact that autopsy studies both in the United States and in Japan show identical rates for metastatic involvement of lymph nodes and of bone marrow (see Fig. 11) can be interpreted as showing that regional lymphatic spread and hematogenous retrograde transport to the column and other bone regions are closely connected. The additional finding of lung metastases in two-thirds of cases with lymph node and bone marrow involvement can be explained by the communication of the venous periprostatic and prevertebral venous plexus with the azygos veins, which
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Chapter 30 Prostate Cancer: an Overview
are directly connected with the vena cava inferior. It follows from this that it is only in the very early stages of local lymphatic spread that there can be any hope of local curative lymphatic operative tumor clearance. These reflections are important because they can influence the development of a catalog of indications for sentinel and pelvic lymph node extirpation and investigation projects. That means that it is very important to perform bone and lung-investigations before surgical procedures are started.
Significance of Degree of Malignancy and Number of Biopsies Taken for N-staging and the Sentinel Lymph Node Concept According to the experience of pathologists, foci of high-grade prostate cancer can be found in a set of the typical six-point biopsy series. This leads to the conclusion that high-grade cancers develop as subclones in the course of cancer extension. McNeal (1993) investigated this problem again and demonstrated the derivation of high-grade cancers as more or less extended subclones in lowgrade cancers within the prostate gland. Usually the majority of nonextended microcarcinomas develop from preexistent dysplasia. Investigations of nonextended early cancer of the prostate show areas with high-grade cancer in only 3% of cases. Knowledge of these proportions seems to be important for the development of a sentinel lymph node concept that is suitable for application in the treatment of prostate cancer, especially with the aim of finding the limits for N-staging in early cancer cases with a low grade of malignancy.
Smith et al.'s (1983) investigations already make it clear that locoregional metastatic spread depends heavily on how malignant the primary is (Tables 9, 10). These data help in preoperative calculation of the risk of locoregional cancer progression. In addition, the following data published by Walsh et al. (1994) can be used to obtain a prospective assessment of 10-year survival, depending on Gleason grade and capsule infiltration or perforation by the cancer (Fig. 8). These data allow easier formulation of indications for a differentiated sentinel lymph node (SLN) search based, for instance, on the new results and developments published by the Augsburg research group (Wawroschek et al. 1999, 2000). Danella et al. (1993) reported that in their group of patients with clinically localized prostatic cancer, 5.7% had nodal metastases. The predictive value in patients with prostate-specific antigen levels elevated to > 40 ng was 53%. The authors emphasize that laparoscopic lymph node dissection should be the method of choice in view of the low rate of nodal metastases. In the context of these important facts, in addition to local regional operative pelvic cancer clearance, if the near future were to see improvements in prostate cancer grading including the emergence of important prognostic factors indicative of likely proliferation and blood vessel invasion with a high predictive value these would be greatly appreciated.
Table 9. Distribution of tumor grade by stage Stage
Well differentiated
Moderately differentiated
Poorly differentiated
n
n
n
(%)
(%)
Total no. of patients
(%)
A1
28
(68)
12
(29)
1
(3)
41
A2
7
(21)
19
(58)
7
(21)
33
B1
53
(34)
94
(60)
9
(6)
156
B2
27
(18)
106
(69)
21
(13)
154
C
10
(15)
44
(64)
14
(21)
68
125
(28)
275
(61)
52
(11)
452
Basic Research for Complete Pelvic Lymph Node (N-) Staging Table 10. Incidence of pelvic node metastasis by histological grade and clinical stage [from Smith et al. (1983)] Stage
Well differentiated
Moderately differentiated
Poorly differentiated
Total no. of patients
No.
No.
No.
No.
(%)
(%)
(%)
0/1
(%)
A1
0/28
0/12
0/41
A2
0/7
5/19
(26)
3/7
(43)
8/33
(24)
B1
2/53
(4)
13/94
(14)
3/9
(33)
18/156
(12)
B2
5/27
(18)
29/106
(27)
9/21
(43)
43/154
(28)
C
5/10
(50)
18/44
(41)
13/14
(93)
36/68
(53)
125
(28)
275
(61)
52
(11)
452
(23)
Fig. 8. Actuarial probability of freedom from recurrence of elevated PSA in relation to stage and Gleason grade. These data are based on follow-up studies of 955 men treated at Johns Hopkins Hospital by Walsh et al. (1994)
Is the Primary Cancer Detection Rate Higher with Twelve Biopsies than with Six?
Basic Research for Complete Pelvic Lymph Node (N-) Staging
Prospective randomized studies carried out in 244 men by Naughton et al. (2000) and comparing the impact of the number (6 versus 12) prostate biopsies on cancer detection did not show higher detection rates when 12 core biopsy specimens were taken and investigated in a screening program (P = 0.9). At around the same time a report of a study conducted by Ravery et al. (2000) to evaluate 303 consecutive cases showed an overall detection rate for prostate cancer of 38.9% in their patient population, the rate being higher by 6.6% when more biopsy investigations were done (6.5% in men with PSA 10 ng/ml or less and 7% in men with PSA >10 ng/ml). (For more information on increases in detection rates see also: Eskew et al. 1996; Beurton et al. 1997; Ravery et al. 1999.)
Metastatic Involvement of the Main Node Groups and Statistical Evaluations of Side Differences Weingårtner et al. (1996) tried to find mean values in an attempt to answer the question of how many lymph nodes need to be investigated to give the complete metastatic profile in the pelvis. They performed investigations both on cadavers and in living cancer patients. The means found were 22.7 for the cadavers (Ô10.2, range 8±56) and 20.5 for the prostate cancer patients (Ô6.6, range 10±37). In the patient group, involvement of pelvic lymph nodes was significantly more frequent on the left side (see Fig. 9). Lymph nodes were more frequently enlarged in cancer patients than in controls, regardless of whether they were cancer infil-
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Chapter 30 Prostate Cancer: an Overview
Survival Rate Versus Lymph Node Metastasis
Fig. 9. Main pelvic lymph node groups that can be involved in metastatic spread. Note that the left-sided lymph nodes are more frequently involved
trated or tumor free. Therefore, enlarged lymph nodes cannot be used for diagnostic purposes as they are in breast or lung cancer, e.g. in imaging investigations. These results indicate that it is impossible to use CT or MRI to diagnose metastatic cancer involvement of the pelvic nodes. The rates of metastatic lymph node involvement from prostate cancer in the different pelvic positions (iliac and obturator) are shown in Fig. 9. In Gervasi et al.'s (1989) series of 511 prostate cancer patients, N0 and N+ patients were compared for metastatic lymph node involvement over a median follow-up of 8.6 years; the P-value was less than < 0.00005 (Table 11). The hematogenous metastatic rates determined for N+ patients were: N1 N2 N3
80% 84% 88%
In a comment on Gervasi's results (see Table 11), Paulson (1989) suggested that hematogenous metastatic spread develops more or less in parallel at the same time. This suggestion seems to hold true for many cancer cases progressing by the hematogenous route, but we cannot at present relate this assumption to particular cancer cases on the basis of specific clinical and molecular biological features (Fig. 10). However, in spite of these tentative conclusions, locoregional pelvic cancer clearance (tumor-free margins of the primary, complete node dissection) should be consistently developed in an independent way. Before a sentinel node search is conducted distant metastases should be excluded. The frequencies and sites of hematogenous metastases are listed in Fig. 11. It is worth emphasizing that in the prostate the lymphatics follow the larger lymph channels leaving the prostate posteriorly and then spread primarily to the perivesical, hypogastric, obturator, presacral and presciatic and obturator lymph nodes as the first stations (McLaughlin et al. 1976). These results are already quite old and are not fully included in the current routine principles of lymph node clearance. This posterior extracapsular region could be one of the points where the contrast solution for SLN labeling could be injected. Systemic iron oxide (Sinerem) injection should also be discussed again as a possibility for labeling the first (sentinel) stations. In Schçssler's investigations (1993) in cases with palpable disease (stages B1, B2, C), 36% had lymph node involvement. This value corresponds to many other series investigated in different clinics (Flocks et al. 1959; McCullough et al. 1974, 1977; McLaughlin et al. 1976; Bruce et al. 1977; Wilson et al. 1977; Freiha et al. 1979; Brendler et al. 1980; Grossman et al. 1980; Fowler and Whitmore 1981; Catalona and Stein 1982; Donohue et al. 1982). Widely different frequencies have been recorded for metastases to the external iliac lymph nodes: Nicholson and Richie (1997) McLaughlin et al. (1976) Arduino and Glucksman (1962) Bruce et al. (1977) Schçssler et al. (1993)
17% 10% 57% 54% 30%
Basic Research for Complete Pelvic Lymph Node (N-) Staging Table 11. Actuarial all-cause and cancer-specific survival rates at 5, 10 and 15 years by extent of nodal metastases (percent Ô 2 SE) (from Gervasi et al. 1989) All-cause survival rate
Cancer-specific survival rate
5 Years %
10 Years %
15 Years %
5 Years %
N0
90Ô3
62Ô6
36Ô14
98Ô2
83Ô6
70Ô13
N+
65Ô8
32Ô9
6Ô10
75Ô7
43Ô11
21Ô17
N1
68Ô15
40Ô19
±
82Ô13
60Ô19
±
N2
63Ô11
22Ô11
±
72Ô10
34Ô15
±
N3
69Ô17
35Ô22
±
75Ô17
42Ô24
±
Fig. 10. Distant metastases (actuarial rate) by presence and extent of nodal metastases. Vertical bars indicate 95% confidence intervals (mean Ô SE). Although distant metastases appeared less rapidly in the N1 subgroup, the rate of devel-
10 Years %
15 Years %
opment of distant metastases was parallel in each of the three subgroups of N+ cancer patients (see Gervasi et al. 1989, Table 11)
Fig. 11. Sites and frequencies of metastases from prostate cancer and most common sites of prostate cancer metastases found at autopsy in the United States and Japan [from Bostwick and Eble (1993) with permission]
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Chapter 30 Prostate Cancer: an Overview
These wide differences (10% to nearly 60%) in the rates of external iliac lymph node metastases are disturbing when we are trying to collect clearcut information for use as a basis for the development of a SLN concept. The percentages of cases upstaged to D1 from the different lower stages according to Schçssler (1993) evaluations of lymph node involvement are as follows: A2 B1 B2 C
27% 15% 52% 50%
The percentages for stages B2 and C are very high. Better information on prognostic factors is thus long overdue. When all aspects are considered together, two principles seem to be the most important indicators of regional lymph node involvement and thus to constitute indications for a search for sentinel nodes and in addition, when the sentinels are positive, for pelvic lymphadenectomy. These two most important principles are:
1. Evaluation of grade of malignancy with rating of nuclear grade plus, if possible, evaluation of the percentages of cancer cells in DNA synthesis and in the proliferative compartment, using the antibody MiBI and the CASS 2000 machine for the determination of percentages. 2. Proof of cancer infiltration and perforation of the prostate capsule; when these pathohistological, biologically based parameters allow the conclusion that a high-grade or high-risk cancer is present SLN staging should be performed. · In addition to the standard dissection involving the nodes along the common iliac artery, the external iliac artery, genitofemoral nerve, hypogastric vessels and obturator fossa also need investigation (Flocks et al. 1959; Arduino and Glucksman 1962; Barzell et al. 1977; Bruce et al. 1977; Freiha and Salzman 1977; Nicholson and Richie 1977; Grossman et al. 1980; Fowler and Whitmore 1981; Donohue et al. 1982). · An extended dissection also includes the nodes in the presacral and lateral sacral areas (see also Wawroschek's, Vogt's and Harzmann's First Approach to Detection of Sentinel Nodes in Prostate Cancer in this chapter). It is noteworthy that some investigations have indicated
Fig. 12. Inverted-V peritoneotomy according to See et al. (1993). The peritoneal flap is dissected superficially and folded back along the dotted lines shown in the schematic
Intraoperative and Postoperative Lymph Node Staging in the Treatment of Prostate Cancer
that in approximately 13±15% of cases these locations are the only ones involved in the metastatic process. · The limited dissection procedure is derived from the standard method. The lateral border is limited by the lateral margin of the lateromedial aspect of the external iliac artery instead of the genitofemoral nerve (Brendler et al. 1980; Paulson 1980; Lieskovsky and Skinner 1983; Gervasi et al. 1989; McDowell et al. 1990). The common iliac artery is left undissected, which is easily understood in view of the difficulty of implementing lymph node and lymph vessel clearing principles in the pelvic region. · A fourth possibility is obturator fossa node dissection (Kozlowski and Grayhack 1987; Winfield and Kavoussi 1991; Winfield et al. 1991), which is a simpler procedure with low morbidity rates. · In comparison with linear peritoneotomy, an inverted-V peritoneotomy, which is designed to allow wider exposure of the target tissue, improves the nodal yield of laparoscopic lymphadenectomy (Fig. 12). It may be that inverted-V peritoneotomy will be one of the keys to complete lymphadenectomy in the further development of a sentinel node concept for treatment of prostate cancer. It is clear that high complication rates of standard pelvic lymph node dissection with complication rates nearly equal to those of laparoscopic lymphadenectomy (30±32% for both methods) complicate the development of sophisticated methods for SLN dissection programs. The complications are: hemorrhage, bowel laceration, ureteral injury, and development of lymphocele.
Is Laparoscopic Lymph Node Staging Equivalent to Open Pelvic Lymph Node Dissection? Compatibility with a Pelvic SLN Concept Parra et al. (1992) state that laparoscopic node excision gives node detection rates identical with those obtained with open operative dissection. No more nodes were found after laparoscopic node dissection from the surgical margins by open reoperation in patients who had undergone second-
ary prostatectomy. Nonetheless, the application of this method has limitations. · Trocars (three 11 mm and two 5 mm in diameter) need to be inserted at five locations , distributed over the lower parts of the abdomen. · This method has a similar complication rate to open biopsy. · The fundamental problem of cancer progression after nodectomy in cancer-positive cases is not improved. Therefore, improved local clearance in the sense of the SLN concept has not yet been reached.
Intraoperative and Postoperative Lymph Node Staging in the Treatment of Prostate Cancer Intraoperative lymph node staging in frozen sections needs close cooperation between pathologists and their technicians, because sometimes microfoci of cancer infiltration are visible even at the section surface. Double investigations of frozen sections from each lymph node slice and of imprint cytology of each slice of the nodes can increase efficiency and lower the false-negative rate. However, we should always keep in mind that the quantity of tissue lost is much greater in frozen sections than in paraffin embedding and paraffin sectioning. Therefore, when two-step surgery is planned (node evaluation and prostatectomy) basing a decision for prostatectomy exclusively on frozen sections of the lymph nodes is of restricted value. This question becomes even more difficult when attempts at development of a SLN concept are afoot, because sentinel nodes, as the key nodes in metastasis, must be investigated in serial sections, a technical procedure that is more reliable and easier to perform when the paraffin technique is used. In recent times, results of some screening- and comparative studies have been published to allow evaluation of the efficiency of different methods. Epstein et al. (1986) presented their N-staging data based on a series of 299 cases. They emphasized that the detection of metastases by the frozen section technique is quite precise. The average extension of the metastases was 2.5 mm, and the false-negative rate was 3.5%. In a frozen section lymph node analysis carried out by Davies (1995) a 90% diagnostic efficiency could be reached, which is similar to that of MRI analysis (88%). However, the aggregated sensitivity
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Chapter 30 Prostate Cancer: an Overview
of MRI was less than 67% that obtained with frozen section analysis. In our opinion, the histopathological efficiency can still be increased by intraoperative serial section analysis using an immunohistochemical technique newly developed by Hæfler and Nåhrig, in which the staining procedure takes only 12±20 min (see also Chapter 17). As in staging procedures used for other cancers [see Chapter on Melanoma (Chapter 25)], Okegawa et al. (2000) also performed RT-PCR studies of the dissected lymph nodes for staging prostate cancer by preliminary investigations, to detect early lymph node metastases, and to define the indications for prostatectomy more precisely. Positive results were obtained in 11% of stage pT2a and in 25% of stage pT2b cases. Invasion of prostate cancer into seminal vesicles did not significantly alter the frequency of involved nodes (61% versus 70%), as published by Barzell et al. (1977).
Is Whitmore's Staging Scheme Established in 1984 Still Compatible with Our Current Knowledge? The establishment of indications for a search for SLNs is at least partly hampered by the fact that the clinical staging devised by Whitmore in 1984 is incompatible with tumor biology in important points. To help readers understand the critical points, first of all the topographically oriented scheme of Whitmore should be described: A2: Any quantity of cancer within the prostate, without discrimination between the different degrees of malignancy, meaning by implication high-grade cancer types. B1: Cancer nodule involving less than half of a lobe. B2: Cancer nodule involving more than half of a lobe or bilateral cancer nodes. C: Local extension of any cancer beyond the prostate gland. D1: Prostate cancer with positive pelvic nodes. D2: Prostate cancer with distant metastasis. It is clear that inclusion of all high-grade cancers in stage A2 must give worse results in terms of tu-
Table 12. Rates of lymph node involvement in different stages of prostate cancer in the collective published by Schçssler et al. (1993) Stage
No. of cases
Cases with positive nodes No.
%
Ul a
28
0
0
A2
11
3
27
B1
21
3
15
B2
21
11
52
C
6
3
50
a
Adenocarcinoma of prostate detected by ultrasound only and in addition with view to the literature [see also Table 13, also from Schçssler et al. (1993)]
mor progression than B1 cancers with involvement of less than half of a lobe of the prostate. The reason why the Whitmore scaling cannot be used as a basis of decision about in which cases lymph node staging will be helpful for further decision-making (sentinel node labeling, prostate adenectomy, etc.) lies in values given (for example) by Schçssler et al. (1993) (Table 12). A decision in favor of lymph node dissection is made possible by the fact that lymph node involvement is more frequent (according to collective evaluations) in A2 than in B1 stages (26% vs 16%). However, the background to this marked discrepancy is that all extensions and all grading groups are included under A2! This seems a poor basis for preoperative selection of the cases in which lymph node involvement must be assumed. The percentages of different rates of lymph node involvement published by different working groups on the basis of the Whitmore staging (A2± C), are listed in Table 13. Some investigations give the impression that lymph node involvement is found almost exclusively in cases in which the cancer has broken out through the prostate capsule. However, a systematic search for nodal micrometastases by means of modern immunohistochemical techniques reveals micrometastases in 16% of pT3N0 cases and also in lower pT stages (Gomella et al. 1993; Moul et al. 1994). In the context of these findings we must see that many case series are incorrectly staged. This knowledge has a marked influence on our new approaches to developing a sentinel node concept.
Is Whitmore's Staging Scheme Established in 1984 Still Compatible with Our Current Knowledge? Table 13. Laparoscopic standard of pelvic node dissection for prostate cancer. Incidence of positive nodes according to clinical stage: review of the literature according to Schçssler et al. (1993) Reference
Clinical stage A2 Total no. of patients
B1
B2
Patients with positive nodes n (%)
Total no. of patients
Patients with positive nodes n (%)
59
13 (22)
179
26 (15)
99
46 (46)
±
±
Freiha et al. (1977)
2
0 (0)
13
2 (15)
44
10 (22)
41
24 (58)
Bruce et al. (1977)
3
0 (0)
6
0 (0)
13
5 (38)
8
6 (75)
Donohue et al. (1982)
Total no. of patients
C Patients with positive nodes n (%)
Total no. of patients
Patients with positive nodes n (%)
Nicholson and Richie (1977)
±
±
26
2 (8)
14
2 (14)
6
2 (33)
McLaughlin et al. (1976)
±
±
19
4 (21)
17
5 (29)
24
12 (50)
Brendler et al. (1980)
22
3 (14)
58
11 (19)
27
14 (52)
17
10 (58)
Catalona and Stein (1982)
9
3 (33)
49
14 (28)
28
9 (32)
±
Grossman et al. (1980)
47
25 (53)
18
3 (17)
14
4 (28)
9
5 (55)
Fowler and Whitmore (1981)
±
75
5 (7)
129
56 (43)
96
58 (60)
29 (22)
165
35 (21)
100
37 (37)
116
51 (44)
0 (0)
36
5 (14)
29
9 (31)
19
10 (52)
Gervasi et al. (1989)
130
Wilson et al. (1977)
8
±
±
McCullough et al. (1977)
±
±
±
±
±
±
27
19 (70)
Flocks et al. (1959)
±
±
±
±
±
±
382
144 (37)
745
341 (46)
Totals
280
73 (26)
644
The metastatic rates in a series of 521 patients investigated by Petros and Catalona (1992) were as follows: A1 A2 B1 B2
0% 3.3% 5.3% 9.7%
In a series of 452 cases investigated by Smith et al. (1983), especially in the B2 group the rate of me-
107 (16)
514
197 (38)
tastases was hardly more than half of Schçssler's rate. With a view to tumor malignancy grade, in total metastases were detected in only 10% of lowgrade cancers, in 24% of moderately differentiated cancers, and in 54% of high-grade tumors (poorly differentiated). The fact that the rate of metastases from welldifferentiated cancers (A1 = 0%, B1 = 4%) is very low led to the conclusion that lymphadenectomy should not be performed in these cases even at the
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Chapter 30 Prostate Cancer: an Overview
beginning of the 1980s. Conversely, in poorly differentiated cases in stage C, metastatic behavior can be assumed in more than 90% (93% according to Smith et al. 1983). In conclusion, on the basis of their own results and those in the literature, Petros and Catalona (1992) reflect on genuine changes in our estimates of the stage at which prostate cancer is currently diagnosed. The authors emphasize that the main factors in the lower metastatic rates seem to be: · Higher index of suspicion · Earlier detection · More aggressive intervention to establish the diagnosis · Ultrasound-guided prostate biopsies · More widespread screening for prostate cancer.
Development of a SLN Concept in Relation to Tumor Stages Evaluation of Preconditions Recently Huland (1998) tried to discuss the value of radical prostatectomy in node-positive cases. In a first statement he declared that in the course of last 10 years, in stages T1 and T2 lymph node involvement has decreased from 20 to less than 7%. In a second statement he deals with the relapse rates recorded by Abbas and Scardina (1993), Catalona and Smith (1994), and Walsh et al. (1994): nearly 100% in stages N1. He goes on to say that according to these studies that have emanated from Johns Hopkins, Houston and St. Louis Hospitals and to other studies it seems doubtful whether ever a patient with positive node(s) could be cured by radical prostatectomy and lymphadenectomy (Abbas and Scardino 1993; Catalona and Smith 1994; Walsh et al. 1994). Huland cites the Gæteborg studies and emphasizes that among 514 patients 319 died from progression of their prostate cancer; 131 of these 319 cases (41%) needed a ªtransurethralº operation, and 98 needed palliative radiation therapy to the urinary bladder. In 53 cases (17%) urine had to be diverted into the cranial part of the urinary bladder. In approximately 20% of cases a prostatectomy could help to avoid later severe complications that could otherwise be caused by growth of the cancer, but we have no method of identifying the groups ahead of
time. Therefore, a wait-and-see strategy is mostly adopted with the background intention of performing palliative radiation therapy if necessary. In these conditions there is only one choice, as has long been the case in many clinics: · Investigation of the six routinely taken biopsies, with the possibility of dividing the cases into two main groups ± Low-risk group with regional lymph node involvement in a maximum of 2% of cases: low grade (I) with limited intraprostatic extension, no capsule perforation ± High-risk group with regional lymph node involvement in up to approximately 30%. · Giving the patient information, with the aim of making him feel able to give informed consent to further treatments. This means regional lymph node investigations on frozen sections during the operation and prostatectomy in patients with negative nodes. This is the most frequently practiced concept, and it does not fit in directly with the concept of sentinel node labeling. Changes are needed to bring about better quality of the investigations and of decision-making process. The sentinel lymph node concept is already practiced in many different ways and could be adapted to the prostate cancer problem as follows: · To obtain the most clear-cut information possible about the localization, especially when the positions of the sentinel nodes are atypical, it is necessary, especially in cases in the high risk group, to wait for the results obtained in paraffin sections of the nodes (principally investigated in the same way as in breast cancer or melanoma cases). · Decisions about prostatectomy can then be made with informed consent from the patient and the possibility of later adjuvant radiation therapy can also be discussed with him. It has long been unclear whether the survival rate of N-positive cases can be increased by more discriminating and continuous surgical removal of regional lymph nodes. This is partly because no results of systematic comparative studies of groups treated with and without node resection, each subdivided into low- and high-grade groups, are available. However, it is easy to understand why this is so, because it must be seen that it would be unethical not to dissect the regional lymph nodes, i.e., the iliac and ob-
Current Survival Rates as a Measure of Improvements in Lymph Node Staging and Clearance
turator lymph nodes on both sides, in the case of larger tumors, especially when the prostatic capsule is shown by histological investigation to be tumor infiltrated, something that can already be detected in the biopsies in special cases. This dilemma is further complicated by the fact that some authors see laparoscopic and open surgical procedures for lymph node extirpation as competing methods. With this rather confused situation, the approach to looking for sentinel node(s) has been founded on a very unclear basis. Many points are still open and urgently need to be cleared up. The following questions arise in this context of the approach that is striven for: 1. Can laparoscopic and open surgical pelvic lymphadenectomy be recognized as methods of equal value? 2. Is it possible to label the cancer within the prostate gland with the aim of secondary sentinel lymph node labeling using the methods described by Harzmann and his group, for example (see Wawroschek et al. 1999, 2000)? 3. Can labeling of sentinel nodes with atypical locations be helpful in revealing micrometastases? Ad 1: Minimally invasive surgical methods allow excision of the iliac and obturator lymph nodes on both sides for pathohistological investigation of almost the same quality as is possible with an open operative procedure. If this statement were absolutely correct, the approach could be to perform histopathological examination of the laparoscopically dissected nodes, followed in node-negative cases by transurethral or perineal prostatectomy. However, this therapeutic approach does not allow labeling of prostate gland with 99mTc and a search for the sentinel regional lymph node(s) by means of the gamma probe, because SLNs in atypical locations cannot be dissected by laparoscopic methods. This procedure would only be possible with open operative methods. In addition, there is real doubt among urologists about the comparability of minimally invasive and open lymphadenectomy. Ad 2: As is generally well known, it is already difficult to obtain significant prostate gland material from the six different areas of the gland, because the procedure for obtaining core biopsies of the prostate gland is very painful for the patient. On this basis, we can be sure that the injection of 2 ml colloidal solution, for instance, into the prostate gland is tol-
erated by most patients, but is not ideal in terms of lymphatic flow from the tumor region to the SLN(s). In addition, because it is often not possible to distinguish the outline of the cancer within the gland, the injection would be given directly into cancer tissue, which seems to be dangerous, especially in view of the increased pressure that must follow the injection of 2 ml of the labeling-solution, which can cause blood and lymphatic vessels to open (see also discussion of this problem in Chapter 7, which is focused on breast cancer labeling procedures). On the other hand periprostatic injection of the contrast solution also seems to be problematic, because venous blood vessels of the plexus prostaticus can be opened, followed by bleeding and thrombosis (see Fig. 13). Ad 3: The influence of lymphogenic micrometastases on tumor progression cannot be judged precisely at present, because the data available are in a highly degree divergent and based on different preconceptions. Therefore, the following options must be thought through before we can find better solutions: · Is it possible to localize small cancers very accurately by ultrasound and inject labeling solution into the interstitial non-cancer-infiltrated part of the prostate gland body? · Is it possible to localize smaller foci of cancer, for instance in cases with multifocality, and inject labeling solution into the interstitial prostate gland body? · Is it possible to inject the contrast solution into the vicinity of the primary outside the gland body but in highly reduced volumes of maximally 0.2± 0.5 ml in order to reduce the interstitial pressure to a high degree so as to avoid opening of blood vessels, which is otherwise induced by high pressure and leads to interruption of the continuity of vascular wall structures?
Current Survival Rates as a Measure of Improvements in Lymph Node Staging and Clearance by the Sentinel Node Concept When surgical lymph node clearance, especially in cases with occult or micrometastases, needs to be extended, as already proposed by Wawroschek, Vogt, and Harzmann, the procedure should be oriented on the current survival rates.
467
468
Chapter 30 Prostate Cancer: an Overview Fig. 13. Venous pelvic bloodstream: Note the intensively developed venous plexus prostaticus (PP) and plexus presacralis. The PP is closely connected to the prevertebral and vertebral plexuses. These connections are relevant after veins have been opened and venous blood pressure has risen in connection with prostate and pelvic lymphadenectomy, as they allow so-called retrograde transport of cancer cells into the vertebral bone marrow. After Leibovitch et al. (1995)
Cheng et al. (1993) published the overall survival rates achieved with different therapeutic principles (see Table 14). In other series, e.g. that published by Hanks (1993), the results obtained with adjuvant radiation therapy have also been limited (see Table 15). The data presented in Tables 14 and 15 confirm that operative procedures obviously have some benefit but that this is limited compared with irradiation therapy, and suggest that orchidectomy prolongs survival. In these circumstances, and in view of the fact that by 10 years after the primary diagnosis most patients have reached the mean general survival age, it seems that sentinel node detection with curative intent is limited, when all stages are taken together; therefore, sentinel node detection must be focused on the early stages of cancer development with histologically occult metastases and micrometastases, such as those detectable only by immunohistochemical serial sectioning, to improve locoregional clearance. Such efforts may improve the statistically evaluated success rate, but must be seen mainly under the aspect of individual therapy.
Table 14. Five years respectively ten years survival rates in D1-prostate cancer patients (non-randomized study) at 631 cases by Cheng et al. (1993) (IO intraoperative, PO postoperative) Therapy regimen
Survival 5 Years
10 Years
Prostatectomy and orchidectomy (PO, n = 251)
91%
78%
Prostatectomy alone (PO, n = 78)
91%
75%
Irradiation and orchidectomy (IO, n = 97)
84%
54%
Orchidectomy alone (PO, n = 60)
84%
45%
Whereas in locoregional tumor clearance in breast cancer irradiation therapy (homogeneous irradiation after wide excision of the primary) is very successful in preventing local recurrence and in general in improving healing rates, the same level of success obviously cannot be reached in radiotherapy for prostate cancer (see Tables 14 and 15).
Does Radical Prostatectomy Improve the Results in Lymph Node-Positive Cases (D1)? Table 15. Outcome of radiation therapy oncology. Groups of patients with node positive and negative disease treated with radiation No.
Survival
Free of any failure
5 years
10 years
5 years
10 years
T1B, T2 Node negative
104
87%
63%
85%
67%
Node positive
43
60%
24%
38%
20%
Node negative
47
82%
58%
69%
49%
Node positive
59
65%
26%
32%
10%
T3, T4
Table 16. Comparison of survival rates in cases with and without radical prostatectomy Stages A and B with pelvic lymph node metastasis D1
Patients with radical prostatectomy Group 1
Patients without radical prostatectomy Group 2
P-value
Control without positive nodes
11.2 years
5.8 years
0.005
1±2 positive nodes
20.2 years
5.9 years
0.015
Complication rates
9.5%
24.6%
Because radiotherapy has limited success even in low-grade cases and in early lymphogenous metastatic spread, it seems that even in many patients in the early N1 (D1) stages, systemic hematogenous spread has already occurred. This has already been underlined by the results published by Gervasi et al. (1989). The risk of distant metastases and of death from prostate cancer has been found to be much higher in cases with positive nodes than in node-negative cases (P < 0.00005).
Does Radical Prostatectomy Improve the Results in Lymph Node-Positive Cases (D1)? The discussion of this question has given rise to some controversy. Opinions on this point vary quite widely and are frequently related to individual patients' preconceptions. However, more recent investigations by Frazier et al. (1994) give a significant answer to this problem · With reference to D1 cases and survival · With reference to complication rates in cases with and without prostatectomy (see Table 16).
The survival advantage of patients who have undergone a radical prostatectomy was independent of any adjuvant therapeutic support. Radical retropubic prostatectomy had no perioperative complications in 72% of the cases. Complication rates were significantly associated with anesthesiological problems and comorbidity rather than age (ASA class P = 0.006; operative blood loss P = 0.015) (Dillioglugil et al. 1997). Parra et al. (1996) recommend perineal prostatectomy in low-risk cases (PSA < 10 ng/ml, Gleason score < 7). In his 75 low-risk cases he found no nodal metastases. In contrast, among 81 cases with worse parameters metastases were detected in 5 (= 6.1%).
In Conclusion · In prostate cancer regional lymph node involvement depends heavily on: ± Degree of malignancy ± Stage: whereas in grade I pT1N involvement is nearly zero; in pT2±3 (B2, C) lymph node involvement is very much more frequent.
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Chapter 30 Prostate Cancer: an Overview
· When lymph nodes are involved the healing rates are low, in some statistics near zero. · When 99mTc is used for sentinel node detection (Wawroschek et al. 1999, 2000), it is possible for atypically localized sentinel nodes to be detected which would not be detected on open or laparoscopic lymphadenectomy. · Laparoscopic lymphadenectomy is roughly comparable in value to an open operative procedure, but does not allow removal of atypically localized SLNs. · The chances of achieving more efficient locoregional tumor clearance by an operative procedure are low, because of the dense networks of lymph and blood vessels (plexus prostaticus, presacral plexus) in the pelvis, which are limiting factors. · Immunohistochemical methods (use of cytokeratin, PSA antibodies) are helpful in the detection of micrometastases. · The following improvements could be helpful to increase tumor-free survival: ± Development of strongly improved sentinel node detection systems ± Intraoperative fast immunohistochemical stainings (Nåhrig, Hæfler) for detection of micrometastases (in sentinel nodes) and extended lymphadenectomy depending on the result. · Meticulous care to avoid opening venous blood vessels in tumor-infiltrated areas to prevent retrograde transport via the venous plexus systems. · Improvements of locoregional radiation therapy, to make it better adapted to the cell cycle of the cancer.
Wawroschek's, Vogt's and Harzmann's First Approach to Detection of Sentinel Nodes in Prostate Cancer Following on from these open questions, Harzmann and his group performed a pilot project with injection of 2 ml of 99mTc containing contrast solution transrectally into the body of the prostate gland. They then faded out the central prostatic region and looked for the localization of the SLNs by scintigraphic investigations. With this method they were able to detect the positions of SLNs outside of the iliac and obturator regions, which are
not normally excised during routine lymphadenectomy. Even though this approach has made it possible to detect atypically localized SLNs, these investigations must be seen in a critical light, especially with reference to the points discussed above. Such atypically localized SLNs can be localized in the promontory or presacral region (see Fig. 16). This has some similarities to the situation in the treatment of rectal cancer. As is well known, in this cancer the healing rates could be significantly increased by operative excision of the presacral region, thus excluding local recurrence. New approaches are necessary to clarify whether it would be possible to inject minimal amounts of contrast solutions into the capsule region, that is to say into regions where the invasive prostatic cancer is nearest to the capsule or infiltrating the capsule, and to look for the regional lymph nodes that might be involved in a metastatic process. It seems to be essential for the volume of contrast solutions injected to be absolutely necessary so as to avoid vascular defects in the injection region and with these also hematogenous metastatic processes in the sense of so-called retrograde transport via plexus prostaticus prevertebral plexus into bone marrow of the lumbar column or into the ossa ilei (see Fig. 13). In conclusion, · Sentinel node labeling in prostatic cancer cases is still in a developmental stage. · The absolutely preliminary results presented by the Harzmann group ± Indicate new ways for operative principles ± Give an answer on possible atypical metastatic processes in presacral or other node groups. · According to these reflections and results new approaches seem to be possible. · But, the knowledge currently available to us is not adequate to allow recommendations on how to proceed rotuinously in the future. New approaches are necessary for more differentiated schemes concerning · Site of injection for contrast media. · Reduction of the amount of fluid injected. We understand from Wawroschek and his colleagues (personal communication) that animal experiments in dogs are in progress to elucidate the facts on the most efficient injection sites, determi-
Wawroschek's, Vogt's and Harzmann's First Approach to Detection of Sentinel Nodes in Prostate Cancer
nation of the most appropriate volume of solution to be injected and how the total volume injected might be reduced. As things are, it is not possible to be absolutely sure that propagation of lymphatic and hematogenous spread is avoided. It is astonishing that the points above are not seriously discussed in all new efforts to develop new techniques. We think a new discussion should not be started on iatrogenic induction of hematogenous spread, as this was under discussion as much as 25 years ago, but reflection on the problems touched upon does seem to be relevant. Dynamic lymphoscintigraphic investigations were carried out by Harzmann et al. (2000) preoperatively on the basis of an informed consent. The gamma probe examinations were performed intraoperatively before pelvic staging lymphadenectomy. Harzmann's group followed the principle of performing total-body bone and CT scans, investigating the acid phosphatase and prostate-specific antigen levels, and also performing transrectal ultrasonography, all preoperatively. After these, 99m Tc nanocolloid (Nanocoll, Sorin, Italy) was injected into the prostate, one or two injections being given into each prostate lobe. When this procedure was followed the total activity reached 100 MBq with a volume of 2 ml. Harzmann's group oriented their applications to experiences obtained in breast cancer cases. Scintigraphic investigations in the anteroposterior and dorsal projections were carried out 12 min and 2±4 h after injection (Sopha camera, DSX, LEAP collimator, 100 000 counts/picture). Radioactivity of the SLNs was measured using a gamma probe optimized for the measurement of 99m technetium (C-trak: Car-wise Medical Products Co. Morgan Hill, Calif., USA) (see also chapter 12). As usual in other regimens of sentinel node detection the prostate gland was shielded by a tungsten plate, placed between the prostate and the lymph nodes intraoperatively to inhibit radiation coming from the prostate gland, which could enhance inadequate measurements of activity over the lymph node(s). In their description, the Harzmann group explains that a first operative step is the removal of the nodes detected by preoperative dynamic scintigraphy and intraoperative application of the gamma probe. However, the group emphasizes that
only the area of node localization can be determined, because there exists no means of imaging the course of the blood vessels at the same time. Nonetheless, in accordance with the sentinel node concept only those lymph nodes with measurable radiation were recognized as sentinels and removed intraoperatively. Subordinate lymph nodes of the particular lymphatics were excluded from the operative procedure. In normal conditions, precise allocation of subordinate lymph nodes is only successful in the case of nodes along the external and common iliacal arteries. As in many histopathology laboratories the nodes were cut in 2-mm-thick slices before paraffin embedding. Besides H and E staining, immunohistochemical studies using antibodies directed to cytokeratin were also used for detection, especially of single cancer cells or very small cancer cell clusters. Preliminary results obtained by Harzmann's group showed that in a series of patients with stage 2A disease (26 cases with grades II and III), 4 of 11 cases had 1±2 micrometastases and in 3 of 4 cases metastases were found exclusively in the SLNs. It is remarkable that the largest positive node measured only 6 mm. The mean number of lymph nodes in pelvic lymphadenectomy was 17.4 (range 12±20). Vogt et al. (2002) have recently summarized the Augsburg results again. They are collected in Table 17, which gives an overview of labeled versus positive SLN, total positive nodes versus positive SLN, and atypical localizations of positive SLN. The authors emphasize clearly: · Since conspicuous nodes in the presacral and in the anteromedial area of the internal iliac artery are not included in the conventional pelvic lymphadenectomy program, in two of the four patients seen by the Harzmann team the micrometastases would not have been discovered or excised. Had tumor progression developed from these nodes an unfavorable outcome would have been inevitable, but, the authors clearly point out that the more precise surgical procedure demands an operating time of nearly 5 h. · Laparoscopic techniques can hardly be used in view of this increased duration and of economic calculations. All in all, the Harzmann concept must be viewed critically because of the large volume of the contrast solution injected, but on the other
471
472
Chapter 30 Prostate Cancer: an Overview Table 17. SLN-positive cases of prostate cancer evaluated by the Augsburg group (study of 25 cases; Vogt et al. 2002) pT
Grade
Gleason grade
pT3b
G2b
7
pT3a
G2b
pT2v
No. of labeled SLN vs total LN
Positive nodes vs positive SLN
Localization of positive LN
2/22
1/1
F. obt.
7
3/16
3/3
Ext. iliac., F. obt., presacral
G2b
6
4/18
1/1
Ext. iliac.
pT2b
G2b
5
5/17
1/1
Int. iliac.
pT4
G2b
7
10/36
4/3
F. obt. ext. iliac., int. iliac.
pT2b
G2b
7
6/18
2/1
F. obt.
pT2a
G2b
5
3/22
1/1
F. obt.
pT2b
G2b
7
6/15
4/4
Ext. iliac, int. iliac., presacral
pT3a
G3a
7
2/13
2/2
Ext. iliac.
pT4
G3a
7
4/27
7/4
F. obt. ext. iliac., int. iliac.
pT3b
G3a
7
2/22
2/2
Ext. iliac., F. obt.
pT3a
G3a
8
6/24
4/4
F. obt. ext. iliac., int. iliac.
pT4
G3a
7
4/26
3/3
Ext. iliac., int. iliac.
pT4
G3a
6
2/23
3/2
Int. iliac., ext. iliac.
pT3b
G3a
8
4/24
3/3
Ext. iliac., F. obt., presacral
pT2b
G3a
7
5/24
4/3:
F. obt. ext. iliac.
pT2b
G3a
9
1/20
1/1
Int. iliac.
pT3b
G3a
9
3/11
2/1
F. obt.
pT2b
G3a
6
6/36
1/1
Int. iliac.
pT3b
G3a
8
4/12
1/1
Ext. iliac.
pT4
G3a
8
6/16
8/6
F. obt. ext. iliac., int. iliac.
pT2b
G3a
7
8/29
3/3
Ext. iliac., int. iliac.
pT3b
G3a
9
7/27
6/5
F. obt. int. iliac., ext. iliac.
pT3b
G3b
9
4/21
4/3
Presacral, int. iliac.
hand the detection of micrometastases is impressively improved and can be of value for the patient. However, these improvements contrast with the current situation, according to which laparoscopic pelvic lymphadenectomy is performed, allowing the detection of micro- and macrometastases in a limited range, but a cancer-infiltrated prostate is left untreated because curative surgery is not possible. On the other hand, it must be emphasized that radical prostatectomy can minimize local complications, which develop in more than 20% of patients treated without curative intent.
Harzmann's group points out: · Preoperative lymphoscintigraphy yields supplementary information that is helpful in intraoperative gamma probe-guided identification of SLNs. · All lymph nodes identified by scintigraphy preoperatively must be detected by means of the gamma probe and removed as SLNs. The authors also emphasize that presacral and hypogastric lymph nodes cannot be detected by preoperative scintigraphic investigations because of the prostate shielding. On the basis of this, it would be logical to check these nodes as precisely as possible by histological examination.
Experiences of the Augsburg Research Group
Anatomically it seems to be clear (Fig. 15) that following attempts to dissect sentinel lymph nodes only locally, · Tumor cells within the lymphatic network in the pelvis have a high chance of growing to maturity. · Cancer cells still present locally immediately after breaking through the prostate capsule have a high chance of invading the venous blood vessels, from where they can be retrogradely transported via the prevertebral plexus into the bone marrow of the column (Fig. 13) (Batson 1940).
Fig. 15, originally published by Fældi and Kubik 2002). The schematic illustrations also make it possible to estimate how the obturator lymph nodes can be reached through the so-called obturator window (see also Fig. 12).
Experiences of the Augsburg Research Group
Figure 14 demonstrates the iliac and obturator lymph node groups, which are the main target nodes (basins) for metastasis from prostate cancer. Readers should be aware that these schematics, mostly depicted in anatomical topographic illustrations of the pelvic lymphatic-network, do not include intercalar (prerectal) lymph nodes, at least some of which are connected with higher located presacral and promontorial lymph nodes (see also
In the past few years the members of the Augsburg Research Group in Germany have made valuable progress. This section gives an overview of important learning effects (see Figs. 15, 16) with reference to the questionable, possibly incomplete, documentation of the pelvic lymph node basins. The group looked for more information about drainage from the prostate gland and found the original schematic published by Fældi, which clearly documents the direct flow from parts of the prostate gland to the presacral and deep pelvic nodes (Fig. 15).
Fig. 14. a View from left side into pelvis: the iliacal and obturatoric lymph nodes can be seen in groups (black).
b View from right side into the pelvis: again the iliacal and obturatoric lymph nodes can be seen in groups (black)
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Chapter 30 Prostate Cancer: an Overview Fig. 15. Early documentation of lymphatics and regional lymph nodes of the ductus deferens, glandulae seminales, and prostate gland (according to Fældi, Germany). The original topographical view of the lymphatic drainage of the prostate gland given by Fældi already notes the possibility of drainage to the presacral lymph nodes (4) and also to the prerectal small lymph nodes (8). The different node groups are indicated (1 lateral lacunar lymph node, 2 intermediate external iliac lymph nodes, 3 medial external iliac lymph nodes, 4 promontory common iliac lymph nodes, 5 internal iliac lymph nodes, 6 lateral sacral lymph node, 7 prevesicular lymph node, 8 intercalated nodes)
Experience of pelvic lymph node labeling was growing as a few series of prostate cancer cases with more than 100 patients in each collective were studied. Even after finishing their studies on a first series of 117 cases, the group was convinced that without node labeling the original SLNs are left in place in 8±10% of cases (see Fig. 16). In the top-view photograph shown in Fig. 16 lymph nodes are marked (black circles) that would have been not excised had the lymph node labeling procedures not been performed: the rate of missed detection, meaning non-excision, of lymph nodes is 5% for presacral lymph nodes and 3.4% for the prerectal lymph nodes (see Fig. 16).
Performance of the Labeling Procedure in Prostate Cancer Cases The first step in the labeling procedure is the ultrasound-guided preoperative injection of tracer into the prostate; the status after injection is demonstrated in Fig. 17.
Detection of the SLN(s) after Labeling
99m
Tc-nanocolloid
After injection of the labeled nanocolloid solution, the prostate region is faded out. The regionally located sentinel nodes can be detected by scintigraphy as little as 15 min after the injection procedure and can be clearly seen for 1.5±2.5 h after injection of the labeling solution. The labeling of pelvic SLNs is demonstrated in two cases in Figs. 18 and 19.
Removal of Labeled Lymph Nodes from the Paraprostatic, Iliac, Obturator, and Retrocolic Basins The main advantages of the new surgical strategies with preparation according to the labeling programs that have been developed are: · The possibility of selecting the best access to reach lymph nodes with suspected involvement (e.g. accessible from the obturator window).
Removal of Labeled Lymph Nodes from the Paraprostatic, Iliac, Obturator, and Retrocolic Basins Fig. 16. Pelvic target (sentinel) lymph node groups involved in prostate cancer metastasis. The presacral nodes and distal nodes along the internal iliac artery that are less frequently removed routinely though they can be primarily involved are indicated by black circles (A external iliac artery, B internal iliac artery, C obturator artery)
· The possibility of removing atypically located lymph nodes, e.g., those in the presacral and deep pelvic region, which otherwise would not be removed. · Optimal monitoring of all putatively involved nodes. A top-view of an operation site demonstrates a chain of lymph nodes labeled by the SLN-detecting techniques (arrows) though far distant from the iliacal blood vessels; these nodes would not have been included in the ªen bloc-resectionº procedure used for iliacal lymph node excision (Fig. 20). This experience supports the use of the SLN concept for nodal cancer clearance in prostate cancer cases also.
Fig. 17. Prostate after injection of cancerous region
99m
Tc-nanocolloid into the
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Chapter 30 Prostate Cancer: an Overview
Fig. 18 a, b. Scintigraphic image a 45 min after and b 100 min after injection of 99mTc-nanocolloid solution to a patient with prostate cancer. By 100 min after the injection two supraprostatic lymph node groups are labeled
Fig. 19 a, b. Labeling of the right-sided iliacal nodes in a case with prostate cancer. One node is sited in a directly paraprostatic position (arrow) (a, b); after 2.5 h two nodes are strongly labeled and can be detected using the gamma probe (b)
Fig. 20. Demonstration of a surgically prepared lymph node chain (white arrows) detected by the SLN labeling procedure, at a site far distant from the main-stem of the prepared iliac vessels
References
Is FDG-PET Helpful in Detection and N-staging of Prostate Cancer? N. Avril, W. Weber, M. Schwaiger
Various studies have shown that FDG is not suitable for diagnosing changes in the prostate gland, as prostate cancer is often not accompanied by an increase in glucose metabolism. In a study of primary prostate cancer, Effert et al. (1996) noted only low metabolic activity in most tumors, which was not related to tumor grade or stage. Data from 11 patients with localized prostate cancer and 2 with benign prostate hyperplasia confirmed these results (Hofer et al. 1999). Following radical prostatectomy and an increase in prostate-specific antigen (PSA), it is not possible to differentiate between scar tissue and local recurrence by means of FDG-PET. Of 6 patients with a local recurrence diagnosed by biopsy, 5 had false-negative results in the PET scan (Hasemann et al. 1996). At the same time, 2 out of 4 patients with negative biopsies showed enhanced FDG-uptake. Therefore, metabolic activity of local recurrences following radical prostatectomy cannot be distinguished from vascularized metabolic active scar tissue by FDG-PET. In a study of 34 patients with metastasized prostate cancer, Shreve et al. (1996) examined the value of FDG-PET for the diagnosis of bone metastases, using CT, bone scintigraphy, and clinical follow-up as a reference. Among the 22 untreated patients there were 202 bone metastases in all, only 131 of which were detected using FDG-PET. In the case of small metastases, the low sensitivity of 65% is due at least in part to partial volume effects. The most important cause, however, is the low metabolic activity and the resultant low FDG accumulation of prostate tumors and their metastases. Despite this, a high positive-predictive result of 98% was obtained for metabolically active lesions. The results obtained by Shreve et al. have been confirmed by other studies conducted by smaller groups. In a comparison with positive foci identified using skeletal scintigraphy, Yeh et al. (1996) found only some 18% of the lesions in 13 patients with pretreated bony prostate metastases, which had previously been classified as refractory to hormone treatment. 'In summary, in most cases of prostate cancer FDG-PET is not helpful in the detection and delineation of prostatic primaries, which means it also has no value for the SLN concept, because sentinel node localization depends at least in part on the
localization of the primary. FDG-PET also cannot be used to find cancer-infiltrated regional lymph nodes in early stages of metastasis.
Can Sentinel Node Labeling be Improved According to Animal Experimental Studies? The current international literature and, especially, the experience and knowledge available within the Augsburg Group, current practice needs further improvement. The intention is now to use the lowest possible dosages of radioactivity and the smallest possible injection volumes, with the total volume to be injected split into small portions for multifocal injection into the prostate parenchyma. Injection of the labeling solution should be ultrasound guided. It is important to avoid injection into the venous vessels of the prostate plexus. These points are of basic importance for the developments of experimental research plans. New approaches should be developed further and tested in dogs.
References Abbas F, Scardino T (1993) Why neoadjuvant androgen deprivation prior to radical prostatectomy is unnecessary. Urol Clin North Am 23:587±604 Allsbrook WC Jr, Mangold KA, Johnson MH, Lane RB, Lane CG, Epstein JI (2001) Interobserver reproducibility of Gleason grading of prostatic carcinoma: general pathologists. Hum Pathol 32(1):81±88 Altay B, Kefi A, Nazli O, Killi R, Semerci B, Akar I (2001) Comparison of Gleason scores from sextant prostate biopsies and radical prostatectomy specimens. Urol Int 67(1):14±18 Arduino LJ, Glucksman MA (1962) Lymph node metastases in early carcinoma of the prostate. J Urol 88:91 Barzell W, Bean MA, Hilaris BS, Whitmore WF Jr (1977) Prostatic adenocarcinoma: relationship of grade and local extent to the pattern of metastases. J Urol Vol 118:278±282 Batson OV (1940) Function of vertebral veins and their role in spread of metastases. Ann Surg 112:138 Berner A, Waere H, Nesland JM, Paus E, Danielsen HE, Fossa SD (1995) DNA ªploidyº serum prostate specific antigen, histological grade and immunohistochemistry as predictive parameters of lymph node metastases in T1± T3 M0 prostatic adenocarcinoma. Br J Urol 75:26±32 Beurton D, Barthlmy Y, Fontaine E (1997) Twelve systematic prostate biopsies are superior to sectant biopsies for diagnosing carcinoma: a prospective randomized study. Br J Urol 80:239
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Chapter 30 Prostate Cancer: an Overview Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE (1994) Eliminating the need for bilateral pelvic lymphadenectomy in select patients with prostate cancer. J Urol 151:1315±1320 Bostwick DG, Eble JN (1993) Prostatic adenocarcinoma metastatic to inguinal hernia sac. J Urol Pathol 1:193 Brendler CB, Cleeve LK, Anderson EE , Paulson DF (1980) Staging pelvic lymphadenectomy for carcinoma of the prostate: risk versus benefit. J Urol 124:849 Bruce AW, O'Cleireachain F, Morales A, Awas SA (1977) Carcinoma of the prostate: a critical look at staging. J Urol 117:319 Carlson GD, Calvanese CB, Kahane H, Epstein JI (1998) Accuracy of biopsy Gleason score from a large uropathology laboratory: use of a diagnostic protocol to minimize observer variability. Urology 51(4):525±529 Catalona WJ, Stein AJ (1982) Staging errors in clinically localized prostatic cancer. J Urol 127:452 Catalona WJ, Smith DS (1994) 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 152:1837±1842 Cheng CWS, Bergstralh EJ, Zincke H (1993) Stage D1 prostate cancer: a non randomized comparison of conservative treatment options versus radical prostatectomy. Cancer Suppl 71(3):996±1004 Conrad St, Graefen M, Pichlmeier U, Henke RP, Hammerer PG, Huland H (1998) Systematic sextant biopsies improve preoperative prediction of pelvic lymph node metastases in patients with clinically localized prostatic carcinoma. J Urol 159:2023±2029 Danella JF, Kernion JB de, Smith RB, Steckel J (1993) The contemporary incidence of lymph node metastases in prostate cancer: implications for laparoscopic lymph node dissection. J Urol 149:1488±1491 Davies GL (1995) Sensitivity of frozen section examination of pelvic lymph nodes for metastatic prostate cancer. Cancer 75:662±668 Dillioglugil O, Leibman BD, Leibman NS, Kattan MW, Rosas AL, Scardino PT (1997) Risk factors for complications and morbidity after radical retropubic prostatectomy. J Urol 157:1760±1767 Donohue RE, Mani JH, Whitesel JA, Mohr S, Scanavino D, Augspurger RR, Biber RJ, Fauver HE, Wettlaufer JN, Pfister RR (1982) Pelvic lymph node dissection. Guide to patient management in clinically locally confined adenocarcinoma of prostate. Urology 20:559 Effert PJ, Bares R, Handt S, Wolf JM, Bull U, Jakse G (1996) Metabolic imaging of untreated prostate cancer by positron emission tomography with 18-fluorine-labeled deoxyglucose. J Urol 155:994±998 Epstein JI, Oesterling JE, Eggleston JC, Walsh PC (1986) Frozen section detection of lymph node metastases in prostatic carcinoma: accuracy in grossly uninvolved pelvic lymphadenectomy specimens. J Urol 136:1234±1237 Eskew LA, Bare RL, McCullough DL (1996) Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 157:199 Flocks RH, Culp D, Porto R (1959) Lymphatic spread from prostatic cancer. J Urol 81:194 Fældi M, Kubik S (2002) Lehrbuch der Lymphologie, 5th edn, p 150. Urban and Fischer, Munich Fowler JE Jr, Whitmore WF Jr (1981) The incidence and extent of pelvic lymph node metastases in apparently localized prostatic cancer. Cancer 57:2941
Frazier HA II, Robertson JE, Paulson DF (1994) Does radical prostatectomy in the presence of positive pelvic lymph nodes enhance survival. World J Urol 12:308±312 Freiha FS, Salzman J (1977) Surgical staging of prostatic cancer: transperitoneal versus extraperitoneal lymphadenectomy. J Urol 118:616 Freiha FS, Pistenma DA, Bagshaw MA (1979) Pelvic lymphadenectomy for staging prostatic carcinoma: is it always necessary? J Urol 122:176 Gervasi LA, Mata J, Easley JD, Wilbanks JH, Seale-Hawkins C, Carlton CE Jr, Scardino PT (1989) Prognostic significance of lymph nodal metastases in prostate cancer. J Urol 142:332 Gomella LG, White JL, McCue PA, Byrne DS, Mulholland SG (1993) Screening for occult nodal metastasis in localized carcinoma of the prostate. J Urol 149:776±778 Gregori A, Vieweg J, Dahm P, Paulson DF (2001) Comparison of ultrasound-guided biopsies and prostatectomy specimens: predictive accuracy of Gleason score and tumor site. Urol Int 66(2):66±71 Grossman IC, Carpinielle V, Greenberg SH, Malloy TR, Wein AJ (1980) Staging pelvic lymphadenectomy for carcinoma of the prostate: review of 91 cases. J Urol 124:632 Hanks GE (1993) The challenge of treating node positive prostate cancer. An approach to resolving the questions. Cancer 71 [3 Suppl]:1014±1018 Haseman MK, Reed NL, Rosenthal SA (1996) Monoclonal antibody imaging of occult prostate cancer in patients with elevated prostate-specific antigen. Positron emission tomography and biopsy correlation. Clin Nucl Med 21:704±713 Hofer C, Laubenbacher C, Block T et al (1999) Fluorine-18fluorodeoxyglucose positron emission tomography is useless for the detection of local recurrence after radical prostatectomy. Eur Urol 36:31±35 Huland H (1998) Welchen Stellenwert hat die radikale Prostatektomie beim Lymphknoten positiven Prostatacarcinom? Urologe 37:138±140 King CR, Long JP (2000) Prostate biopsy grading errors: a sampling problem? Int J Cancer 90(6):326±330 Koksal IT, Ozcan F, Kadioglu TC, Esen T, Kilicaslan I, Tunc M (2000) Discrepancy between Gleason score of biopsy and radical prostatectomy specimens. Eur Urol 37(6): 670±674 Kozlowski JM, Grayhack JT (1987) Carcinoma of the prostate. In: Gillenwater JY, Grayhack JT, Howard SS, Duckett JW (eds) Adult and pediatric urology, vol 2, chap 34. Year Book Medical Publishers, Chicago, pp 1126±1130 Kramer STA, Cline WA Jr, Farnham R, Carson CC, Cox EB, Hinshaw W, Paulson DF (1981) Prognosis of patients with stage D1 prostatic adenocarcinoma. J Urol 125:817± 819 Leibovitch I, Westenfelder K, Vaught J, Rowland RG (1995) Orthostatic abnormal penile erections: a consequence of retroperitoneal lymphadenectomy with vena caval resection. J Urol 154:533±534 Lieskovsky G, Skinner DG (1983) Technique of radical retropubic prostatectomy with limited pelvic node dissection. Urol Clin N Am 10:187 Lilleby W, Torlakovic G, Torlakovic E, Skovlund E, Fossa SD (2001) Prognostic significance of histologic grading in patients with prostate carcinoma who are assessed by the Gleason and World Health Organization grading systems in needle biopsies obtained prior to radiotherapy. Cancer 92:311±319
References Loening SA, Schmidt JD, Brown RC, Hawtrey CE, Fallon B, Culp DA (1977) A comparison between lymphangiography and pelvic node dissection in the staging of prostatic cancer. J Urol 117:752 McCarthy P, Pollak HM (1991) Imaging of patients with stage D prostatic carcinoma. Urol Clin N Am 18:35 McCullough DL, McLaughlin AP, Gittes RF (1977) Morbidity of pelvic lymphadenectomy and radical prostatectomy for prostatic cancer. J Urol 117:206 McCullough DL, Prout GR Jr, Daly JJ (1974) Carcinoma of the prostate and lymphatic metastases. J Urol 111:65 McDowell GC II, Johnson JW, Tenney DM, Johnson DE (1990) Pelvic lymphadenectomy for staging clinically localized prostatic cancer. Indications, complications, and results in 217 cases. Urology 35:476 McLaughlin AP, Saltzstein SL, McCullough DL, Gittes RF (1976) Prostatic carcinoma: incidence and location of unsuspected lymphatic metastases. J Urol 115:89 McNeal JE, Villers A, Redwine EA, Freiha FS, Stamey TA (1990) Histologic differentiation, cancer volume and pelvic lymph node metastases in adenocarcinoma of the prostate. Cancer 66:1225±1233 McNeal JE (1993) Prostatic microcarcinomas in relation to cancer origin and the evolution to clinical cancer. Cancer (Suppl 3) 71:984±991 Moul JW, Lewis DJ, Ross AA, Kahn DG, Ho CH, McLeod DG (1994) Immunohistologic detection of prostate cancer pelvic lymph node micrometastases correlation to preoperative serum prostate specific antigen. Urology 43:68 Naughton CK, Miller DC, Mager DE, Ornstein DK, Catalona WJ (2000) A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: Impact on cancer detection. J Urol 164:388±392 Nicholson TC, Richie JP (1977) Pelvic lymphadenectomy for stage B1 adenocarcinoma of the prostate: justified or not? J Urol 117(2):199±201 Oesterling JE, Chan DW, Epstein JI, Kimball AW Jr, Brucek DJ, Rock RC, Brendler CB, Walsh PC (1988) Prostate-specific antigen in the preoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J Urol 139:766±772 Okegawa T, Nutahara K, Higashihara E (2000) Detection of micrometastatic prostate cancer cells in the lymph nodes by reverse transcriptase polymerize chain reaction is predictive of biochemical recurrence in pathological stage T2 prostate cancer. J Urol 163:1183±1188 Parra RO, Andrus C, Boullier J (1992) Staging laparoscopic pelvic lymph node dissection comparison of results with open pelvic lymphadenectomy. J Urol 157:875±878 Parra RO, Isorna S, Perez MG, Cummings JM, Boullier JA (1996) Radical perineal prostatectomy without pelvic lymphadenectomy: selection criteria and early results. J Urol 155:612±615 Partin AW, Carter HB, Chan DW, Epstein JI, Oesterling JE, Rock RC, Weber JP, Walsh PC (1990) Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol 143:747±752 Paulson DF (1980) The prognostic role of lymphadenectomy in adenocarcinoma of the prostate. Urol Clin N Am 7:615
Paulson DF (1989) Remark to the publication of Gervasi et al. J Urol 142:336 Petros JA, Catalona WJ (1992) Lower incidence of unsuspected lymph node metastases in 521 consecutive patients with clinically localized prostate cancer. J Urol 147:1574±1575 Ravery V, Billeboud T, Toublanc M, Boccon-Gibod L, Hermieu JF, Moulinier F, Blank E, Delmas V, Boccon-Gibod L (1999) Diagnostic value of ten systematic TRUS-guided prostate biopsies. Eur Urol 35:298 Schçssler WW, Pharaud D, Caillie TG van (1993) Laparoscopic standard pelvic node dissection for carcinoma of the prostate: is it accurate. J Urol 150:898±901 See WA, Cohen MB, Winfield HN (1993) Inverted V-peritoneotomy significantly improves nodal yield in laparoscopic pelvic lymphadenectomy. J Urol 149:772±775 Shreve PD, Grossman HB, Gross MD, Wahl RL (1996) Metastatic prostate cancer: initial findings of PET with 2deoxy-2-[F-18]fluoro-D-glucose. Radiology 199:751±756 Smith JA Jr, Seaman JP, Gleidman JB, Middleton RG (1983) Pelvic lymph node metastasis from prostatic cancer: influence of tumor grade and stage in 452 consecutive patients. J Urol 130:290±292 Stamey TA, Freiha FS, McNeal JE, Redwine EA, Whitmore AS, Schmid HP (1993) Localized prostate cancer: relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 71(Suppl 3):933±938 Vogt H, Wawroschek F, Wengenmair H, Wagner T, Kopp J, Dorn R, Græber S, Heidenreich P (2002) Sentinel lymph node diagnostic in prostate carcinoma. Technique and clinical evaluation. Nuklearmedizin 41:95±101 Walsh PC, Partin AW, Epstein JI (1994) Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 152:1831±1836 Wawroschek F, Vogt H, Weckermann D, Wagner T, Harzmann R (1999) The sentinel lymph node concept in prostate cancer ± first results of gamma probe-guided sentinel lymph node identification. Eur Urol 36:595±600 Wawroschek F, Vogt H, Bachter D, Weckermann D, Hamm M, Harzmann R (2000) First experience with gamma probe guided sentinel lymph node surgery in penile cancer. Urol Res 28:246±249 Weingårtner K, Ramaswamy A, Bittinger A, Gerharz EW, Dæge D, Riedmiller H (1996) Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J Urol 156: 1969±1971 Whitmore WF Jr (1984) Natural history and staging of prostate cancer. Urol Clin N Am 11:205 Wilson CS, Dahl DS, Middleton RG (1977) Pelvic lymphadenectomy for the staging of apparently localized prostatic cancer. J Urol 117:197 Winfield HN, Kavoussi LR (1991) Laparoscopic pelvic node dissection. Surg Tech Urol 4:1 Winfield HN, Donovan JF, See WA, Loening SA, Williams RD (1991) Urological laparoscopic surgery. J Urol 146: 941 Yeh SD, Imbriaco M, Larson SM, Garza D, Zhang JJ, Kalaigian H, Finn RD, Reddy D, Horowitz SM, Goldsmith SJ, Scher HI (1996) Detection of bony metastases of androgen-independent prostate cancer by PET-FDG. Nucl Med Biol 23:693±697
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Chapter 31
Cancers of the Urinary Tract
Urinary Bladder Cancer Basic Knowledge Important for Lymph Node Dissection Strategies In the majority of cases, in their early stages urinary bladder cancers develop as papillary exophytic cancers, as a rule with lower degrees of malignancy (grade I and II cancers). According to newer results, focal or general p53 positivity of the cancer cell nuclei in immunohistochemical evaluations can be used to monitor for tumor progression with early or already advanced cancer invasion. In a third of cases these papillary lesions are multiple. Approximately 50% of the patients will have superficial tumor recurrence ± again without basal invasion ± after initial excision of the lesion. Such lesions are usually treated by local excision. Depending on how systemic the precancerous state of the urothelium is, in many cases recurrences arise repeatedly in different parts of the mucosa throughout the whole of the subsequent life-span. The long-term disease-related survival in patients with pTa±pT1 cancers ranges from 75% to 85%. In cases with early basal stroma invasion, local administration of BCG or chemotherapy can be effective (Herr et al. 1985, 1986; Huffman et al. 1985; Staiano-Coico et al. 1985; Bretton et al. 1989). Patients who develop tumor invasion of the internal muscular structures (pT2) can occasionally be treated and cured by transurethral local resection. The rarer primary carcinoma in situ (described by Melicow and Melamed as long ago as in 1953) generally shows no papillary structures but develops fissures of the markedly atypical urothelium at an early stage, with bleeding into the bladder and hematuria (Melamed et al. 1992, 1993). This cancer type is characterized by early local invasive cancer
31
progression with locoregional and hematogenous spread and has a bad prognosis. However, in all more advanced cases · With deeper wall infiltration · With multifocality and beginning wall infiltration · With consecutive tumor invasion after diagnosis of ªprimary carcinoma in situª partial or total cystectomy or radiation therapy can be considered and are in fact performed in many cases. As a rule, radical cystectomy involves removal of the urinary bladder, the perivesical tissue, the prostate and seminal vesicles in men, and the uterus, salpinges, and ovaries, and in some cases the anterior vaginal wall and urethra, in women. In most cases these radical surgical strategies are associated by systematic pelvic lymph node dissection. Reasons for and rates of complications in laparoscopic pelvic lymph node dissection were carefully analyzed by Kavoussi et al. (1993 c) in 372 patients undergoing surgical procedures. The complication rate was 15% (vascular injury, genitourinary and bowel lesions, venous thrombosis, obturator nerve palsy, infections, and lymphedema). In approximately 25% of patients with complications surgical intervention was necessary for their treatment. The group also reports difficulties in the laparoscopic approach to the seminal glands (Kavoussi et al. 1993 b, c). Up to now there are very few publications describing studies in which a sentinel lymph node (SLN) search has been successfully performed. This negative result in the literature search corresponds to the facts that in most cases there is phase-shifted multifocality in cancer development and that we do not know exactly where the cancer first infiltrates the muscular wall. In view of these facts, peritumoral blue dye or 99mTc-nanocolloid injection for SLN labeling is very difficult.
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Chapter 31 Cancers of the Urinary Tract
First Attempts at Detection and Clearance of Sentinel Nodes before Cystectomy
Fig. 1. pT-staging of urinary bladder cancer according to Spieûl et al. (1990, p. 247)
Only in rare cases with exclusively focal cancer development, initially with a high grade of malignancy (high Ki67 rate) and expression of such unfavorable biological parameters as p53 positivity and basal wall infiltration in the first biopsy (confirmed by ultrasound investigation) could peritumoral labeling (blue stain and/or 99mTc-nanocolloid) be helpful in the detection of isolated tumorrelated SLN(s) or basin(s). A sophisticated prospective randomized study might be helpful to elucidate this confused situation. When we reflect on the T or pT scaling summarized by the TNM Classification Group (see Fig. 1), we feel that the earliest it will be possible to detect cases characterized primarily by fast local growth and involvement of corresponding SLN(s) is when the T (pT) 3a±3b groups are re-examined for involved regional lymph nodes in preoperative staging (see Chapter 32). The present unclear situation can easily be understood in cases in which total cystectomy is planned, because in such cases multiple local resections have already been performed and the recurrent lesions have had different intravesical locations. Therefore, all pelvic nodes on both sides are generally removed.
At present, publications on indications for and performance of a search for SLN(s) in urinary bladder cancer are extremely rare. Nonetheless, it seems that activities in this direction have been launched. In a first communication Sherif et al. (2001) reported on lymphatic mapping and detection of SLNs in patients with urinary bladder cancer. The authors recruited 13 patients, all of whom met the criteria qualifying them for radical cystectomy. The patients received intravesical injections of 99mTc-labeling solution and blue dye marker around the tumor field. The injection of the radioactive tracer was followed by lymphoscintigraphy to make the lymphatic flow and the localizations of SLNs localization visible. Intraoperatively the nodes were visualized optically as a result of the blue color and even greater reliability of highly sensitive node detection was achieved by using the gamma probe in this study. The SLNs and also the routinely removed lymph nodes were histologically evaluated. Sentinel nodes were detected in 11 of the 13 cases (85%). In 4 cases the sentinel nodes contained metastases. In each of these cases metastasis was seen only in the detected SLN. There were no false-negative SLNs. Obviously this series is still a small one, but it is worth emphasizing that three of the metastatic nodes were located outside the normally removed nodes of the fossa obturatoria.
Conclusion Overall, the field of systematic evaluation of the significance of using the SLN labeling concept for improvement of locoregional cancer clearance is wide open. New approaches require improved mapping of the mucosa of the bladder, improved imaging to allow precise measurement of the depth of invasion in all fields of the mucosa, and specially tailored node-seeking programs that will work out the optimum site and depth of injection, the best labeling fluid, and the significance of combined labeling (blue dye solution and/or 99mTc-colloid solutions etc.) for individual cases.
Renal Cell Cancer
Cordon-Cardo analyzed the tumor-associated antigens (M344 and 19A 211) primarily expressed on low-grade urinary bladder cancers as long ago as in 1992. The expression rate of Ta±T1 cancers was 77%, but rather lower in the case of deeply infiltrating cancers (10%). Either one or both of the aforementioned tumor-associated antigens are expressed in 80% of low-grade papillary superficial and in situ carcinomas. These results, especially in association with other markers, suggest that screening programs could be helpful when decisions have to be made on cystectomy and the search for SLNs.
Staging by Means of Positron Emission Tomography in Urinary Bladder Cancer
positive results were recorded. This translates into a sensitivity of 67%, a specificity of 86%, and an accuracy of 80%. The authors showed that PET results are better than those of classic staging examinations, even though it was not possible to detect micrometastases by means of PET. Similar results were obtained by Heicappell et al. (1999), who, in a study of eight patients with bladder cancer, were able to detect two out of three histologically positive lymph nodes using FDG-PET, the smallest metastasis detected being 9 mm in diameter. Although the number of patients studied is still small, FDG-PET appears to be better than conventional staging methods for lymph node staging of bladder cancer.
N. Avril, W. Weber, M. Schwaiger
Renal Cell Cancer
First Screening Evaluations Regarding Local and Distant Cancer Progression
Is the Sentinel Node Concept Applicable?
Kosuda et al. examined 12 patients with bladder cancer with FDG-PET and obtained a true-positive result for each of 8 patients. In addition to this, 17 distant metastases were correctly identified with PET, as were 2 out of 3 lymph node metastases. In 2 cases it was possible to delineate a local recurrence of radiation-induced changes with the aid of FDG-PET. As in the case of RCC, the most serious limitation of FDG-PET in primary tumor diagnosis was the excretion of FDG via the efferent urinary tract. This made the results difficult to evaluate, despite continuous retrograde bladder irrigation. For the PET diagnosis of bladder cancer, therefore, an additional radiopharmaceutical, 11C-methionin, reflecting amino acid transport into cells, was used. 11C-methionin is not excreted via the kidneys. Ahlstræm et al. showed in a group of 23 patients that it is possible to image bladder tumors that are over 1 cm in size. The authors nevertheless concluded that 11Cmethionin PET was no better in the staging of bladder cancer than other conventional methods. The largest study on lymph node staging of bladder cancer using FDG-PET was published by Bachor et al. (1999). In a group of 64 patients, 14 cases of lymph node metastasis were correctly identified, while a false-negative result was obtained for each of 7 patients. For 37 patients the lymph nodes were classified as true-negative, while in 6 others false-
J Does Locoregional Lymph Node Dissection Improve the Prognosis? The diagnosis and treatment of RCC have evolved constantly in recent years (Marberger et al. 1981; Golimbu et al. 1986; Guiliani et al. 1990; Morgang and Zincke 1990; Tammela et al. 1991; Steinbach et al. 1992; Nicfero and Coughlin 1993; Kessler et al. 1994; Thrasher et al. 1994; McCaffrey and Motzer 1996; Campbell et al. 1997; Silver et al. 1997). This corresponds to improved surgery, e.g., partial nephrectomy in early cases, development of laparoscopy-assisted nephrectomy, and initial steps toward immunotherapy regimens. For a long period many pathologists assumed that highly differentiated and sharply delineated renal cell tumors with diameters £ 2 cm behave biologically in the same way as benign tumors. On the basis of these pathohistologically and clinical experiences, today's experts tell us that in cases with small RCCs treated by partial nephrectomy or laparoscopic resective techniques locoregional lymph node dissection is not necessary, because the expected rate of node involvement is approaching zero (see also Nishiyama and Terunuma 1995; Winfield et al. 1995 a). In the United States, according to Russo (2000) the number of cases of RCC diagnosed per year has now reached 30 000 (61% in male and 39% in female patients).
483
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Chapter 31 Cancers of the Urinary Tract
RCC accounts for 2±3% of all malignancies and 2.3% of all cancer deaths in the States. Approximately 4% of all RCC are simultaneous or phaseshifted bilateral cancers (Cheng et al. 1991; Jacqmin et al. 1992; Kletscher et al. 1995; Nissenkorn and Bernheim 1995; Grimaldi et al. 1998). The frequency of this cancer type has increased six-fold in recent decades. Lymph node metastases occur in 10±15% of cases without detectable hematogenous spread (Herrlinger et al. 1984, 1991; Guiliani et al. 1990; Studer et al. 1990; Ditonno et al. 1992; Phillips et al. 1993). In correlation studies on the invasiveness of RCCs, Guiliani et al. (1990) found a lymph node involvement of 13% in cases with tumor extension confined to Gerota's fascia and in nearly three times that (37%) in cases with infiltration beyond Gerota's fascia. Golimbu's studies (1986) (41 cases, nonrandomized) showed a 10±15% benefit in stage II cases after lymph node dissection compared with 141 patients who underwent nephrectomy only. The following newly developed operative principles are widely accepted or in development: · Partial nephrectomy in early cases (nephronsparing surgery) (Provet et al. 1991; Gill et al. 1993; Licht et al. 1993, 1994; Novick 1993; Campbell et al. 1994; Herr 1994, 1999; Lee and Kim 1994; Butler et al. 1995; Lerner et al. 1996) · Adrenalectomy to prevent systemic hematogenous spread starting from vascular structures of the adrenals · Laparoscopic or laparoscopy-assisted nephrectomy (Kavoussi et al. 1993a; Kerbl et al. 1994; Gill et al. 1995; McDougall 1995; Hayakawa et al. 1997) · For locoregional tumor clearance regional lymph node dissection is generally accepted (Wood 1990). The generally accepted reasons for lymph node dissection in RCC are: · Inclusion of resection of incipient metastases (N1) or micrometastases in the surgical strategies; · Improvement of the clearance concept by high operative accuracy to give a well-prepared basis for adjuvant therapeutic regimens. Clinically, the use of ultrasound, CT, and MRT and PET have improved the early detection rate from approximately 10±15% to more than 50% (Levine et al. 1989; Russo 2000).
When these tumors are discovered as incidental findings or very early they are mostly in £ stage 2 (diameter > 2.5 cm, limited to the organ) in 75% of cases. The 5-year survival rate is *75% (Aslaksen and Gothlin 1991; Aso and Homma 1992; Tsukamoto et al. 1992). Kessler et al. (1994) compared 67 patients (group A) who underwent nephrectomy in 1979± 1983 following diagnosis by intravenous pyelography with 121 patients (group B) who underwent nephrectomy in 1983±1989 following diagnosis by ultrasound and computed tomography scan. Incidental asymptomatic tumors were found in 18 of the 67 cases (26.9%), in group A and in 57 of the 121 (47.1%) in group B (P < 0.001). The incidence of small tumors (< 5 cm in diameter) was significantly lower in group A than in group B (25.4% vs 47.9%, P < 0.01). The disease-free 5-year survival rate for group A was 40%, as opposed to 80% for group B. These results allow the conclusion that the use of modern techniques has improved survival and stopped progression in a high proportion of cases.
Staging before Surgical Treatment Two staging systems exist: · The Robson system · The TNM system developed by the UICC. In international communications and publications the UICC-related TNM system is preferred, and this is the one that is used in most clinics. The American Joint Committee on Cancer (AJCC) modified the 1993 primary-related T definition in 1998 and included all primaries £ 7 cm in diameter in the class of T1 cancers (Fleming et al. 1998). With reference to metastasis, extension of the primary is important, but the metastatic potential of the different subtypes of RCC, ranging from potentially aggressive through clear cell, intermediate and papillary to chromophobic carcinomas, seems to be more important (Zbar et al. 1994, 1995; Franklin et al. 1996; Perez et al. 1996; Weirich et al. 1998). Such typing is not yet included in the routine biological definitions used. The TNM classification is summarized in Table 1 according to the currently accepted features. Table 2 summarizes the use of the TNM classification for staging.
Lymph Drainage of RCC Differs with Laterality Table 1. TNM clinical classification
Table 2. Stage grouping
T: Primary tumor
Stage I
T1
N0
M0
TX
Primary tumor cannot be assessed
Stage II
T2
N0
M0
T0
No evidence of primary tumor
Stage III
T1
£ 7 cm; limited to kidney
T1 T2 T3
N1 N1 N0, N1
M0 M0 M0
T2
> 7 cm; limited to kidney
Stage IV
T3
Tumor extends into major veins or invades adrenal gland or perinephric tissues, but does not extend beyond Gerota's fascia
T4 Any T Any T
N0, N1 N2 Any N
M0 M0 M1
T3 a
Tumor invades adrenal gland or perinephric tissues, but does not extend beyond Gerota's fascia
T3 b
Tumor grossly extends into renal vein(s) or vena cava below diaphragm
T3 c
Tumor grossly extends into vena cava above diaphragm
T4
Tumor invasion extending beyond Gerota's fascia
N: Regional lymph nodes NX
Regional lymph nodes cannot be assessed
N0
No metastasis in regional lymph nodes
N1
Metastasis in a single regional lymph node
N2
Metastasis in > I regional lymph nodes
M: Distant metastasis MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
As well known to urologists, an unfavorable aspect of RCC is that hematogenous metastasis has already occurred by the time of the initial diagnosis in many cases, as in the case of thyroid and liver cell cancers. This fact corresponds to the close connection of the proliferating cancer cells to an abundant preexisting and ± during carcinogenesis ± growing vascular system, which is in direct contact with cancer cells without any interstitial fibrous stroma parts. These circumstances explain why in some cases thrombosis occurs in cancer cell-infiltrated renal veins before regional lymph node involvement develops. Because renal vein thrombosis occurs only in a low frequency, operative locoregional lymph node control is justified in every case of the stages mentioned.
Lymph Drainage of RCC Differs with Laterality The main lymphatic basins of left- and right-sided RCCs are listed in the following groupings Right-sided kidney Site of lymph nodes: Precaval Retrocaval Interaortocaval (Not paracaval!)
Left-sided kidney Site of lymph nodes: Paraaortic Preaortic Retroaortic Caveat! Large lymph vessels coming from intestine and taking their course to the cisterna
In order to make it easier to imagine the topographical structures of the renal lymphatic basins of both sides, Fig. 2 demonstrates the exact localizations of the named and listed lymph nodes and lymph node groups on both sides and also clearly documents · How difficult it is to implement the operative strategies in these retroperitoneal structures; · How difficult the different overlapping tissue structures make it to obtain useful information about the lymph node structures and whether they contain metastases before proceeding to surgery. For a discussion on the effectiveness of the various imaging systems the reader is referred to pp. 484, 489, 493). The surgical preparation of lymph nodes along the aorta and the vena cava inferior is extremely difficult. The existence of an intensively developed lymphatic network means it is possible for a lymphatic metastasis to cross over to the contralateral side. This danger of such crossing over becomes
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Chapter 31 Cancers of the Urinary Tract
Fig. 2. Retroperitoneal situs demonstrating the lymphatic basins, important for renal cell cancer (RCC) drainage from kidneys on both sides
greater with progression of lymphatic metastasis; or it can happen as a result of bypassing or as a skip metastasis. Lymphatic preparation involves the danger of damaging large lymphatic ducts coming from the intestinal cisterna. The clinical staging (stages I±IV; see also Fig. 3) summarizes collectives that allow better and simpler clinical understanding, especially about the clinical decisions that need to be made on whether adjuvant therapies are indicated. It is important to realize that with stages I and II patients are usually free of lymph node and distant metastases. However, this is only relevant when the noninvolvement of regional (sentinel) nodes is demonstrated by optimal histopathological evaluations. The grouping of the stages is summarized in Table 2.
The different stages, I±IV, of RCC are morphologically documented in Fig. 3, which gives a rough overview that can be used in comparative studies with results obtained by radiodiagnostic imaging systems. Fig. 4 illustrates the typical localization of RCC in the upper part of the kidney. The cancer shown already measures 9 cm in its largest diameter, but macroscopic inspection does not reveal any breakthrough in the capsular regions. This is a positive sign in the battery of questions on ªoperabilityº. However, in the central parts cancer growth has diffusely involved parts of the renal pelvis. This is an important point with reference to regional lymphatic spread, because the peripelvic lymphatics can drain cancer cells via the perihilar soft tissue to the regional nodes (see Fig. 2).
Lymph Node Staging in RCC Fig. 3 a. Staging of renal cell cancer. Note the regional lymph nodes and cancer induced thrombosis of renal vein in stage III and distant metastasis (lung bone brain) in stage IV
Cytology of RCC
Lymph Node Staging in RCC
Preoperative FNAC or intraoperative histology and/ or cytology in material from lymph nodes helps in the attainment and confirmation of regional R0 resection. This is documented by cytological investigations, as demonstrated in Figs. 5±7. When there is uncertainty about whether a kidney tumor is a primary or a metastasis (e.g., from a lung cancer) the simultaneous expression of both cytokeratin and vimentin (typical for RCC) can confirm the diagnosis of RCC (Figs. 4±6).
· Is there a chance of defining and detecting SLN(s)? · Are there chances of improvements to maximal locoregional tumor clearance? Urologists are aware of the vascular flow connections between the renal parenchyma with its capsular vasculature and the adrenal glands. The incidence of adrenal involvement ranges up to 4±5%. In Sagalowsky's studies (1994) in 695 cases it was 4.3%, with an incidence of approx. 30% for lymph node involvement. Despite resection of the cancer-
487
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Chapter 31 Cancers of the Urinary Tract
Fig. 3 b. Renal cell cancer infiltrating the upper half part of the kidney (max. diameter 9 cm). Note the typical yellow colour of the cancer with red coloured areas after bleeding into the cancer tissue from strongly developed capillary vascularisation of the cancer
infiltrated adrenals approximately 80% of the patients died within 2 years. With due consideration for all these facts together, in spite of the present low success rate with
adrenalectomy (Gill et al. 1994; Kim et al. 1998), in RCC cases with the typical localization of the primary in the upper pole region of the organ the corresponding adrenal is generally resected en bloc together with the kidney. This surgical strategy is important to reduce (a) locoregional recurrence rates and also (b) the potential for secondary hematogenous metastasis. Insuperable problems are posed by attempts to determine the significance of any SLN and to define and determine its location, because the strategies used in other tumor types are not applicable. It seems to be impossible to give a peritumoral injection of blue dye or any labeled solution into the kidney preoperatively to allow a search by eye or by means of the gamma probe for drainage of the contrast or labeling solution. On the other hand, the definition of N1 and N2 is very simple and does encourage the development of a SLN concept. As pointed out in Table 1, staging as N1 means that only one node shows lymphogenic-metastatic cancer infiltration, whereas infiltration of two nodes or more requires that the disease be classified as in the N2 stage. From this it follows that N0 means the sentinel node is negative and N1, that the sentinel node is positive; we must add that infiltration of more than one node cannot be excluded.
Fig. 4. Lymph node metastasis in a case with RCC: cytology of a lymph node puncture: cancer cells of a moderately to poorly differentiated RCC
ªChecklistº of Possible Methods of Lymph Node Investigation Fig. 5. Same case as in Fig. 4: cytology of a lymph node metastasis. Immunohistochemical staining of cytokeratins of the moderately differentiated cancer cells of a RCC; note the intense positive (red) cytokeratin reaction
Fig. 6. Renal cell cancer with sarcomatoid parts. Positive immunohistochemical reactions with antibodies directed to vimentin (double expression of cytokeratins and vimentin)
ªChecklistº of Possible Methods of Lymph Node Investigation 1. Under present conditions peritumoral injections directly around the primary are not practicable and must be ruled out, but perihilar and capsular labeling positions must be reflected. 2. The method of systemic ultrasmall particles of iron oxide (USPIO) application also does not seem practicable, because lymph nodes with pre- and retro-aortic locations, those up- and downstream of the vena cava and those with interaortocaval locations cannot be evaluated to obtain optimal results. In addition, the high frequency of spontaneous intratumoral bleeding with blockade of the si-
nus histiocytes as a result of spontaneous blood resorption blocks the phagocytosis of USPIO particles, which also falsifies the results of imaging. 3. The reader is referred to Chapter 32 for an evaluation of PET in RCC. To summarize points 1±3, at least at present there is no possible way to obtain a clear result by radio- and nuclear-medical methods that would answer the question of whether regional lymph nodes are cancer infiltrated or not. [This excludes the diagnosis of large metastases evaluated by CT, which is justified, because in investigations of 163 RCC cases by CT scanning (Studer et al. 1990) of 43 patients who had enlarged lymph nodes (1±2, mean of 2 cm in diameter, median 1.4 cm) only
489
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Chapter 31 Cancers of the Urinary Tract
42% showed metastatic involvement, while in the other 58% only a resorptive hyperplastic inflammatory reaction was found. Therefore, the goal of optimal locoregional tumor clearance can only be achieved by intraoperative continuous preparation and resection of the regional lymph nodes, including all nodes in N1 and N2 position, as documented in the scheme. Under these conditions, a single cancer-infiltrated node located near the kidney can be declared as N1 and equated with a sentinel node. However, because it is impossible to evaluate one node intraoperatively by histological examination supported by immunohistochemical staining in serial sections, and because several lymph nodes can all be sentinel nodes (there is no absolute prevalence of any one specific node as the sentinel) a statement about lymph node positivity or negativity cannot be based on investigation of only one node. Therefore, all regional lymph nodes according to the scheme (see Fig. 2 and the attributive scheme with the denominations of the important lymph node groups for right- and left-sided RCCs) must be prepared and resected in continuity. It seems clear that at least the N2 extension of lymph node involvement includes the possibility of supraphrenic lymph node involvement and, especially in left-sided primaries, opens up the possibility of invasion of the large chylic vessels and of drainage into the chylic cisterna. From there the cancer cells can be transported via the ductus thoracicus and the venous angle directly into the bloodstream (see Fig. 2).
Do Immunohistochemically Detectable Prognostic Factors have Significance for Treatment Strategies Including the Search for Sentinel Lymph Nodes? In 17 of 19 cases with RCC, Ljungberg et al. (2001) found an overexpression of p53 oncoprotein (grade 1 = sparse staining in 1±5% of the tumor cells, grade 2 = 5±50% and grade 3 = > 50% of tumor cells) in a total of 19% of cases, and significant correlations with stage (P = 0.016) and grade (P = 0.020), but not with ploidy or S-phase. High p53 expression correlated with shorter cancer-specific survival (P = 0.003), but these differences were only found in papillary and chromophobic cancers and not in cancer cases with conventional RCC. The authors conclude that p53 immunoreactivity seems to be a valuable tool for prospective biological assessment of specific RCC subtypes. These results are strongly supported by those yielded by investigations carried out by Girgin et al. (2001). These authors investigated 50 cases. The survival function of each parameter was estimated by Kaplan-Meier and log-rank tests and the significance of each parameter for survival was evaluated by logistic regression analysis. The results obtained are summarized in Table 3. In conclusion, in cases with mutated p53 overexpression it seems to be important to exclude hematogenous metastasis before a patient-related program for SLN labeling is started. The organ involvement must be ruled out systematically because of the increased tendency of p53-positive tumors to spread systemically. Markovic-Lipkovski et al. (2001) documented that N-cadherin and some integrins (mostly notably alpha 3, alpha 6 and alpha 5) are associated with the capacity of RCC for local and distant can-
Table 3. Survival rates of p53-positive renal cell cancers (RCCs) in different pT stages n
50
Mutated
Survival (%) dependent on stage and grade
p53 rate
pT2
pT3
pT2±3 Grades N+ 1±2
Grades 3±4
pT2
pT3
20%
87%
61%
0%
51,5%
+66,67%
33,3%
±91,48%
71,43%
p = 0,0462
92,3%
Survival rates p53+ versus p53±
p = 0,002
p = 0,0392
Total pT2±3 N+
p53+
p53±
0%
33%
84,2%
Regression analysis/ grade/ stage/ p53+
100% p = 0,0027
p < 0,03
Is Retroperitoneal Lymphadenectomy Helpful in Extending Survival in Patients with Hematogenous Metastases from RCC?
cer spread, regardless of tumor grade. Whether immunohistochemical proof of N-cadherin in a RCC would be sufficiently significant to justify preoperative FNAC to obtain sufficient information about the risk of cancer metastasis is an open question. Apart from this it might be that heterogeneous expression of adhesion molecules with positive and negative cell populations results in a false-negative diagnosis, because in FNAC only a low proportion of cancer cells are evaluated.
Detection of SLNs by Cancer-specific Immune Response? RCCs are tumors that have a distinctive antigenicity. This special characteristic results in specific and nonspecific immune responses: · The first one is characterized by a cancer-destructive immune reaction mediated by dendritic reticulum cells, T-lymphocytes, and the macrophage system. This pathway has meanwhile been tested in approaches to development of immunotherapeutic regimens. · The second is represented by the cytotoxic power of natural killer cells. The cancer cell-detecting mechanisms are unknown, though it may be that activated immune cells that have accumulated in SLNs can be detected by immunoscintigraphic procedures. However, it is known that after incorporation into the cancer cell membrane amphophile proteins and lipoproteins (perforins) give rise to cancer cell destruction. In addition, there are obviously nondestructive immune responses with enlargement of the germinal centers even in the very early stages of cancer cell precipitation in the marginal areas of the lymph nodes. However, at present this working formulation can only be tested in experimental approaches. Chu et al. (1999) tried to develop such systems, but their work also still seems to be at the stage of
experimental preparation. Therefore, the question remains as to whether such a system can be developed and used clinically in routine sentinel search programs.
Is there a Benefit of Extensive Lymphadenectomy over Sampled Lymphadenectomy? This question is of interest: it might be assumed that extensive lymphadenectomy would remove more atypically located SLNs and achieve a more comprehensive resection of the lymphatic network. Ou et al. investigated this question in 137 patients with RCC (81 underwent radical nephrectomy with sampled lymphadenectomy: stage I was recorded in 43 of these, stage II in 16, and stage III in 22; while 56 patients underwent radical nephrectomy with extensive lymph node dissection: stage I in 30, II in 11, III in 15 of these). The results obtained are shown in Table 4.
Is Retroperitoneal Lymphadenectomy Helpful in Extending Survival in Patients with Hematogenous Metastases from RCC? This question has been investigated at the NCI by Vaselli et al. (2001), who performed a retrospective analysis. Surgery notes were used to evaluate whether all nodes affected by ªlymphadenopathyº were resected or whether any were left in situ. A total of 154 patients with metastatic RCC underwent cytoreductive nephrectomy in preparation for an interleukin-2-based therapeutic regimen. The 82 patients with metastatic RCC who had no preoperative retroperitoneal lymphadenopathy survived longer (median 14.7 months) than the 72 with lymphadenopathy (median 8.5 months). The P-value for this difference was 0.0004. Continuation to complex extrarenal resection during nephrectomy is justified: it can be recommended since no significant difference in the response rate for interleucin-2 or mean
Table 4. 5-Year survival rates of RCC patients after sampled and after extensive lymphadenectomy (LD) Mean no. of nodes investigated in sampled LD
Mean no. of nodes investigated in extensive LD
Sampled LD survival stages
Extensive LD survival stages
I
II
III
I
II
III
4 (range 1±8)
16.1 (range 9±32)
98%
80%
38%
92%
84%
40%
491
492
Chapter 31 Cancers of the Urinary Tract
survival compared with those of patients undergoing nephrectomy alone was detectable. These facts allow the additional conclusion that optimal retroperitoneal lymph node clearance is an important therapeutic strategy, especially in M0 cases.
Adrenal-sparing Surgery in Cases with RCC It is necessary to consider whether adrenal-sparing surgery is justified or would prejudice sentinel node search programs. Paul et al. (2001) evaluated a total of 866 patients who had undergone nephrectomy and ipsilateral adrenalectomy. Of these patients, 27 (3.1%) had adrenal metastases, 63% of which were on the left and 37%, on the right; 21 of the 27 had multiple metastases. Only 6 (0.7%) of all 866 cases presented with a solitary ipsilateral adrenal metastasis. In uni- and multivariate analysis tumor size and M-stage were the best preoperative predictors of adrenal involvement. The conclusion of the clinical research group was that adrenalectomy is not necessary on oncological grounds. The authors emphasize that additional prospective studies should be carried out. · Justification for adrenal-sparing surgery. The results obtained from Paul et al.'s investigations in a large number of cases indicate that at least in cases with smaller cancers up to approximately 4±5 cm in diameter adrenalectomy does not seem to be indicated, especially when there is only a single ipsilateral cancer, no infiltration of Gerota capsular structures, and no intraoperatively detected regional lymph node metastases. · Disturbance of sentinel node search. It seems to be clear that, in the case of SLN labeling, the volume of labeling solution injected into the space between the kidney pole and the adrenal must be small and great care must be taken to avoid injection into blood vessels. Theoretically at least, labeling by peripolar injection should be possible. A low rate of metastatic adrenal-involvement has also been published by Xu et al. (1998). In contrast to the result-based
statements issued by Paul et al. (2001) are the recommendations of Huang-Bohm et al. (2001). These authors still advocate adrenalectomy, even though there is more and more support for organsparing surgical strategies.
Proposal for Sentinel Node Labeling in RCCs In a first experimental study program the following proposal for the evaluation of the lymphatic drainage of RCCs located in the upper renal-pole can be made: · Because at present only intraoperative labeling seems to be possible, the blue dye strategy is initially probably best for new approaches. · Considering that most RCCs develop within the upper pole of the kidney and the lymphatic drainage at least of a few millimeters of the superficial renal cortex follows the vascular loop structures of these cortex parts, the lymphatics from superficial cancer parts and the Gerota capsular region should drain to the corresponding SLNs (Figs. 2 and 7). Therefore, these tissue regions could be one site for localized two-dimensional blue dye injection. In addition, attempts should be made to site labeling injections above and around the hilus, because drainage from the upper kidney parts, and in particular from RCCs located there, passes this region (Fig. 7). When results of this approach are positive additional use of 99mTc-nanocolloid solution could improve them. It is the opinion of urologists that in patients who are free from distant metastases at the time of operation, survival depends mainly on the subphrenic lymphatic progress. This has stimulated the development of new diagnostic and surgical strategies to improve locoregional cancer clearance. Therefore, besides the development of new sophisticated diagnostic and surgical methods, animal experimental studies could help to answer important questions that are still open. This synoptic research work could be helpful in the development of an improved SLN concept.
Can FDG-PET Help in N-staging of RCC and Bladder Cancer? Fig. 7. Demonstrates the topography of regional lymph nodes of both kidneys important for locoregional cancer clearance. The possibilities of SLN-labeling by capsular and perihilar application of labeling solutions should be evaluated
Can FDG-PET Help in N-staging of RCC and Bladder Cancer? Renal Cell Cancer In diagnosis of primaries, Bachor et al. (1999) analyzed the results in 29 cases. Of 26 RCCs, 20 were identified by PET, while in 6 cases false-negative results were recorded. Diagnostic accuracy depended on the degree of differentiation. G1 tumors were detected only in 44% (4 out of 9). In differential diagnosis FDG-PET showed no specificity. Positive signals were also obtained in cases with angiolipoma, pericytoma and pheochromocytoma.
The results of lymph node staging were judged to be true positive in 3 patients and true negative in 25 patients. There were no false-negative PET findings. Compared with other imaging methods (CT and MRI) available today, PET does not have any significant advantages in the staging of retroperitoneal lymph nodes in RCC. Delgado Dominguez (2001) remarked that MRI permits multiplanar analysis and facilitates detection and characterization of lesions and that it allows clear depiction of the relationship of the tumor to the adjacent structures, opening the way for efficient surgical planning. The value of FDG-PET and CT as preoperative diagnostic instruments was recently confirmed by Ramdave et al. (2001). These investigations were made possible by support from the Ludwig-Institute in Australia. The
Table 5. Accuracy of PET and CT influence on treatment strategiesa
a
FDG-PET and CTevaluation results Case numbers
PET/CTaccuracy
Partial nephrectomy
17
94%
3
Metastatic bone involvement in renal cell cancers by (2001)
Treatment alterations
99m
based on PETresults
in cases investig. for recurrence or metastat. disease
total 6 (35%); 3 because of benign lesions or metastases
4/8 = 50%
Total changes based on PETresults
40%
Tc-MDP is analyzed and reported by Robertson and Al-Nahhas
493
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Chapter 31 Cancers of the Urinary Tract
accuracy of tumor detection for FDG-PET and CT was 94%. Using preoperative FDG-PET investigations criteria could be developed for partial nephrectomy or avoidance of surgical treatment. In addition, changes to treatment strategies could be decided on. An overview of the main results is summarized in Table 5.
garded with extreme caution, not only because surgery is incomplete, but additionally because of the danger of severe local bleeding.
Laparoscopic Retroperitoneal Partial and Radical Nephrectomy in RCCs
In a preliminary pilot study Yoshimura et al. (2001) used a microwave coagulator during laparoscopic partial nephrectomy in cases with small tumors. They report that the operation time was shortened and blood loss was minimal. In addition, there was no deterioration in renal function. The authors find that their method is useful and less invasive than other surgical treatment procedures. Since this method is largely unbloody, in cases with low-grade suspicion of regional lymphatic spread the regional lymph nodes could also be examined, to reach the highest degree of reliability for total clearance.
Is this Strategy Compatible with Development of a Sentinel Node Approach? Recent years have seen a steady increase in the number of international publications on partial or radical retroperitoneal laparoscopic nephrectomy (Kavoussi 1993; Kavoussi et al. 1993 a; Kerbl et al. 1994; Lee and Kim 1994; Nishiyama et al. 1995; Winfield et al. 1995 b; Dumm et al. 2000; Cicco et al. 2001; Ono et al. 2001; Yoshimura et al. 2001; Zisman et al. 2001). Cost calculations related to laparoscopic urological surgery were presented by Winfield et al. (1995 a). Preoperative radioimaging by CT, MRI, FDGPET is an important instrument to confirm unifocality, extension, breakthrough of the capsule, and the existence of larger lymph node metastases and distant metastases. Based on findings obtained from preliminary calculations regarding partial nephrectomy, in cases with small, sharply delineated, RCCs nephron-sparing surgery seems to be justified in selected cases. This opinion is supported by newer publications in the international literature. Recently Sullivan and Frydenberg (2001) recommended nephron-sparing surgery, for instance in cases with small tumors, and especially in patients with bilateral cancers. In their collective of 23 cases 17% of the patients had benign tumors and they had no recurrences. Laparoscopic surgery can be supported in cases with small tumors (< *3 cm), because regional lymph node involvement is extremely rare in such cases. It is, however, necessary to consider whether laparoscopic nephrectomy, including lymph node staging, is possible in more extensive cancer with the suspicion of regional lymphatic spread? In our opinion, in such cases restricted surgical programs including laparoscopic nephrectomy must be re-
Use of Microwaves as a Styptic in Partial Nephrectomy
To summarize all the problems and facts discussed above: · In early stages of RCC there is a high chance that no lymphatic spread has developed. · Larger cancers > 7 cm involve a high risk of lymphatic and hematogenous spread. · No concept has been developed for clear detection of SLNs. Last years thousands of papers on RCC were published, but no plausible or already tested project on sentinel node search and detection. · Local lymphatic clearance is especially difficult, because there is an overlapping lymphatic network on both sides (see Fig. 2). Because many cases develop local (retroperitoneal) recurrences, based on incomplete locoregional lymphatic clearance, we need new ideas to define sentinel lymph nodes of RCCs with or without cancer involvement more clearly.
Adjuvant Therapy Regimens in Cases with Metastatic RCC (Godley and Taylor 2001) Standard adjuvant therapies are · Cytokine-based therapy regimens with little benefit of macrophage colony-stimulating factor · Retinoic acid · Adoptive immunotherapy
References
· Chemotherapy regimens: ± Capecitabine ± Floxuridine ± Vinblastine · Nonmyeloablative stem cell transplantation.
References Ahlstræm H, Malmstræm PU, Letocha H, Andersson J, Langstræm B, Milsson S (1996) Positron emission tomography in the diagnosis and staging of urinary bladder cancer. Acta Radiol 37:185±185 Aslaksen A, Gothlin JH (1991) Imaging of solid renal masses. Curr Opin Radiol 3:654±662 Aso Y, Homma Y (1992) A survey on incidental renal cell carcinoma in Japan. J Urol 147:340±343 Bachor R, Kotzerke J, Reske SN, Hautmann R (1999) Lymph node staging of bladder neck carcinoma with positron emission tomography. Urologe A 38:46±50 Bretton PR, Herr HW, Kimmel M, Fair WR, Whitmore WF Jr, Melamed MR (1989) Flow cytometry as a predictor of response and progression in patients with superficial bladder cancer treated with bacillus Calmette Gurin. J Urol 141:1332±1336 Butler BP, Novick AC, Miller DP, Campbell SA, Licht MR (1995) Management of small unilateral renal cell carcinomas: radical versus nephron-sparing surgery. Urology 45:34±40 Campbell SC, Novick AC, Streem SB, Klein E, Licht M (1994) Complications of nephron sparing surgery for renal tumors. J Urol 151:1177±1180 Campbell SC, Novick AC, Herts B, Fischler DF, Meyer J, Levin HS, Chen RN (1997) Prospective evaluation of fine needle aspiration of small, solid, renal masses: accuracy and morbidity. Urology 50:25±29 Cheng WS, Farrow GM, Zincke H (1991) The incidence of multicentricity in renal cell carcinoma. J Urol 146:1221± 1223 Chu Y, Hu HM, Winter H, Wood WJ, Doran T, Lashley D, Bashey J, Schuster J, Wood J, Lowe BA, Vetto JT, Weinberg AD, Puri R, Smith JW 2nd, Urba WJ, Fox BA (1999) Examining the immune response in sentinel lymph nodes of mice and men. Eur J Nucl Med 26 (Suppl 4):S50±S53 Cicco A, Salomon L, Hoznek A, Saint F, Alame W, Gasman D, Antiphon P, Chopin DK, Abbou CC (2001) Results of retroperitoneal laparoscopic radical nephrectomy. J Endourol 15(4):355±359 Cordon-Cardo C, Wartinger DD, Melamed MR, Fair W, Fradet Y (1992) Immunopathologic analysis of human urinary bladder cancer. Characterization of two new antigens associated with low-grade superficial bladder tumors. Am J Pathol 140:375±385 Delgado Dominguez E (2001) [MR in renal masses.] Arch Esp Urol 54:583±592 Ditonno P, Traficante A, Battaglia M, Grossi FS, Selvaggi FP (1992) Role of lymphadenectomy in renal cell carcinoma. Prog Clin Biol Res 378:169±174
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Chapter 31 Cancers of the Urinary Tract Hoang-Bohm J, Martinez Portillo FJ, Roth G, Alken P (2001) Adrenalectomy within the scope of tumor nephrectomy? Urologe A 40(1):46±51 Huffman JL, Fraded Y, Cordon-Cardo C, Herr HW, Pinsky CM, Oettgen HF, Old LJ, Whitmore WF Jr, Melamed MR (1985) Effect of intravesical bacillus Calmette-Gurin on detection of a urothelial differentiation antigen in exfoliated cells of carcinoma in situ of the human urinary bladder. Cancer Res 45:5201±5204 Jacqmin D, Saussine C, Roca D, Roy C, Bollack C (1992) Multiple tumors in the same kidney: incidence and therapeutic implications. Eur Urol 21:32±34 Kavoussi LR (1993) Re: Retroperitoneal laparoscopic nephrectomy: initial case report. J Urol 150(4):1255 Kavoussi LR, Kerbl K, Capelouto CC, McDougall EM, Clayman RV (1993 a) Laparoscopic nephrectomy for renal neoplasms. Urology 42:603±609 Kavoussi LR, Schçssler WW, Vancaillie TG, Clayman RV (1993 b) Laparoscopic approach to the seminal vesicles. J Urol 150(2 Pt 1):417±419 Kavoussi LR, Sosa E, Chandhoke P, Chodak G, Clayman RF, Hadley HR, Loughlin KR, Ruckle HC, Rukstalis D, Schuessler W, Segura J, Vancaille T, Winfield HN (1993 c) Complications of laparoscopic pelvic lymph node dissection. J Urol 149(2):322±325 Kerbl K, Clayman RV (1994) Advances in laparoscopic renal and ureteral surgery. Eur Urol 25:1±6 Kerbl K, Clayman RV, McDougall EM, Kavoussi LR (1994) Laparoscopic nephrectomy: the Washington University experience. Br J Urol 73:231±236 Kessler O, Mukamel E, Hadar H, Gillon G, Konechezky M, Servatio C (1994) The effect of the improved diagnosis of renal cell carcinoma on the course of the disease. J Surg Oncol 57:201±204 Kletscher BA, Qian J, Bostwick DG, Andrews PE, Zincke H (1995) Prospective analysis of multifocality in renal cell carcinoma: Influence of histological pattern, grade, number, size, volume and DANN ploidy. J Urol 153:904±906 Kosuda S, Kison PV, Greenough R, Grossman HB, Wahl RL (1997) Preliminary assessment of fluorine-18 fluorodeoxyglucose positron emission tomography in patients with bladder cancer. Eur J Nucl Med 24:615±620 Lee SE, Kim HH (1994) Validity of kidney-preserving surgery for localized renal cell carcinoma. Eur Urol 25:204± 208 Lerner SE, Hawkins CA, Blute ML, Grabner A, Wollan PC, Eickholt JT, Zincke H (1996) Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol 155:1868±1873 Levine E, Huntrakoon M, Wetzel CH (1989) Small renal neoplasms. Clinical pathologic and imaging features. AMJ 153:69±73 Licht MR, Novic AC (1993) Nephron sparing surgery for renal cell carcinoma. J Urol 149:1±7 Licht MR, Novick AC, Goormastic M (1994) Nephron sparing surgery in incidental versus suspected renal cell carcinoma. J Urol 152:39±42 Ljungberg B, Bozoky B, Kovacs G, Stattin P, Rarrelly E, Nylander K, Landberg G (2001) p53 expression in correlation to clinical outcome in patients with renal cell carcinoma. Scand J Urol Nephrol 35:15±20
Marberger M, Pugh RCB, Auvert J, Bertermann H, Constantini A, Gammelgard PA, Petterson S, Wickham JE (1981) Conservative surgery of renal cell carcinoma: the EIRSS experience. Br J Urol 53:528±532 Markovic-Lipkovski J, Brasanac D, Mçller GA, Mçller CA (2001) Cadherins and integrins in renal cell carcinoma: an immunohistochemical study. Tumori 87:173±178 McCaffrey JA, Motzer RJ (1996) What is the role of nephrectomy in patients with metastatic renal cell carcinoma. Semin Oncol 23:19±20 McDougall E (1995) Minimally invasive therapy. J Urol 153(3 Pt1):712±713 McDougall EM, Clayman RV, Elashry O (1995) Laparoscopic nephroureterotomy for upper tract transitional cell carcinoma: the Washington University experience. J Urol 154: 975±980 Melamed MR (1992) Papillary tumors of the bladder. J Cell Biochem (Suppl) 161:44±47 Melamed MR, Voutasa NG, Grabstald H (1993) Natural history and clinical behaviour of in situ carcinoma of the human urinary bladder 1964. CA Cancer J Clin 43:348± 370 Morgan WR, Zincke H (1990) Progression and survival after renal-conserving surgery for renal cell carcinoma: experience in 104 patients and extended follow up. J Urol 144:852±857 Nicfero J, Coughlin BF (1993) Diagnosis of renal cell carcinoma: value of fine needle aspiration cytology in patients with metastases or contraindications to nephrectomy. AJR 161:1303±1305 Nishiyama T, Terunuma M (1995) Laparoscopy-assisted radical nephrectomy in combination with minilaparotomy: report of initial 7 cases. Int J Urol 2:124±127 Nissenkorn I, Bernheim J (1995) Multicentricity in renal cell carcinoma. J Urol 153:620±622 Novick AC (1993) Renal sparing surgery for renal cell carcinoma. Urol Clin North Am 20:277±282 Ono Y, Kinukawa T, Hattori R, Gotoh M, Kamihira O, Oshima S (2001) The long-term outcome of laparoscopic radical nephrectomy for small renal cell carcinoma. J Urol 165(6 Pt1):1867±1870 Ou YC, Ho HC, Cheng CL, Ka YL, Lin CH, Yang CR (2001) The role of lymphadenectomy in the radical nephrectomy for renal cell carcinoma. Zhonghua Yi Xue Za Zhi (Taipei) 64:215±222 Paul R, Mordhorst J, Busch R, Leyh H, Hartung R (2001) Adrenal sparing surgery during radical nephrectomy in patients with renal cell cancer: a new algorithm. J Urol 166:59±62 Perez-Ordones B, Hamed G, Campbell S, Erlandson RA, Russo P, Gaudin PB, Reuter VE (1997) Renal oncocytoma: a clinicopathologic study of 70 cases. Am J Surg Pathol 21:871±883 Philips PE, Messing EM (1993) Role of lymphadenectomy in the treatment of renal cell carcinoma. Urology 41:9±15 Provet J, Tessler A, Brown J, Golimbu M, Bosniak M, Morales P (1991) Partial nephrectomy for renal cell carcinoma: indications, results and implications. J Urol 145:472±476 Ramdave S, Thomas GW, Berlangieri SU, Bolton DM, Davis I, Danguy HT, Macgregor D, Scott AM (2001) Clinical role of F-18 fluorodeoxyglucose positron emission tomography for detection and management of renal cell carcinoma. J Urol 166:825±830
References Robertson LP, Al-Nahhas A (2001) Renal cell carcinoma detected by 99mTc-MDP bone imaging. Clin Nucl Med 26:264±266 Russo P (2000) Renal cell carcinoma: presentation, staging and surgical treatment. Semin Oncol 27:160±176 Sagalowsky AI, Kadesky KT, Ewalt DM, Kennedy TJ (1994) Factors influencing adrenal metastases in renal cell carcinoma. J Urol 151:1181±1184 Sherif A, De la Torre M, Malmstrom PU, Thorn M (2001) Lymphatic mapping and detection of sentinel nodes in patients with bladder cancer. J Urol 166:812±815 Silver DA, Morash C, Brenner P, Campbell S, Russo P (1997) Pathological findings at the time of nephrectomy for renal mass. Ann Surg Oncol 4:570±574 Spiessl B, Beahrs OH, Hermanek P, Hutter RVP, Scheibe O, Sobin LH, Wagner G (1990) TNM atlas, 2nd edn (supported by UICC) Springer, Berlin Heidelberg New York Staiano-Coico L, Huffman J, Wolf R, Pinsky CM, Herr HW, Whitmore WF Jr, Oettgen HF, Darzynkiewicz Z, Melamed MR (1985) Monitoring intravesical bacillus Calmette-Gurin treatment of bladder carcinoma with flow cytometry. Urol 133:786±788 Steinbach F, Stæckle M, Mçller SC, Thuroff JW, Melchior SW, Stein R, Hohenfeller R (1992) Conservative surgery of renal cell tumors in 140 patients: 21 years of experience. J Urol 148:24±29 Studer UE, Scherz S, Scheidegger J, Kraft R, Sonntag R, Ackermann D, Zingg EJ (1990) Enlargement of regional lymph nodes in renal cell carcinoma is often not due to metastases. J Urol 144:243±245 Sullivan M, Frydenberg M (2001) Nephron-sparing surgery for small incidental renal cell carcinoma. Aust NZ J Surg 71(6):349±353 Tammela TL, Leinonen AS, Kontturi MJ (1991) Comparison of excretory urography, angiography, ultrasound and computed tomography for T category staging of renal cell carcinoma. Scand J Urol Nephrol 25:283±286 Thrasher JB, Robertson JE, Paulson DF (1994) Expanding indications for conservative renal surgery in renal cell carcinoma. Urology 43:160±168
Tsukamoto T, Kumamoto Y, Yamazaki K, Miyao N, Takahashi A, Masumori N, Satoh M (1991) Clinical analysis of incidentally found renal carcinomas. Eur Urol 19:109 Vasselli JR, Yang JC, Linehan WM, Shite DE, Rosenberg SA, Walther MM (2001) Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma. J Urol 166:68±72 Weirich G, Glenn G, Junker K, Merino M, Stoerkel S, Lubensky I, Choyke P, Packs S, Amin M, McLellan M, Walther W, Linehan M, Zbar B (1998) Familial renal oncocytoma: clinocopathological study of 5 families. J Urol 160:335±340 Winfield HN, Donovan JF Jr, Troxel SA, Rashid TM (1995 a) Laparoscopic urologic surgery. The financial realities. Surg Oncol Clin North Am 4(2):307±314 Winfield HN, Donovan JF, Lund GO, Kreder KJ, Stanley KE, Brown BP, Loening SA, Clayman RV (1995 b) Laparoscopic partial nephrectomy: Initial experience and comparison to the open surgical approach. J Urol 153:1409± 1414 Wood DP (1990) Role of lymphadenectomy in renal cell carcinoma. Urol Clin North Am 18:421±426 Xu C, Niu Z, Lu J, Wang J (1998) Adrenal sparing surgery for renal cell carcinoma. Chin Med J (Engl) 111(10):877± 880 Yoshimura K, Okubo K, Ichioka K, Terada N, Matsuta Y, Arai Y (2001) Laparoscopic partial nephrectomy with a microwave tissue coagulator for small renal tumor. J Urol 165 (6 Pt1):1893±1896 Zbar B, Tory K, Merino M et al (1994) Hereditary papillary renal cell carcinoma. J Urol 151:561±566 Zbar B, Glenn G, Lubensky IA, Schmidt L, Glenn G, Choyke P, Walther MM, Lerman M, Linehan WM (1995) Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 153:907±912 Zisman A, Pantuck AJ, Belldegrun AS, Schulam PG (2001) Laparoscopic radical nephrectomy. Semin Urol Oncol 19:114±122
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Closing Remarks
The sentinel lymph node concept is scientifically correct and is meanwhile largely accepted in many clinics. Nonetheless, in view of the different types and sites of the primaries treated by various clinical disciplines, its implementation is beset by many general and clinic-specific problems. Partly because of these same problems, there are also pronounced differences between continentals and countries in the level of general acceptance and the quality of performance. We owe it to Nieweg, of The Netherlands, that the main advances made in recent years have been distilled and summarized; his summary was presented in part at the Santa Monica Conference held in December 2000. An overview was subsequently published in the European Journal of Nuclear Medicine in 2001, in which the main points listed below were recorded. 1. As a rule, the search for the sentinel lymph nodes (SLNs) is easiest to handle in malignant melanoma, and compared with other primaries it is most successful in this condition. In keeping with this, the SLN concept is accepted almost all over the world in melanoma treatment. Uren et al. (2000 a, b) stressed at the conference that in 25% of their cases malignant melanomas drained to unexpected locations (see Uren et al. 1998, 1999 a, b). Uren and his group studied 2045 patients within 13 years: in 148 of these cases (7.2%) they found so-called interval nodes (see also Uren et al. 2000 a, b) (nodes between the primaries and the SLNs); micrometastases were found in 14% of these nodes. The authors advise surgical removal of such nodes, together with any additional sentinel nodes in the standard basins. In some patients the interval nodes are the only nodes that contain metastases. Dynamic studies can help to distinguish ªfirst-echelonº lymph nodes from ªsecond-echelonº nodes, which need not be removed.
32
The surgeons at the Santa Monica Conference in 2000 were in agreement that a two-fold diagnostic evaluation by means of the gamma-ray detection probe and the blue dye method should be used. Four studies performed in community hospitals showed that the sentinel node can be identified in 94±98% of cases. Most American research groups were of the opinion that sentinel node biopsy is now standard in medical care. But there is no consensus on this so far. In this context it is of interest that Thompson, at the Sydney Melanoma Unit, explained that SLN biopsy is not currently accepted as standard in medical care in Australia (see also Thompson 1997, 1999, 2000). In most European countries efforts are made to restrict investigative programs for evaluation of the SLN concept to clinical trials (Kroon et al. 1998). In Germany, however, many departments of dermatology within municipal and university hospitals have meanwhile integrated the search for the SLN(s) routinely and monitor their patients within regionally administered follow-up programs. The main reason for this cautious evaluation of the SLN biopsy in routine treatment procedures is the lack of results obtained in randomized trials. Morton et al. (2001) have initiated a multicenter randomized melanoma study to evaluate the real and measurable value of regional controls based on the SLN concept in terms of survival. The trial involves 1784 patients being treated or followed up in 16 centers. The SLN has been identified in 94% of the cases. Comparative concluding results of this study are not available at present. The gravity and difficulty of the procedures applied within the SLN node concept can be derived from the results of a 1062-patient melanoma trial presented by Cascinelli. The false-negative rate of 27% at the beginning of the study was depressing for the participating teams, but as the study pro-
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gressed the SLN identification rate and the quality of node evaluation increased satisfactorily. It is encouraging that in another study investigating 812 cases the rate of false-negative cases ranged between zero and 10% in the participating centers. One of the main advantages of carrying out a search for the SLN is the improvement in locoregional staging, and with this also support in decisions on adjuvant regimens. Cascinelli et al. (2000) have published further detailed information. In their study of 892 cases the regional nodal relapse rate was 6%. Multivariate analysis revealed the SLN status as the most significant prognostic factor (P = 0.000), followed by the thickness of the primary (P = 0.001). Brand new data have been presented by the Amsterdam group (Vuylsteke et al. 2003). The main data are summarized in Table 1. These data confirm that clinical treatment that is in keeping with the SLN concept is absolutely reliable and the survival data seem promising, although it is difficult to confirm the statistical significance of the therapeutic effect in prospective studies. Blumenthal et al. (2002) also conclude that SLN dissection is reliable and safe, being associated with less morbidity than elective lymphadenectomy. In Morton's series the 5-year survival rates were 90±95% in node-negative cases and 65% in nodepositive cases (see also Morton et al. 1999). 2. With regard to breast cancer evaluations, 26 investigators presented their identification rates. These varied between 79% and 100%. According to Nieweg's report the mean value was 93%. In addition, 27 research groups published their false-negative rates, which ranged from zero to 33% (median 7%). Nieweg suggests that the falsenegative rate should be and can be reduced to < 5%. With regard to the techniques used for SLN detection, he reports that a Swedish multicenter
breast cancer trial using double labeling with blue dye and 99mTc-colloid found the SLN to be positive for cancer by use of the radioactive method alone in 26% and by use of the blue dye method alone in 8%. This important result gives another signal indicating that both methods should be used simultaneously (see also Chapter 7). · In the context of the new developments in breast cancer treatment it is easy to understand the wide discrepancies in the degree of acceptance of the SLN concept in different parts of the world, because on the one hand the welltried and internationally practiced concept of intraoperative histologically based cancer diagnosis in frozen sections followed by axillary revision (levels I and II) is easy to perform, while on the other hand, those of us who work in accordance with the SLN concept need a secure histo- or cytopathological diagnosis before the SLN labeling procedure is started. · The SLNs must be very carefully investigated by serial sectioning leading to immunohistochemical investigations. · In cases with a positive SLN a second operation with axillary revision is an urgent priority and must be carried out immediately. All these procedures need continuity of interdisciplinary cooperation between specialists in nuclear medicine, surgeons, and pathologists working together to adapt treatment protocols in the light of documented and internationally recognized new knowledge and of their own experience, in order to keep false-negative rates as low as possible. Discussions about the value of searching for the SLN in high-grade breast cancers (grade III, high S-phase value) still reveal a great deal of controversy. At the St. Gallen Conference (1998) the participants defined low-, moderate-, and high-risk groups of breast cancers and assigned adequate therapy regimens to each of these groups. The fea-
Table 1. Main, most recent data presented on diagnosis and treatment of malignant cutaneous melanoma by the Amsterdam group (Vuylsteke et al. 2003)
a
5-Year survival a
No. of patients
Median follow-up
SLN detection rate
SLN positive rate
False negative rate
Overall
SLN negative
SLN positive
209
72 months
99.5%
19%
9%
87%
92%
67%
For difference between SLN negative and SLN positive, P=0.0001
Technical News Table 2. Breslow stages and corresponding survival rates £ 1.0 mm
< 2.0 mm SLN positive
> 2.0 mm SLN negative
Survival 100%
Survival superior
Survival worse
tures used for subclassification of the different risk groups and the corresponding therapy regimens are summarized in Chapter 33, Tables 10 and 11. The introduction of the sentinel node concept into the progressive strategies of surgical breast cancer treatment protocols is also newly supported by many international well-known clinical research groups (Burak et al. 2002; Haid et al. 2002; Hansen et al. 2002; Meijer et al. 2002; Shivers et al. 2002; Badgwell et al. 2003). The most important reasons for these positive recommendations are: · Less postoperative morbidity in the form of arm complaints and mid-arm swelling (Burak et al. 2002). · Improvements to the prognosis of patients with node-negative breast cancer (Meijer et al. 2002). · Detection of a higher rate of axillary sentinel nodes. Statement of only a low rate of skip metastases in the US National Multicenter Study (Shivers et al. 2002). · Low frequency of disease recurrence in SLNnegative cases, with avoidance of extended axillary node dissection (Badgwell et al. 2003). The Dallas group, whose results were presented by Beitsch, found positive SLNs in 10% of cases of ductal carcinoma in situ (DCIS). These results confirm the statements made in the section on DCIS in Chapter 15 to the effect that SLN investigations should be carried out at least in cases with DCIS extending over > 2.5 cm. With regard to the treatment of breast cancer, current international experience demonstrates very clearly that the SLN concept cannot be practiced except when there is interdisciplinary cooperation among highly qualified surgeons, specialists in nuclear medicine, and pathologists. All this makes it easy to understand why the National Cancer Institute of the United States warns against hasty abandonment of axillary lymph node dissection, because up to now no results of extensive follow-up studies have been presented in international journals.
3. In the case of head and neck, lung, gastrointestinal, and urogenital tumors we are just starting to use the SLN concept; our aim is to determine how it can best be introduced and used to avoid ineffective lymph node revisions and increase cure rates. In these tumor categories, the finding of SLN located outside the expected basins can play an important part in improving the results of surgery, since locoregional cancer clearance can be individually and very precisely tailored to suit the unique topographical constellation in each patient.
Technical News Nieweg et al. reported on studies in San Diego, USA, which were designed to test 99mTc-diethylenetriamine pentaacetic acid (DTPA)-mannosyl dextran in animal experiments. Properties making this tracer suitable for use in searching for SLN are the possibilities of rapid injection and site clearance and of low secondary node accumulation. Wallace et al. (2001) recently reported the synthesis of 99mTc-DTPA-mannosyl dextran and preliminary results about its biological behavior in an original publication. In their concluding remarks, the authors emphasize that this molecule is the first of a new class of diagnostic agents, which are based on a macromolecular ªbackboneº with a high density of sites for the attachment of substrates and imaging reporters. Further results showing any clinical advantages are eagerly awaited. With reference to the preparation of colloid solutions, van der Schors (2000) obtained 2.5-fold radiochemical purity by preparing the 99mTc-colloid solutions in vacuum vials. Technical progress is also rapid in the field of handling improvements and standardization of laparoscopic probes. Tsuchimochi, working in the Department of Radiology within the Faculty of Medicine of Kagoshima University in Japan, has developed a device with a view-field of 44.8 mm by 44.8 mm and a spatial resolution of 1.6 mm FWHM. To increase the local lymphatic flow to the sentinel nodes ªlocal massageº was recommended by Waddington et al. (2000). Readers will, however, recall that precise statements have been published on the sites of injection for the labeling solutions, which should be only a
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few millimeters from the margins of the primaries. Such mechanical irritations seem dangerous, because they can foster intravasal cancer cell transport. Nothing at all is known about whether special drugs added to the labeling solution can accelerate the lymphatic flow. The short remarks presented in this chapter on the brand new products published yearly demonstrate that every year many new experiences recorded in different working fields come to our knowledge. This concerns the different types and sites of cancer as well as technical information on devices used, such as improved and specialized gamma probes and radionuclides and colloid solutions used. The SLN concept is constantly being extended to increasing numbers of frequent and also important tumor types.
References Badgwell BD, Povoski SP, Abdessalam SF, Young DC, Farrar WB, Walker MJ, Yee LD, Zervos EE, Carson WE 3rd, Burak WE Jr (2003) Patterns of recurrence after sentinel lymph node biopsy for breast cancer. Ann Surg Oncol 10(4):376±380 Blumenthal R, Banic A, Brand CU, Ris HB, Lardinois D (2002) Morbidity and outcome after sentinel lymph node dissection in patients with early-stage malignant cutaneous melanoma. Swiss Surg 8(5):209±214 Burak WE, Hollenbeck ST, Brand CU, Ris HB, Lardinois D (2002) Sentinel lymph node biopsy results in less postoperative morbidity compared with axillary lymph node dissection for breast cancer. Am J Surg 183(1):23±27 Cascinelli N, Belli F, Santinami M, Fait V, Testori A, Ruka W, Cavaliere R, Mozzillo N, Rossi CR, MacKie RM, Nieweg O, Pace M, Kirov K (2000) Sentinel lymph node biopsy in cutaneous melanoma: the WHO Melanoma Program experience. Ann Surg Oncol 7(6):469±474 Haid A, Kæberle-Wçhrer R, Knauer M, Burtscher J, Fritzsche H, Peschina W, Jasarevic Z, Ammann M, Hergan K, Sturn H, Zimmermann G (2002) Morbidity of breast cancer patients following complete axilla dissection or sentinel node biopsy only: a comparative evaluation. Breast Cancer Res Treat 73(1):31±36 Hansen NM, Grube BJ, Giuliano AE (2002) The time has come to change the algorithm for the surgical management of early breast cancer. Arch Surg 137(10):1131± 1135 Hunt JA, Thompson JF, Uren RF, Howman-Giles R, Harman CR (1998) Epitrochlear lymph nodes as a site of melanoma metastasis. Ann Surg Oncol 5(3):248±252
Meijer S, Torrenga H, van der Sijp JR (2002) Negative sentinel node in breast cancer patients a good indicator for continued absence of axillary metastases. Ned Tijdschr Geneeskd 146(20):942±946 Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Nieweg OE, Roses DF, Karakousis CP, Mozzillo N, Reintgen D, Wang HJ, Glass EC, Cochran AJ (1999) Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 230(4):453±463 Nieweg OE, Tanis PJ, Rçtgers EJT (2000) Summary of the Second International Sentinel Node Conference. Eur J Nucl Med 28:646 Shivers S, Cox C, Leight G, Beauchamp D, Blumencranz P, Ross M, Reintgen D (2002) Final results of the Department of Defence Multicenter Breast Lymphatic Mapping Trial. Ann Surg Oncol 9(3):248±255 Thompson JF, Saw RP, Colman MH, Howman-Giles RB, Uren RF (1997) Contralateral groin node metastasis from lower limb melanoma. Eur J Cancer 33(6):976±977 Thompson JF, Uren RF, Shaw HM, McCarthy WH, Quinn MJ, O'Brien CJ, Howman-Giles RB (1999) Location of sentinel lymph nodes in patients with cutaneous melanoma: new insights into lymphatic anatomy. J Am Coll Surg 189(2):195±204 Thompson JF, Hunt JA, Culjak G, Uren RF, Howman-Giles R, Harman CR (2000) Popliteal lymph node metastasis from primary cutaneous melanoma. Eur J Surg Oncol 26(2):172±176 Uren RF, Howman-Giles RB, Thompson JF (1998) Failure to detect drainage to the popliteal and epitrochlear lymph nodes on cutaneous lymphoscintigraphy in melanoma patients. J Nucl Med 39(12):2195 Uren RF, Howman-Giles R, Thompson JF (1999 a) Direct lymphatic drainage from a melanoma on the back to paravertebral lymph nodes in the thorax. Clin Nucl Med 24(6):388±389 Uren RF, Thompson JF, Howman-Giles R, Shaw HM (1999 b) Melanoma metastases in triangular intermuscular space lymph nodes. Ann Surg Oncol 6(8):811 Uren RF, Howman-Giles R, Thompson JF, McCarthy WH, Quinn MJ, Roberts JM, Shaw HM (2000 a) Interval nodes: the forgotten sentinel nodes in patients with melanoma. Arch Surg 135(10):1168±1172 Uren RF, Thompson JF, Howman-Giles R (2000 b) Sentinel nodes. Interval nodes, lymphatic lakes, and accurate sentinel node identification. Clin Nucl Med 25(3):234±236 Vuylsteke RJ, van Leeuwen PA, Mçller MG, Gietma HA, Kragt DR, Meijer S (2003) Clinical outcome of stage I/II melanoma patients after selective lymph node dissection: long-term follow-up results. J Clin Oncol 21(6):1057± 1065 Wallace VDR, Hoh CK, Mattrey RF (2001) A synthetic macromolecule for sentinel node detection: 99mTc-DTPAmannosyl dextran. J Nucl Med 42:951±959
Chapter 33
Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types K. Possinger, A. Schauer, F. Griesinger, A. C. Roever
Introduction In various cancer types the spread of cancer into the sentinel lymph nodes or more or less extensively into regional basins is one of the indications for adjuvant or neoadjuvant chemotherapy. Tested and internationally accepted regimens are used as the basis of individual decision making. However, in many cases the decision on adjuvant cancer treatment has to be tailored to the individual case under scrutin and based on knowledge and evaluation of important individual biological and prognostic features. Therefore, it is only possible to lay down the most important international currently practiced therapy regimens related to the different cancer types discussed in the part of this book devoted to them.
Basic Remarks: Side Effects and their Clinical Detection (see Table 1) Some substances have known frequent side effects, and prophylactic medication is recommended to deal with these. Examples are ifosfamide or cyclophosphamide (mesna is given to prevent cystitis) and cisplatin at doses > 60 mg/m2, with which amifostine is given to prevent nephrotoxicity. Furthermore, it may have affinity to proteins that regulate magnesium absorption.
Table 1. Side effects and their clinical detection Side effect
Organ-related methods used in detection
Cardiotoxicity
Echocardiography, measurement of ejection fraction
Nephrotoxicity
Control of electrolytes, urea, creatinine, especially creatinine clearance
Neurotoxicity
Detailed anamnesis, neurological examination, superficial (contact) and deep (vibration) sensitivity, reflexes
Ototoxicity
Audiogram
Hepatotoxicity
Transaminases, in chronic states: Quick, albumins, etc.
Bone marrow toxicity
Blood count
33
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Adjuvant Chemotherapy Regimens for Breast Cancer Classification According to Risk Factors Well-established risk factors for recurrence of breast cancer are: · Tumor size · Nodal status
· Grading · Endocrine responsiveness · Age According to these risk factors a classification into minimal, average (moderate) and high risk was established and recently modified at the St. Gallen Consensus Meeting 2003 (Table 2). Approaches to therapy are based on this risk stratification (Table 3).
Chemotherapy and Endocrine Therapy Regimens Table 2. Classification according to risk factors for patients with node-negative breast cancer (modified according to Goldhirsch et al. 2003) Risk category Minimal
Average
Endocrine responsive
Endocrine nonresponsive
ER and/or PR positive and all of the following: pT £ 2 cm, grade 1, age > 35 years
Not applicable
ER and/or PR positive and one of the following: pT > 2 cm, grade 2±3, age < 35 years
ER and PR negative
The most frequently used regimens are shown in this chapter (Tables 4±12). The efficacy of the adjuvant treatment depends largely on the dosage applied and on the frequency of therapy courses. Therefore reduction of the dosage and lengthening of the cycles should be avoided. The cytostatic regimens are listed first. Note that CMF is still the most frequently used basic regimen (Tables 4, 5); in cases with higher degrees of malignancy (even in N0 stages) and in cases with positive nodes or HER/neu overexpression, however, anthracyclin-containing therapy regimens (Tables 6±9) are definitely preferred. In cases with
Table 3. Adjuvant systemic treatment for patients with operable breast cancer (modified according to Goldhirsch et al. 2003) Risk category
Endocrine responsive
Endocrine nonresponsive
Premenopausal
Postmenopausal
Premenopausal
Postmenopausal
Node negative, minimal risk
Tamoxifen or none
Tamoxifen or none
Not applicable
Not applicable
Node negative, average risk
GnRH analogue + tamoxifen or chemotherapy ? tamoxifen or tamoxifen or GnRH-A
Tamoxifen (or aromatase-inhibitor) or chemotherapy ? tamoxifen
Chemotherapy
Chemotherapy
Node positive
Chemotherapy ? tamoxifen (Ô GnRH-A) or GnRH-A + tamoxifen
Chemotherapy ? tamoxifen or tamoxifen
Chemotherapy
Chemotherapy
Table 4. Classic CMF regimen (Bonadonna 1995) Symbol C M F
Expansion Cyclophosphamide Methotrexate 5-Fluorouracil
6 cycles, every 4 weeks
Dosage 100 mg/m
Route
Days
p.o.
2
i.v.
Bolus
Days 1, 8
2
i.v.
Bolus
Days 1, 8
40 mg/m 600 mg/m
Mode
2
Days 1±14
Adjuvant Chemotherapy Regimens for Breast Cancer Table 5. Modified i.v. CMF regimen (Bonadonna 1995) Symbol
Expansion
C
Dosage
Cyclophosphamide
M
600 mg/m
Methotrexate
F
Route
Mode
Days
2
i.v.
Bolus
Days 1, 8
2
i.v.
Bolus
Days 1, 8
2
i.v.
Bolus
Days 1, 8
40 mg/m
5-Fluorouracil
600 mg/m
6 cycles, every 4 weeks Table 6. Regimens including anthracycline/anthraquinone: doxorubicin/cyclophosphamide (AC) Symbol A C
Expansion
Dosage
Adriamycin (doxorubicin)
Route
Mode
Days
2
i.v.
Bolus
Day 1
2
i.v.
Bolus
Day 1
40 mg/m
Cyclophosphamide
600 mg/m
Four cycles, every 3 weeks; caveat: doxorubicin-limiting dosage Table 7. FEC (Levine 1998) Expansion
Dosage
5-Fluorouracil
Route
Mode
Days
2
i.v.
Bolus
Days 1, 8
2
Bolus
Days 1, 8
500 mg/m
Epirubicin
60 mg/m
i.v.
Cyclophosphamide
75 mg/m2
p.o.
Days 1±14
Six cycles, every 4 weeks; caveat: epirubicin-limiting dosage Table 8. Doxorubicin/cyclophosphamide ? paclitaxel (AC ? T) (Henderson et al. 1998) Symbol A=D C
Expansion
Dosage
Doxorubicin
Route
Mode
Days
2
i.v.
15-min infusion
Day 1
2
i.v.
30-min infusion
Day 1
i.v.
90-min infusion
Day 1
60 mg/m
Cyclophosphamide
600 mg/m
Repeat from day 22 for a total of four cycles; then paclitaxel T
175 mg/m2
Paclitaxel
Four 3-week cycles of cyclophosphamide followed by four 3-week cycles of paclitaxel Table 9. TAC (Nabholtz 2002, 2003) Expansion Docetaxel Doxorubicin Cyclophosphamide
Dosage
Route
Mode
Days
2
i.v.
1-h-infusion
Day 1
2
i.v.
bolus
Day 1
2
i.v.
15-min-infusion
Day 1
75 mg/m 50 mg/m 500 mg/m
Six 3-week cycles; caveat: doxorubicin-limiting dosage Table 10. Tamoxifen (Fisher et al. 1996)
a
Agent
Dose
Route
Regimen
Tamoxifen
20 mg (absolute)
p.o.
Daily, continuous a
Duration: 5 years
505
506
Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types Table 11. Anastrozole (Buzdar 1996) Agent
Dose
Route
Regimen
Anastrozole
1 mg
p.o.
Daily
Table 12. Letrozole (Dombernowsky 1998) Agent
Dose
Route
Regimen
Letrozole
2.5 mg
p.o.
Daily
c-erb B1 and B2 overexpression, substitution of tamoxifen (Table 10) by anastrozole or letrozole (Tables 11, 12) is possible. A few publications documenting current international experience may give some indication in which cases it is better to use the new substances in preference to tamoxifen. In a joint analysis of two randomized trials investigating three versus six cycles of CMF, Colleoni et al. (2002) showed that three cycles rather than six cycles were adequate in both studies for patients older than 40 years with estrogen-receptorpositive tumors (n = 594; risk ratio 0.86; 95% confidence interval 0.68±1.08; P = 0.19). The 95% confidence interval excluded an adverse effect of more than 2% with respect to absolute 5-year survival. In contrast, three cycles appeared to be inferior to six cycles for women under 40 years old (n = 190; risk ratio 1.25; 95% confidence interval 0.87±1.80; P = 0.22) and for women with estrogenreceptor-negative tumors (n = 302; risk ratio 1.15; 95% confidence interval 0.85±1.57; P = 0.37).
Comments on Steroid Receptor Expression Threshold for Tamoxifen Therapy and on Effectiveness of Anastrozole and Letrozole Responsiveness to endocrine therapy regimens depends on the expression of ER and/or PR in the cancer cells (percentage of positive cancer cells and staining intensity). The exact threshold beyond which steroid hormone receptor expression limits the endocrine responsiveness of tumors is unknown. At present, approximately 10% positive staining of cancer cell nuclei might be considered a threshold for definite endocrine response.
With a view to the far-reaching consequences (choice of the optimal therapy regimen, long-term high costs), highly skilled immunohistochemical quantitative receptor analysis with appropriate quality controls is necessary. Information on the percentage of positive cancer cells and the staining intensity, summarized in individual cases as grade I±III, must be dealt with by the investigating pathologist.
Pros and Contras of Tamoxifen for Breast Cancer Prevention (Scientific Discussion see Cykert 2003) Comments on the International Breast Cancer Intervention Study (IBIS-1) report (Sept 14, p 187, 2002) criticize the underestimation of tamoxifen's benefit in breast cancer prevention and the lack of important explanations for tamoxifen-related mortality rates (Cykert 2003). In addition, Caine et al. (2003) recommend thrombosis prophylaxis and doubt whether patients at risk should receive tamoxifen in the first place. In the authors' reply, Cuzick for IBIS reflects on the overall reduction in breast cancer by one third (N.B. similar results in the IBIS group and in European trials), but emphasizes that there is a serious need for thrombosis prophylaxis.
Alternatives to Tamoxifen Buzdar et al. stressed the effectiveness of anastrozole (1 mg respectively 10 mg/day) as long ago as 1996. They state that the effects are similar to those of megestrol acetate, which was in trial at the same time. Anastrozole was even effective in postmenopausal women with advanced breast cancer that had progressed during tamoxifen therapy. In 2003, Buzdar reported on new findings, comparing anastrozole (1 mg once daily) alone and in combination with tamoxifen (20 mg once daily). In summary, he states that anastrozole is quite effective: (a) in breast cancer prevention; (b) in the early stages of breast cancer as already documented; and (c) also in cases of receptor-positive cancer that has progressed since the menopause. In the comparative studies of ATAC and tamoxifen (2002) an improvement in disease-free survival was demonstrable in hormone-receptor-positive,
Adjuvant Chemotherapy Regimens for Breast Cancer
but not in hormone-receptor-negative, cases. The incidence of phase-shifted development of contralateral breast cancer was significantly lower in the group treated with anastrozole than in subjects treated with tamoxifen (P = 0.007). In addition, tolerance of anastrozole was also superior to that of tamoxifen, anastrozole less frequently being followed by: Endometrial carcinoma development
P = 0.02
Vaginal bleeding and discharge
P = 0.0001
Cerebrovascular events
P = 0.0006
Venous thrombosis
P = 0.0006
Tamoxifen was better tolerated than anastrozole with respect to musculoskeletal disorders and fractures (P = 0.0001 for each). In a double blind randomized trial Dombernowsky et al. (1998) demonstrated that the aromatase inhibitor letrozole has a dose-dependent effect and is more effective and better tolerated than megestrol acetate (Table 12) in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens. In a phase III randomized clinical trial Ellis et al. (2001) confirmed the results of Dombernowsky et al. (1998). They showed that in postmenopausal patients with ER- and/or PR-positive primaries the response to tamoxifen (20 mg daily: response rate 41%) was inferior to the response to letrozole (2.5 mg daily, response rate 60%). The differences in the response rates ± letrozole versus tamoxifen ± were especially marked in c-erb B1- and/or c-erb B2-positive cancer cases (RR 88 versus 21%, P = 0.004). These results led to the conclusion that c-erb B1 and c-erb B2 signaling through the ER is ligand dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER-positive cancer can be inhibited by potent estrogen deprivation therapy.
Anti-HER2 Therapy At present, no adjuvant therapy is recommended in N0M0 cases. In p185 (HER/neu) N-positive and/or M-positive cases the use of anti-HER (herceptin) within study programs must be discussed and should be recom-
Table 13. Results obtained with first-line anti-HER2-monotherapy (Vogel et al. 2000) Standard dose
High dose
Anti-HER2 regimen
4-mg/kg loading dose, then 2 mg/ kg weekly
8-mg/kg loading dose, then 4 mg/ kg weekly
No. of patients
59
55
Overall response rate
25%
27%
Median time to progression
3.5 months
3.8 months
Median overall survival
22.9 months
25.8 months
mended. There is a positive correlation between overexpression of HER/neu and high proliferation of the cancer, vimentin positivity, BAX positivity, and lymphogenic and hematogenous tumor progression; and a negative correlation between overexpression of HER/neu and ER and PR status and positive BCl2 reaction. Overall, HER/neu tumors generally have a worse prognosis than HER2-negative disease. Anti-HER2 therapy is a monoclonal antibody treatment. In contrast to chemotherapy it inhibits tumor growth without affecting normal tissues and obviously stimulates the patient's immune response directed against the tumor. It is worth knowing that Trastuzumab (herceptin) induces HER2 receptor down-regulation and this results in inhibition of critical signaling pathways (ras-RAF-Mark and PI 3K/Akt) and blocks cell cycle progression by inducing the formation of p27/Cdk2 complexes (Albanell et al. 2003). In a trial involving 222 patients carried out by Cobleigh et al. (2000) the cancer response rate was 16%. Vogel et al. reported at the ASCO meeting in 2000 (see also 2003) on first-line treatment of 114 cases with anti-HER2 monotherapy. The results are summarized in Table 13.
Combined Therapy Modality In the randomized combination study of Slamon et al. (ECCO 1999, Abstract 1261) one patient group received anti-HER2 therapy (H) plus chemotherapy (CT) and a second group, chemotherapy alone
507
508
Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types Table 14. Results of the pivotal anti-HER2 therapy/chemotherapy combination study (Slamon et al., ECCO 1999, Abstract 1261, cited in Cobleigh, MBCC 2000) (CT chemotherapy, H anti-HER2 therapy, P paclitaxel, AC anthracycline + cyclophosphamide) Regimen
No. of patients
Overall response rate (%)
Median time to progression (months)
CT+H
235
49
7.6
CT
234
32
4.6
P+H
92
42
6.9
P
96
16
3.0
AC+H
143
52
8.1
H
138
43
6.1
(Table 14). This was the first treatment for 489 patients using this scheme for advanced cancer, but 90% of the patients had adjuvant therapy. The drugs used were anthracycline plus cyclophosphamide (AC) or paclitaxel (P).
Administration schedule. Anti-HER2 was given weekly; chemotherapy every 3 weeks. With both regimens (AC, P plus anti-HER), overall response and median time to progression were better with added anti-HER2 therapy than alone. In the Leyland-Jones (2003) studies Trastuzumab was given as a loading dose of 8 mg/kg i.v. (day 1) after paclitaxel 175 mg/m2 (day 0). Afterwards Trastuzumab was given at a dosage of 6 mg/ kg on the same day as paclitaxel (175 mg/m2) every 3 weeks for seven cycles. Trastuzumab (herceptin) (Genentech Inc., South San Francisco, Calif.) is not recommended or paid for by insurance companies for the adjuvant treatment of breast cancer. The HERA studies supported by the Roche company to investigate adjuvant HER2-positive cancer cases are still in progress, so that no end-results are yet available. In contrast to this inconclusive state, herceptin therapy is routinely applied for the palliative treatment of HER2-positive cancer cases, and in these circumstances the costs are paid by insurance companies, in Germany for example. The current status on payment in other countries is not known to us at present.
Therapy Regimens for Thyroid Cancer
Therapy Regimens for Thyroid Cancer Radioiodine Therapy Adjuvant treatment of thyroid cancers with iodine131 (radioiodine therapy, RIT) is indicated in all cases of follicular and papillary cancers in which primaries are larger than 1 cm across (pT1a), which in stage pT1b also means N0M0 cases. Most papillary cancers are also 131-iodine sensitive, because 98% of cancers of this subtype synthesize thyroglobulin. The treatment is advised regardless of whether or not there is lymph node involvement, and the main purpose of a search for SLN is therefore the achievement of precise locoregional surgical cancer clearance. RIT is not indicated in anaplastic and medullary thyroid cancers. Execution of RIT. As a rule, RIT is governed by the guidelines of radiation control laws of the different countries. The standard activity used is 1± 3 GBq iodine-131 or the dose is estimated individually according to Marinelli, with the aim of a focal dose of more than 300 mCi (see German Cancer Society 2000). Daily controls are needed during the course of this therapy: · Measurement of activity for dosimetric control · Whole-body scintigraphic evaluation to reach current staging values at the day of release, but not before 72 h after administration of iodine131. Early side effects are seen 8±14 days after completion of RIT: painful swelling of the remaining thyroid gland tissue in 10±20% of cases; transitory gastric symptoms in approximately 30%; transitory bone marrow syndrome (thrombopenia and leukopenia) in approximately 70%; and sialadenitis in about 30%.
Late side effects are sicca syndrome (in 10±20% of cases), bone marrow depression, leukemia (1%), and azoospermia (this is rare). Therapy of Locoregional Recurrence · Primarily surgical locoregional clearance of nodal and/or delineated soft tissue relapses. · Subsequent radioiodine diagnosis and, in the case of focal iodine storage, iodine-131 therapy (standard activity 5±8 GBq iodine-131). · In cases of nonstorage of iodine percutaneous local radiotherapy is used; radiochemotherapy is applied in cases with distant metastases. Therapy of Distant Metastases · In cases with a single metastasis, surgical removal, if possible, is the method of choice. · In the case of local inoperability RIT can be advised when radioiodine storage is sufficient. · In cases with insufficient radioiodine storage percutaneous radiotherapy can be tried. · Depending on the localization, 30 Gy (10 ´ 3 Gy) can be given in 2 weeks or 45±50 Gy in 5 weeks.
Chemotherapy · In cases with diffuse metastasis mono- or combined chemotherapy or radiochemotherapy can be applied. · Monotherapy with doxorubicin is possible. The effects of other agents (cisplatin, carboplatin, etoposide) are small compared with that of doxorubicin. In cases with diffuse metastasis of an undifferentiated cancer the effect of polychemotherapy is superior to that of monotherapy. The use of doxorubicin plus cisplatin or etoposide gives better results than monotherapy with doxorubicin alone. Multimodal therapy regimens should be selected after consultation within interdisciplinary teams and should be applied exclusively in specialized cancer centers.
509
510
Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Therapy Regimens for Head and Neck Cancers Adjuvant therapy regimens can be used with curative intent and for palliation in head and neck cancers. Radiotherapy can theoretically be used · As the sole treatment regimen. · As an additional (supplementary) treatment before or after surgery. · As interstitial brachytherapy to increase the local dosage (boost) after extensive percutaneous radiotherapy or as the only method in focal radiotherapy for a small primary tumor or a relapse. · Postoperatively to allow more precise determination of what further treatment is indicated on the basis of histopathology-supported staging. · Resection with curative intent after neoadjuvant therapy (radiotherapy and/or chemotherapy) must take account of pretherapeutic assessment of the cancer's extension. Such strategies are in contrast to the exact surgical locoregional cancer clearance based on the SLN concept. · In the case of inoperable cancer high-dosage radiotherapy or combined radiochemotherapy is indicated. · Locoregional recurrences in patients who have not previously undergone radiotherapy can be treated by radiotherapy. List of Indications for Radiotherapy · RT is possible in R1 and R2 resection for surgical cancer clearance. · pT4 with cancer infiltration of regional tissue structures (pN2, 3) · Perforation of the lymph node capsule to a limited extent · Regional lymphangiosis carcinomatosa · Depending on the localization of the primary, pT1±3pN0 or pT1±3pN1. In positions 3±5 the strategies of the SLN concept can help to ensure radiotherapy is used more precisely. Combined Radiochemotherapy. In cases of locoregional inoperability locoregional high-dosage radiotherapy is also unsatisfactory. Simultaneous administration of radio- and chemotherapy (RCT) seems to be more successful. The following agents have been used in clinical trials: 5-fluorouracil (5FU), cis- or carboplatin, mitomycin, and taxane.
The use of 5-FU and cisplatin has given the best results. Radiotherapies have been improved with the introduction of hyperfractionated and accelerated radiotherapy. Randomized studies in which RCT is administered according to the preliminary results obtained are in progress. Cancers of the lip, oral cavity, oropharynx, hypopharynx, and larynx must be treated with due consideration for patient age, localization of the primary, disease stage and surgical options open. Especially in advanced stages, radiotherapy or RCT must be considered as the sole treatment or an additional treatment. Current treatment strategies available for oropharyngeal and laryngeal cancers and the option of SLN-related N staging are presented in Table 15.
Intraoperative Radiotherapy of Head and Neck Cancers Intraoperative electron beam radiotherapy (IORT), used at the Mayo Clinic for head, neck and skull base cancers in dosages of 6±15 MeV (6 MeV is the dosage most commonly used) at doses of 12.5± 22.5 Gy produces tumor control and survival in patients who are likely to have microscopic residual disease, especially in sites where it is difficult to resect, such as the skull base (Pinheiro et al. 2003).
Combined Radiochemotherapy: New Approaches With chemoradiotherapy ªFARº (= 5 Fluorouracil 250 mg/day i.v.), vitamin A (50,000 U/day i.m.) and external radiation (2 Gy/day up to 60±70 Gy) in T2N0 glottic cancer, the cumulative 5-year voice preservation and complete laryngeal preservation rates were 91% and 87%, respectively. The cumulative 5-year disease-free survival rate was 97% (Kumamoto et al. 2002). ªHyperradplatº (hyperfractionated radiation and intra-arterial cisplatin) combination therapy in stage III and IV head and neck cancers has been successfully tried by Valentino et al. (2002). These authors recommend new evaluation techniques, such as metabolic imaging and molecular analysis, as tools for exploration of interval surgical resections.
Therapy Regimens for Head and Neck Cancers Table 15. Current treatment regimens for oropharyngeal and laryngeal cancers (RND radical neck dissection, ERND extended RND, MRND modified RND, SND selective lymph node dissection, RCT radiochemotherapy, RT radiotherapy) Localization of primary
Lip
Oral cavity
Stage-related indications
Pharynx
Larynx
Oropharynx
Nasopharynx
Hypopharynx
pT1±2
Surgery or primary RT
Surgery or primary RT
pT1: transoral or transcervical excision
Standard: primary RT (PN+N)
pT: transoral or transcervical partial resection of hypopharynx
Supraglottic: T1±3: partial laryngectomy;
pT1±2: Surgery not in sano (R1±2)
Postoperative RT
Postoperative RT
T2±4: lateral pharyngectomy
Occasionally operation
T2: as before plus ipsilateral thyroidectomy
T3: sometimes with partial pharyngectomy
pT3±4
Resection plus plastic reconstruction
Resection plus plastic reconstruction
T3±4: plus laryngectomy
In stages III and IV simultaneous RCT
T3: partial resection of hypopharynx plus laryngectomy plus ipsilateral thyroidectomy
T4: total laryngectomy plus partial pharyngectomy
T4: pharyngolaryngectomy plus ipsilateral thyroidectomy
Glottic: T1: chordectomy
T4: plus mandibulectomy R1±2: postoperative RT
T2: partial resection in special cases laryngectomy
pT2±4 (uvula, palate, tonsil, root of tongue)
T3 and T4: partial pharyngectomy plus laryngectomy (in some cases partial)
+
+
+
N0
In pT1: ªwait and seeº; SLN labeling
In pT1 ªwait and seeº; SLN labeling
SND or observation
N1
SND or MRND
SND or MRND
SND or MRND
In early stages SLN search can be tried
+
+
Subglottic: T1±4: no standard therapy; rare lesion
In pT1: ªwait and seeº or SND, possibly with guidance from search for SLN
Mostly bilateral SND; >T1: bilateral neck dissection; SLN guidance must be evaluated
SND, possibly with guidance from search for SLN, or MRND
SND or MRND, with guidance from search for SLN
N stage
Node positivity still existing after RT: neck dissection
511
512
Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types Table 15 (continued) Localization of primary
Lip
Oral cavity
Pharynx
N2
SND or MRND; in selected cases RND
SND or MRND; in selected cases RND
SND or MRND; in selected cases RND
N3
RND or MRND
RND or MRND
RND, MRND or ERND
In a phase I study (Spencer et al. 2003) in unresectable head and neck cancers chemotherapy and reirradiation was used. 5-Fluorouracil administered as a bolus was escalated from 300 mg/m2 to a 10hour infusion increased by increments of 150 mg/ m2 per day. Hydroxyurea remained constant at 1.5 g. Chemotherapy was given in weeks 1 and 4. RT was given daily: 2.0 Gy per fraction in weeks 1 and 2, followed by a 1-week break, then hyperfractionated in weeks 4 and 5, to give a total dose of 50 Gy. The 1-year survival rate was 41%. A mass reduction of local tumor infiltration in advanced head and neck cancers was achieved at least in some cases by intratumoral cisplatin epinephrin gel (CDD-epi-gel) infiltration (Castro et al. 2003; phase III study in North America). Amdur et al. (2001) reported on radiotherapy and neck dissection for T1±2 sinus piriformis cancers with 5-year local control rates of 90% for T1 cancers and 80% for T2 lesions. Chemotherapy was found to be unlikely to improve larynx preservation, but may have improved local and regional control.
Larynx
N3a (squamous cell cancers): operation before RT
SND (with guidance from search for SLN) or MRND; in special cases RND
SND or MRND; in special cases RND
RND; possibly MRND or ERND
RND; possibly MRND, ERND
therapy for recurrent head and neck cancers has been carried out by Shiga et al. (2002). Patients received either cisplatin and 5-fluorouracil or cisplatin and paclitaxel (Taxol). Response to chemotherapy was significantly correlated with improved survival (progression-free survival P = 0.0005; overall survival P = 0.007). Overexpression of c-erb B2 was associated with significantly decreased progression-free survival (P = 0.023) and overall survival (P = 0.029). Bradford et al. (2003) reported results demonstrating higher sensitivity of head and neck cancers expressing mutated p53. As tested in cell lines, the average ID50 (drug dose required to inhibit 50% of cell growth) of cisplatin was 6.8 lM for cancer cell lines with mutant p53, whereas the average ID50 for wild-type cell lines was 13.7 lM. These results support the importance of testing cancers for mutated p53 tumor suppressor gene activity as an important marker for response to cisplatin in head and neck squamous cell cancers (HNSCC).
Treatment of Cancers with Special Localizations Treatment of Cancer with Specific Oncogene Overexpression and Mutated Suppressor Gene Expression (c-erb B2, p53) Evaluation of the prognostic significance of c-erb B2 overexpression in patients treated with chemo-
After radiotherapeutic locoregional treatment for esthesioneuroblastoma (elective neck irradiation) at 5 years, the local control rate was 59%; the cause-specific survival rate, 54%; and the absolute survival rate, 48% (Monroe et al. 2003).
Chemotherapy Regimens for Lung Cancer
Chemotherapy Regimens for Lung Cancer
New Results and Approaches in Treatment of Small Cell Lung Cancer
Chemotherapy Regimens Most Commonly Used in Treatment of Small-Cell Lung Cancers The regimens most frequently used in small-cell lung cancer (SCLC) are cisplatin + etoposide (Table 16), adriamycin + cyclophosphamide + vincristine (Table 17) and epirubicin + cyclophosphamide + vincristine (Table 18). Another regimen used is carboplatin + etoposide + vincristine (Table 19).
In a randomized phase III study (Reck et al. 2003), patients in stages I±IV with SCLC disease were treated with paclitaxel, the topoisomerase II inhibitor etoposide, and carboplatin. Patients with previously untreated disease showed improved progression-free and overall survival and less frequent hematological toxicities than patients treated with standard therapy. Triple combination therapy (Greco 2003) using topotecan with paclitaxel and carboplatin yielded impressive complete response rates in SCLC treat-
Table 16. Cisplatin (P)/etoposide (E) regimen used in small-cell lung cancer (SCLC) Symbol P E
Expansion
Dose
Cisplatin
Route
Mode
Regimen
2
i.v.
Bolus
Days 1±7
2
i.v.
Bolus
Days 1±3
90 mg/m
Etoposide
100 mg/m
Every 3 weeks Table 17. Adriamycin/cyclophosphamide/vincristine (ACOII) regimen used in SCLC (Niederle 1982) Symbol
Expansion
A
Adriamycin
C O
Route
Mode
Regimen a
60 mg/m2
i.v.
Short time
Day 1
2
i.v.
Short-time
Days 1, 2
i.v.
Bolus
Days 1, 8, 15
Dose
Cyclophosphamide Vincristine
750 mg/m 1.5 mg
a
Every 3 weels Patients < 50 years: 2 mg; < 60 years: 1.5 mg, > 60 years: 1 mg
a
Table 18. Epirubicin cyclophosphamide vincristine (EPICO) Symbol
Expansion
Dose
Epi
Epirubicin
C
Cyclophosphamide
O
Vincristine
Route
Mode
Regimen
2
i.v.
Short term
Day 1
1000 mg/m2
i.v.
Short time
Day 1
2 mg
i.v.
Bolus
Day 1
70 mg/m
Every 3 weeks Table 19. Carboplatin/etoposide/vincristine (CEV) regimen used in SCLC (Eberhardt 1993) Agent Carboplatin Etoposide Vincristine Every 4 weeks
Dose
Route
Mode
Regimen
2
i.v.
Short time
Day 1
2
i.v.
2-h infusion
Days 1, 2, 3
i.v.
Bolus
Days 1, 8, 15, 22
300 mg/m
140 mg/m 1.5 mg
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
ment of 37±51% in cases with recurrence in limited stages. In treatment of SCLC using mitomycin 8 mg/m2 on day 1, vinblastine 4 mg/m2 on days 1±8, and cisplatin 100 mg/m2 on day 1, or the same regimen except with cisplatin substituted by carboplatin 300 mg/m2 on day 1 every 3 weeks the following results were obtained: the carboplatin regimen had a significantly better toxicity profile than the cisplatin-containing regimen (documented by the EORTC questionnaires). The response rates were 43.1 and 38.6%, respectively in the MVP and the MVC arm (P = 0.59). The median survival rates of 10.2 and 7.2 months, respectively, for the cisplatin and carboplatin arms (P = 0.39) did not differ significantly (Paccagnella et al. 2004).
Chemotherapy Regimens for Non-Small-Cell Lung Cancer Surgery and radiotherapy remain the best treatment options for resectable non-small-cell lung cancer (NSCLC). The role of adjuvant chemotherapy in successfully resected NSCLC is still highly controversial. Whereas the largest trial (IALT, International Adjuvant Lung Cancer Trial) (see Tonato 2002) showed a small but significant survival benefit for patients treated with cisplatin-based chemotherapy, the Italian trial (ALPI) (see Alexanian and Torri 2000) and the UK trial (Big Lung Trial) (see Evans 2004) did not show any significant differences. In patients with unresectable tumors combination chemotherapy is the cornerstone of treatment. Patients with a good performance status benefit more from the combination therapy than patients with a poor condition. New drugs have been evaluated (taxanes, gemcitabine, vinorelbine). Up to now there is no standard therapy regimen, but therapies should be platinum based. Tables 20±23 show combination chemotherapy regimens frequently used for the treatment of NSCLC.
Table 20. Cisplatin/gemcitabine (Schiller 2000) Cisplatin Gemcitabine
100 mg/m2
i.v.
Day 1
2
i.v.
Days 1, 8, 15
1000 mg/m
Every 4 weeks Table 21. One example of a new chemotherapy regimen developed for NSCLC and so far applied only under study conditions: carboplatin + paclitaxel Paclitaxel
225 mg/m2
i.v.
Day 1
Carboplatin
AUC 6
i.v.
Day 1
80 mg/m2
i.v.
Day 1
2
i.v.
Days 1, 8, 15
Repetition from day 28 Table 22. Cisplatin/vinorelbine Cisplatin Vinorelbine Every 3 weeks
30 mg/m
Chemotherapy Regimens for Lung Cancer Table 23. Mitomycin C/ifosfamide/cisplatin (MIC) (Rosell et al. 1994) Agent
Dose 2
Mitomycin C
6 mg/m 2
Ifosfamide
3 g/m
2
Cisplatin a
50 mg/m
Route
Mode
Regimen
i.v.
Bolus
Day 1
i.v.
24-h infusion
Day 1
i.v.
1-h infusion
Day 1
Repetition from day 29
Table 24. Vinorelbine as a single agent for elderly patients or those with poor performance status Vinorelbine
30 mg/m2
i.v.
Days 1, 8
11.8% in the IDEAL trials I and II (Iressa dose evaluation in advanced lung cancer).
Every 3 weeks Table 25. Docetaxel as a single agent for elderly patients or those with poor performance status Docetaxel
100 mg/m2
i.v.
Day 1
Every 3 weeks Table 26. Regimen used by Sculier et al. (2000) in a phase II trial of gemcitabine as second-line chemotherapy for NSCLC, with an overall response rate of 72% and a partial response rate of 6% Gemcitabine
1 mg/m2
i.v.
Days 1, 8, 15, every 4 weeks
Partial response 6%
For elderly patients and for patients with a poorer performance status (³ 2) monochemotherapy with a newer drug, such as vinorelbine, docetaxel or gemcitabine, is beneficial (Tables 24±26). Single-agent docetaxel therapy is also discussed by Laurie and Kris (2000).
New Therapeutic Approaches One promising new therapeutic approach is targeted immune therapy. The epidermal growth factor receptor (EGFR) is such a promising target for anticancer drugs, and with EGFR tyrosine kinase inhibitors (gefitinib = Iressa, erlotinib = Tarceva) and a monoclonal antibody against EGFR (cetuximab = Erbitux), new drugs have been developed. Gefitinib has recently been approved in various countries; in Europe it is approved only in Switzerland, and only since April 2004. Gefitinib is used as a single agent in a dose of 250 mg/day orally. Response rates were 18.4% and
New Approaches in Treatment of Advanced Non-Small-Cell Lung Cancer A combination therapy using vinorelbine and docetaxel was carried out by Miller (2000), who also suggested phase II and III studies. Reboul (2004) has recently reviewed past and current strategies for treatment of locally advanced NSCLC. After giving a detailed overview of the phase II and III study results with cis- or carboplatin, accelerated hyperfractionated radiotherapy, and the radiosensitizing effects of cisplatin, he emphasizes the significance of `third-generation drugs,' such as taxanes, vinorelbine and gemcitabine, with favorable toxicity profiles and major radiosensitivity properties. He states that weekly administration of these drugs during a full course of conformational radiotherapy with up to 70 Gy resulted in a median survival excess with a 2-year survival rate of 50% and a 3-year survival rate of 40%. The respective benefits of either induction and consolidation full-dose chemotherapy with these new drugs before or after concurrent chemoradiotherapy are currently being evaluated in phase III studies. Ongoing studies of topotecan/paclitaxel alternating with etoposide/cisplatin and thoracic irradiation in cases with limited SCLCs (Lu et al. 2003) and by Treat (2003) using topotecan and gemcitabine and vinorelbine are in progress. Ginsberg, at the Sloan Kettering Cancer Center (2000), depressed by the results of postoperative chemotherapy, radiotherapy and chemoradiotherapy, has now turned to induction therapeutic regimens (chemotherapy or chemoradiation). Phase II and III studies were encouraging, especially in stages I B and II. Ginsberg (2000) suggests that multimodality treatment with initial induction therapy improves
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
patient tolerance to chemotherapy, and perhaps also survival. Several phase III trials are under way in attempts to confirm these early encouraging reports.
Reduction of Toxicities in the Course of Chemotherapy by Amifostine In locally advanced NSCLCs amifostine was used to reduce radiochemotherapeutical induced toxicities (Antonadou et al. 2003). The grouping was application of paclitaxel 60 mg/m2 or carboplatin once weekly during a 5- to 6-week course of conventional radiotherapy given as 2-Gy daily fractions, 5 days a week up to a total dose of 55± 60 Gy. Endoscopic controlled grade 2 or more advanced esophagitis was significantly reduced by amifostine protection (P = 0.061). Amifostine was also recommended for protection against radiation-induced pneumonitis by Choi (2003). The drug was well tolerated, with low incidences of toxicities (nausea and vomiting 3± 5%) and of transient hypotension during intravenous infusion (7%).
Ongoing Approaches blocking Neoangiogenesis in NSCLC Bates (2003) reported on ongoing studies within the ZD-6474 project carried out in the Microvascular Research Laboratories at the University of Bristol, UK. ZD-6474 is a series of studies in which inhibitors of the vascular endothelial growth factor receptor tyrosine kinase, which also has activity against the epidermal growth factor receptor tyrosine kinase, are being tested. Phase II trials in NSCLC were ongoing in 2003. Successful use of antiangiogenic drugs in combination with chemotherapeutic agents in the treatment of advanced colon cancer patients has encouraged to try attempts to treat NSCLC patients in a similar way (Kerbel 2004). Unfortunately, the initial pilot studies demonstrated that the formation of proangiogenic and angiogenic factors was more difficult in subtypes of NSCLC. However, there may be promising candidates for acutely acting vascular targeting agents. Further research work is in progress to evaluate particular drug targets (e.g. bioactive VEGF receptor-2 bound VEGF). It is necessary to work out how to select the optimal biologic/therapeutic doses of antiangiogenic drugs and how best to monitor antiangiogenic drug activity in tumors and determine the optimal combinations to use with chemotherapy regimens.
Therapy Regimens for Esophageal Cancer
Therapy Regimens for Esophageal Cancer New Protocol in Chemotherapeutic and Combined Treatment In superficial esophageal cancers, analysis by Shimizu et al. 2004 resulted in 5-year overall survival rates of 87% in surgically treated cases only (EMR) and approx. 100% in cases treated with cisplatin and fluorouracil plus 40±46 Gy irradiation. Advanced esophageal cancers can be treated with radiation or chemoradiation using adjuvant or neoadjuvant chemotherapy regimens. In chemoradiation cisplatin + 5-fluorouracil is a standard regimen (Table 27; for more details see Crossby et al. 2004). Crossby et al. (2004) obtained a 2-year survival rate of 67% and a 5-year survival rate of 32% in T4 cases who underwent no surgery. A similar treatment protocol was also followed by Nabeya and Ochiai (2003). In a preliminary phase II study Keresztes et al. (2003), at Cornell University, New York, used the following scheme: Paclitaxel 200 mg/m2 and carboplatin given on days 1 and 22, and esophagectomy (in week 6±8). The resectability rate was 71%, with a complete remission rate of 11%. Urba et al. (2003) used cisplatin combined with paclitaxel and radiotherapy 1.5 Gy twice per day on days 1±5, 8±12 and 15±18. The total dose of radiotherapy amounted to 45 Gy. This cisplatinbased preoperative regimen was well tolerated. The authors emphasize that this is a reasonable approach for patients with esophageal cancer that is still localized. Polee et al. (2003), in Rotterdam, used the following chemotherapy regimens for treatment of advanced esophageal cancers: cisplatin/etoposide, cisplatin/etoposide/5-fluorouracil, cisplatin/paclitaxel (weekly) and cisplatin/paclitaxel (bi-weekly). The 1-, 2- and 5-year survival rates
Table 27. Radiochemotherapy of esophageal cancer Cisplatin 5-Fluorouracil Reduced to
6 mg/m2
Day 1
300 mg/m2
Day (±1)
2
Day (±1)
250 mg/m
RT delivered in 25 fractions over 5 weeks
Every 3 weeks
of all patients were 33%, 12% and 4%, respectively. Ajani et al. (2003), at the M.D. Anderson Cancer Center, used Irinotecan (CPT-11, Camptsar) and cisplatin as step 1, followed by concurrent radiotherapy and chemotherapy with continuous-infusion 5-fluorouracil (5FU) and paclitaxel as step 2. The South West Oncology Study Group (Urba et al. 2004) treated patients with metastatic or recurrent esophageal cancer with gemcitabine, 1000 mg/ m2, on days 1, 8, 15 and cisplatin, 100 mg/m2, on day 15. The cycles were repeated every 28 days. The 3-month survival rate was 81% and the 1-year survival rate 20%. In a further study of neoadjuvant chemotherapy a combination of mitomycin, 6 mg/m2, ifosfamide, 3 g/m2, and cisplatin, 50 mg/m2, was given before esophagectomy. After chemotherapy in patients with advanced esophageal cancers, esophagectomy was possible in 79% (Darnton et al. 2003). The complete responders and the node-negative patients survived significantly longer than those in other categories (P = 0.001). In a further neoadjuvant trial preoperative mitomycin (6 mg/m2), ifosfamide (3 g/m2) and cisplatin (50 mg/m2) was administered at the Birmingham Cancer Research Institute (UK). There was a 61% response rate to this chemotherapy, with 9% complete responses.
Chemoresistance of Esophageal Cancers In the case of esophageal cancer too, it is important to realize that c-erb B2-positive cancers are chemoresistent (Akamatsu et al. 2003). This point must be taken into account in the development of new therapeutic strategies.
Chemoradiotherapy: Assessment of Operability by PET In Munich the Schwaiger-Siewert Group (Wieder et al. 2004) has analyzed the significance of PET in the assessment of operability and surgical strategies in the course of preoperative chemoradiotherapy. This is important to find out which patients will not respond, allowing early modifications of the treatment protocol.
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Chemotherapy Regimens for Gastric Cancer The effect of adjuvant chemoradiotherapy has been investigated in a large intergroup study (Macdonald et al. 2001). The treatment protocol consisted in one cycle of 5-FU + leucovorin (Table 28), followed by radiotherapy + 5-FU and then two cycles of 5-FU + leucovorin. The median overall survival in the surgery-only group was 27 months, as against 36 months in the chemoradiotherapy group. However, adjuvant treatment is still subject to some debate and cannot be described as stanTable 28. 5-Fluorouracil/folic acid regimen (monthly) used for gastric cancer at the Mayo Clinic (Poon et al. 1991) Folic acid
20 mg/m2
i.v.
Bolus
Days 1, 2, 3, 4, 5
5-Fluorouracil
425 mg/m2
i.v.
Bolus
Days 1, 2, 3, 4, 5
Table 29. ECF (Cunningham 1991; see also Ross et al. 1998) Epirubicin Cisplatin 5-FU
50 mg/m2
i.v.
Day 1
2
i.v.
Day 1
2
i.v.
Continuous
7 mg/m2
i.v.
Day 1
2
60 mg/m
i.v.
Day 1
300 mg/m2
i.v.
Continuous
60 mg/m 200 mg/m
Every 3 weeks
Table 30. MCF (Ross 2002) Mitomycin Cisplatin 5-FU Every 3 weeks
dard procedure. Frequently used chemotherapy regimens in metastatic disease are shown in Tables 29 to 31. The Italian Group for the Study of Digestive Tract Cancer (GiSCAD) also used a regimen similar to the Cunningham scheme (Table 32), plus 6Sleucovorin, 250 mg/m2, for weekly preoperative, locally advanced and nonresectable gastric cancer (Cascinu et al. 2004). together with 6S-leucovorin (250 mg/m2) for weekly preoperative chemotherapy of locally advanced unresectable gastric cancer (Cascinu et al. 2004). Kalmar et al. (2003) used the ECF scheme (Table 29) for neoadjuvant treatment of locally advanced gastric cancer, making R0 resection possible in a group of 24 patients (epirubicin and cisplatin on day 1 and continuous infusion of 5fluorouracil on days 1±21; 12 weeks of treatment, followed by 4 weeks without). The group hopes for cure of patients with cancers that are only locally advanced. In a phase II study, Schull et al. (2003) tested a combination of cisplatin and docetaxel (Table 33). DiCosimo et al. (2003) reported on eight phase II and III studies in which docetaxel as a single agent and in combination with cisplatin or epirubicin were used. The group looks foreward to presenting docetaxel as a key drug that will improve the treatment of gastric cancer. Park et al. (2004) combined docetaxel and capecitabine in a preliminary study (42 patients), in the hope that a synergistic interaction of the two drugs mediated by taxane-induced up-regulation of thymidine phosphorylase might increase their efficacy (Table 34).
Chemotherapy Regimens for Gastric Cancer Table 31. Fluorouracil/leucovorin (= folinic acid) regimen in current use for gastric cancer: 1 ´ block A ? Radiotherapy with 4500 cGy; simultaneously 1 ´ block B ? 2 ´ block A, monthly (Macdonald 2000, unpublished) a Block A
Agents
Dose
Leucovorin
Mode
Days given
i.v.
Bolus
Days 1, 2, 3, 4, 5
2
i.v.
Bolus
2
i.v.
Bolus
400 mg/m2
i.v.
Bolus
20 mg/m
5-Fluorouracil B
Route 2
Leucovorin
425 mg/m
20 mg/m
5-Fluorouracil
Days 1, 2, 3, 4, and the last 3 days of radiotherapy
a
In cases with incipient stomatitis, prophylactic oral ice cooling for 30 min at the beginning of the 5-FU injection. In cases with diarrhea: immediate therapy with standard medication (loperamide). In cases with massive (severe) diarrhea or ineffectiveness of standard medication: octreotide (Sandostatin) 100 lg twice daily. Caution: doses should be reduced in cases with elevated bilirubin or alkaline phosphatase values, because of the possibility of severe toxicity Table 32. Regimen used by the Italian Group for the study of digestive tract cancer 40 mg/m2
Cisplatin 5-Fluorouracil
500 mg/m2
Epidoxorubicin
35 mg/m2
Table 33. Regimen tested by Schull et al. (2003) in advanced gastric cancers with primising therapeutic index Cisplatin Docetaxel
2
Days 1, 15
2
Days 1, 15
50 mg/m
50 mg/m
Table 34. Combination of docetaxel and capecitabine used in a perliminary study (Park et al. 2004) Protocol: Capecitabine oral Docetaxel
1250 mg/m2 twice daily on days 1±14 75 mg/m2 i.v. on day 1
Overall response rate
60%
Median progression-free survival
5.2 months
Median overall survival
10.5 months
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Therapy Regimens for Colorectal Cancers Adjuvant chemotherapy is the standard of care for patients with stage III disease, as demonstrated in large clinical trials. These studies were carried out with various regimens using 5-FU and folic acid (examples are shown in Tables 35 and 36). Recently Patel et al. (2004) reported the results obtained at Leeds Cancer Centre (UK) with 5fluorouracil and leucovorin (Table 37).
New approaches to the treatment of advanced colorectal cancers have been established. New drugs, such as irinotecan and oxaliplatin, on the one hand and new modes of administration for well-known drugs, e.g. continuous infusion of 5FU and oral administration of the 5-FU prodrug capecitabine, on the other have shown promising benefit for the patients. Frequently used regimens are shown in Tables 38 and 39.
Table 35. 5-Fluorouracil/folic acid treatment weekly,a as given for colorectal cancer at the ªGITSGº (Petrelli et al. 1989) Agent
Dose 2
Folic acid
500 mg/m
2
5-Fluorouracil a b
500 mg/m
Route
Mode
Timing
i.v.
2-h infusion
Days 1, 8, 15
i.v.
b
Days 1, 8, 15
Bolus
The regimen should be repeated weekly for at least 6 weeks Bolus after end of the folic acid infusion
Table 36. 5-Fluorouracil/folic acid (5-FU/FA) monthly,a as given in the Mayo Clinic for colorectal cancers (Poon et al. 1991) Agent
Dose
Route
Mode
Timing
20 mg/m2
i.v.
Bolus
Days 1, 2, 3, 4, 5
425 mg/m2
i.v.
Bolus
Days 1, 2, 3, 4, 5
Folic acid 5-Fluorouracil a
Repetition on days 29±36; if response is achieved six cycles are administered
Table 37. Regimen used a at Leeds Cancer Centre 425 mg/m2 5-FU
as bolus (5 min)
Once weekly
2
45 mg/m dl-leucovorin a
Once weekly
24-week treatment planned; disease-free intervals achieved
Table 38. FOLFIRI (Saltz 2000) Irinotecan Leucovorin 5-FU
125 mg/m2
i.v.
2
i.v.
Bolus
Days 1, 8, 15, 22
2
i.v.
Bolus
Days 1, 8, 15, 22
20 mg/m 500 mg/m
Days 1, 8, 15, 22
Every 6 weeks Table 39. FOLFOX 6 Oxaliplatin
100 mg/m2
i.v.
2h
Days 1, 15
Leucovorin
400 mg/m
2
i.v.
30 min
Days 1, 15
400 mg/m
2
i.v.
Bolus
Days 1, 15
2
Continuous over 48 h
5-FU 5-FU Every 4 weeks
2400 mg/m
Days 1, 15
Therapy Regimens for Colorectal Cancers
Comparison of FOLFOX, IROX, and IFL In a randomized controlled trial comparing the efficiency of irinotecan and oxaliplatin in a total of 795 patients, Goldberg et al. (2004) obtained the results displayed in Table 40. Based on these results, the authors consider FOLFOX the standard therapy for patients with advanced cancer and recommend it as such. The Spanish group (Cassinello et al. 2003) basically combined the Mayo Clinic protocol with parts of the FOLFOX 6 protocol to give the scheme shown in Table 41. Preliminary results were comparable to other regimens. Shields et al. (2004) administered oxaliplatin, 130 mg/m2, on day 1 of each 3-week cycle and capecitabine at a dosage of 1500 mg/m2 per day in two divided doses on days 1±14 of each cycle. This regimen was effective and convenient. Comparisons with other first-line regimens were recommended.
In a phase II trial (E4296) the Eastern Cooperative group (Marsh et al. 2002) gave 5-FU at a dose of 1 mg/m2 p.o. and eniluracil in a dosage of 10 mg/m2 twice daily for 28 days. The tumor response rate was 13.2%. Advantages of irinotecan (CPT-11) and oxaliplatin have been already demonstrated by the French group (Rougier and Mitry 2001) and the Spanish group (Calvo et al. 2002).
New Radioimmunotherapeutic Approach in Treatment of Advanced Colorectal Cancers Radioimmunotherapeutic efforts are still in their early stages. In a phase I study using 90Y-anticarcinoembryonic antigen chimeric T 84.66 combined with 5-FU administration in patients with advanced colorectal cancers both feasibility and possible advantages were demonstrated. However, further experience is necessary before any decision on the real stage value of this therapeutic strategy is possible.
Table 40. Comparison of FOLFOX, IROX, and IFL (Goldberg et al. 2004) Regimen
Time to progression
Response rate
Median survival
FOLFOX (oxaliplatin; 5-FU + leucovorin by infusion)
8.7 months
45%
19.5 months
IROX (irinotecan and oxaliplatin)
6.5 months
35%
17.4 months
IFL (irinotecan and bolus 5-FU + leucovorin)
6 months
31%
15 months
Table 41. Regimen used by the Spanish group (Cassinello et al. 2003) Oxaliplatin 5-FU Leucovorin Every 4 weeks
85 mg/m2
2 h i.v.
Days 1, 7, 14
2
Bolus
Days 1, 7, 14
2
2 h i.v.
Days 1, 7, 14
500 mg/m
20 mg/m
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Therapy Regimens for Neuroendocrine Tumors Neuroendocrine tumors make up a wide group of malignant diseases with a wide spectrum of clinical syndromes depending on the presence of secreted hormones. Their symptoms derive mainly from hormone secretion rather than from bulky tumors. Treatment options are surgery with curative intent, medical options aiming at controlling the symptoms of the various hypersecretion syndromes, and chemotherapy. With a developing armamentarium of antihormone therapies, chemotherapy is reserved for aggressively growing tumors that are resistant, to other treatments. Frequently used chemotherapy regimens are shown in Table 42. Somatostatin analogs are highly effective in the treatment of somatostatin receptor scintigraphy (SRS scan)-positive neuroendocrine tumors. Standard treatment consists in octreotide or longer acting preparations. Another promising therapy option is a targeted therapy with radiolabeled somatostatin analogues in SRS scan-positive tumors, for example 90Y-dotad-Phe1-Tyc3-octreotide. Preliminary results obtained in phase I and II studies were recently published by Waldherr et al. (2001) and are summarized below. In the phase I study, 29 patients with advanced NETs who had received no previous treatment were each given four single doses of 90Y-DOTATOC with ascending activity at intervals of 6 weeks (cumulative dose 6120 Ô 1347 MBq/m2). Stabilization of the disease was achieved in 20 of the 29 patients, partial remission in 2, and minor response in 4; in 3 of the 29 disease progression was observed.
In the phase II study 41 patients with NET (gastroenteropancreatic and bronchial tumors), 82% of them with therapy-resistant or progressive disease, were each treated with four i.v. injections of a total of 6000 MBq/m2 90Y-DOTATOC, administered at intervals of 6 weeks. The overall response rate obtained in the 41 patients was 24%. Of the 41 patients with endocrine pancreatic cancers, 36 achieved a 24-month survival time (76 Ô 16% calculated by the Kaplan-Meier method). The latest results of evaluating 80 patients in a phase II study as summarized by Waldherr et al. (2001) are displayed in Table 43, which gives more details on the results of therapy. In biotherapy of metastasized cases of NET with the somatostatin analogues octreotide or lanreotide, which has been considered the method of choice (Oeberg 1998; Faiss et al. 1996), the following results were obtained: Response rate in patients with endocrine pancreatic tumors (EPT) Rate of stabilization according to Ruszniewski et al. (1996) Biochemical response rates Objective response rates according to WHO (Krenning et al. 1989)
12% 25±30% 40±70% 4±10%
As an alternative to the specific biological treatment option, in the last few years the use of ligands to the somatostatin receptor, i.e., interferona therapy, has also been offered and practiced. The following data have been published in the literature (see Sporn and Greenberg 1990; Ruszniewski et al. 1996; Oeberg 1998): Biochemical response rate Objective response rate
43% 11%
Table 42. Treatment of patients with neuroendocrine tumors of the gastrointestinal tract (Oeberg 1996) Tumor type
First-line treatment
Second-line treatment
Endocrine pancreatic tumors (EPT)
Streptozotocin + 5-FU streptozotocin + doxorubicin
Somatostatin analog Ô interferon-a
Anaplastic endocrine pancreatic tumors (ana-EPT)
Streptozotocin + doxorubicin; alternative cisplatin + etoposide
Cisplatin + etoposide; streptozotocin + 5-FU streptozotocin + IFN-a streptozotocin + somatostatin analog
Midgut carcinoids
Interferon-a + somatostatin
Cisplatin + etoposide
Hindgut carcinoids
Interferon-a Ô somatostatin
Cisplatin + etoposide
Therapy Regimens for Neuroendocrine Tumors Table 43. Tumor response (WHO standard criteria) in both phase II trials (n = 80) in which patients received either 6000 or 7400 MBq/m2 90Y-DOTATOC (EPT endocrine pancreatic tumor, NET neuroendocrine tumor) Complete remissions (CR) n
Partial remissions (PR) n
Stable disease (SD) n
Progressive disease within or after treatment n
Overall tumor response n
CR, PR, SD %
EPT (n = 27)
2
8
13
4
37
86%
Intestinal NET (n = 20)
±
1
18
1
5
95%
Bronchial NET (n = 10)
1
1
7
1
20
90%
NET of unknown origin (n = 17)
±
5
10
2
29
89%
Other (n = 6)
±
±
4
2
0
67%
All (n = 80)
3
15
52
10
23
85%
Classic Therapeutic Regimens and Newer Approaches McKinnon (1993) emphasized the efficacy of octreotide and omeprazole in improving the hormonal symptoms of carcinoids, islet cell tumors, and medullary thyroid carcinoma. Even in 1993, he stated already that newer cytotoxic chemotherapy regimens had increased the response rates over those of traditional therapy and reflected on the benefits of more aggressive surgical treatment of metastatic processes. Because somatostatin analogues and interferons have sometimes failed to control neoplastic growth of neuroendocrine tumors, Bajetta et al. (1998) tried to improve the previously used FDE regimen as summarized in Table 44. Their new regimen was as effective as other comparable schemes used. The group working at the Swedish Endocrine Oncology Unit (Skogeseid 2001) regards streptozotocin and 5-FU or doxorubicin as the first-line treatment regimen for pancreatic endocrine tumors with liver metastases; in contrast, midgut
Table 44. New regimen used by Bajetta et al. (1998) in patients with neuroendocrine tumors 5-Fluorouracil (5-FU) Dacarbazine (DTIC) Epirubicin
500 mg/m2
i.v.
2
i.v.
2
i.v.
200 mg/m
30 mg/m
Days 1, 2, 3 of each 3-week cycle
carcinoids are often resistant to such systemic regimens. Treatment attempts including interferona and somatostatin analogues are thought preferable. Somatostatin receptor-targeted radiotherapy is still under investigation. At the Memorial Sloan Kettering Cancer Center (Brentjens and Saltz 2001), streptozotocin-based combinations are also recommended as standard first-line treatment for metastasizing pancreatic endocrine tumors. The British London group (Kaltsas et al. 2002) used an alternative nitrosourea compound, instead of streptozotocin, namely lomustine (CCNU), in combination with 5-FU for the treatment of neuroendocrine gastroenteropancreatic cancers. Many reports have dealt with the better activity of chemotherapy in pancreatic NETs than in carcinoid tumors, with response rates of 40±60% and 20%, respectively. The standard chemotherapy for pancreatic NETs is doxorubicin (Adriamycin) and streptozotocin or 5-FU and streptozotocin. In more highly malignant tumors response rates of 41±69% have been reached with use of VP16 and CDDP in combination (Rougier and Mitry 2000). Comparative studies by Hatton and Reed (1997) of dacarbazine, vincristine and cyclophosphamide (DOC) and modified schemes (OPEC and DOPEC) revealed comparable, response rates and side effects. The response rates were acceptable at 53%. Oeberg, working in the Department of Endocrine Oncology at the University Hospital, Uppsala,
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Sweden, reported in 1998 on attempts to use biotherapeutic agents, including interferon and somatostatin analogues, in the treatment of slowgrowing neuroendocrine tumors, such as midgut carcinoids. When treatments of this kind fail tumor-targeted irradiation can be attempted. 131-Iodine-MIBG (metaiodobenzylguanidine) and 99YDOTA (1,4,7,10-tetraazacyclododecane N,N(I),N(II),N(III)-tetraacetic acid) octreotide can be used. Oeberg (2003) summarized the treatment options as follows: 1. Surgery as the only chance of cure. 2. Cytoreductive procedures, including radiofrequency ablation, laser treatment, and chemoembolization. 3. Biological treatments including that with cytotoxic agents such as somatostatin analogues and interferon-a (used for slow-growing neoplasms). 4. Combination regimens, including cisplatin, etoposide, streptozotocin, and 5-FU (reserved for treatment of highly proliferative tumors). In view of the possibility of early systemic spread, the aggressive neuroendocrine Merkel cell cancer needs a) Radiation therapy of the nodal chain in special cases b) Chemotherapy. Up to now, no chemotherapy protocol has been shown to improve survival (Lavenda et al. 2001).
The best treatment strategy for nonsinonasal neuroendocrine cancers of the head and neck is postoperative sequential chemotherapy (platinum + etoposide) and radiation therapy (66 Gy) (Barker et al. 2003). Sinonasal undifferentiated carcinomas (SNUC) and sinonasal neuroendocrine carcinomas (SNEC) are rare entities (Smith et al. 2000). No statistically evaluated results are available. These aggressive cancers are surgically resected with inclusion of regional lymph node dissection. Trials of postoperative radiation and/or chemotherapy are in progress.
Neuroendocrine Small-cell Cancers of the Cervix Neuroendocrine small-cell cancers of the cervix (NECC) are rare. The presence or absence of lymph node metastases is the most important variable. These tumors have a high mortality rate despite aggressive surgery with therapeutic intent. According to Abulafia and Sherer (1995) and Boruta et al. (2001), postoperative chemotherapy, e.g. with a platinum + etoposide scheme (PE) or vincristine + doxorubicin (Adriamycin) + cyclophosphamide (VAC), seems to be most likely to improve the survival rate.
Therapy Regimens for Neuroblastoma
Therapy Regimens for Neuroblastoma Secondary therapeutic regimens for neuroblastoma after primary surgical treatment are focused on the high chemo- and radiosensitivity of this tumor type, which generally develops in the first few years of life. The treatment protocol has been developed by the German Society of Pediatric Oncology. Figures 1 and 2 illustrate the strategy.
Fig. 1. Protocol for the Neuroblastoma Study Program " (NB97); therapy regimens worked out by the German Society for Pediatric Oncology and Hematology, started on 1 January 1998; Chairman of the study was Prof. Dr. F. Berthold, Center for Children's Oncology, University Clinics of Cologne, Joseph Stelzmann Straûe 9, 50924 Cologne, Germany (ADR adriamycin, ASCT autologous stem cell support (transplantation), DTIC dacarbazine, ETO etoposide, G-CSF granulocyte colony-stimulating factor, IFO ifosfamide, VCR vincristine, VDS vindesine, Mycn N-myc, not amplified, RT radiotherapy, Sgl. baby, SR standard risk) (Figure see p. 526)
525
526
Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types Fig. 1 Legend see p. 525
Therapy Regimens for Neuroblastoma Fig. 2. Details of treatment blocks in neuroblastoma treatment protocol elaborated by the German Society for Pediatric Oncology
527
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Fig. 2 (continued)
Therapy Regimens for Malignant Melanoma
Therapy Regimens for Malignant Melanoma The usual therapy regimen for treatment of malignant melanomas is shown in Table 45. For more information the reader is also referred to Chapter 25. In recent years, the adjuvant therapy regimen using Interferon (IFN)-a2 b has been tested in many investigations, its efficacy has been confirmed in some (Agarwala and Kirkwood 2002; Wheatley et al. 2002; Molife and Hancock 2002; Pawlik and Sondak 2003; Mohr et al. 2003). However, the biological profile of melanoma cases in which the therapy is efficient is still not clear, and controversies persist (Sabel and Sondak 2003). In Kefford's cumulative studies (2003) high-dose IFN-a (HDI) treatment did not prolong overall survival. In the specific investigations of Schachter et al. (2003) patients treated for stage II B disease fared better than those treated for stage III, regardless of whether the patients had regional micrometastases or palpable metastases. CNS relapses obviously could not be significantly prevented by adjuvant IFN treatment. In recent randomized studies performed by Hauschild et al. (2003), adjuvant combination therapy using IFN-a2 b (3 million IU/m2, days 1±7 in week 1; then three times weekly in weeks 3±6, repeated every 6 weeks) plus IL-2 (IMU/m2 per day on days 1±4 in week 2 of each cycle) for 48 weeks, did not improve disease-free or overall survival. In their analysis, Kleeberg et al. (2004) combined the data from EORTC studies and from the DKG-80-1 trial. No advantage of adjuvant melanoma treatment with rIFN-a2 or rIFN-c was found in the treatment of high-risk melanoma patients. Hancock et al. (2004) treated 674 patients with thick melanomas (> 4 mm), some of whom had locoregional metastases. Low-dose IFN-a2 a (3 mega units) three times per week for 2 years or until recurrence showed no benefit in these high-risk melanoma cases.
Table 45. Interferon as single-agent chemotherapy for malignant melanoma Agent
Dose
Route
Frequency
Interferon-a
5±10 million IU
s.c.
3 ´ weekly for 1±2 years
Hakansson et al. (2003) used cisplatin (30 mg/ m2 i.v., days 1±3), dacarbazine (250 mg/m2 i.v. days 1±3, IFN-a2 b (10 million IU s.c.) on 3 days a week. Their results demonstrated the occurrence of some antitumor reactivity in the majority of cases. Patients with extensive regressive changes in 75±100% of the biopsies analyzed were also found to have a longer overall survival (P = 0.019). In recent years phase I and II studies of treatment with dendritic cell vaccines in patients with disseminated melanomas have been started. Hershey et al.'s (2004) experience has shown that as a source of antigen for DC vaccines autologous lysates of melanomas may be more effective than melanoma peptides. The negative results of chemotherapy efforts in the 1980s, when dacarbazine (DTIC), vincristine, 5-FU, and hydroxyurea were used, have lately been reconfirmed by Kretschmer et al. (2002). In addition, tamoxifen has been found not to inhibit metastasis of malignant melanoma (Lens et al. 2003); nor has HER/neu evaluation of malignant melanomas with a view to trastuzumab (Herceptin) therapy proved successful (Potti et al. 2003). Medalie and Ackerman (2003) recently demanded that the search for the sentinel node be abandoned, having found no advantage of it in terms of survival. However, their argumentation is diffuse and in important points inadequate. Because of changes in and deviations from treatment protocols and the wide variation in initial biological behavior, it is very difficult to establish cumulative judgments from a purely statistical point of view. In locally advanced cancers surgical clearance aimed at R0 resection is essential, because in individual cases survival is absolutely dependent on the surgical intervention alone and this is optimized by the search for the sentinel node(s) and the determination of the local basins that this allows.
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Therapy Regimens for Soft Tissue Tumors Adjuvant chemotherapy for the treatment of sarcoma remains controversial. For advanced disease doxorubicin and ifosfamide are the most active agents. Tables 46±48 show some frequently used regimens. Table 46. Doxorubicin as single-agent chemotherapy for sarcomas Doxorubicin
70 mg/m2
i.v.
Day 1
Every 3 weeks
Table 47. Mesna, Adriamycin, ifosfamide and dacarbazine (MAID) regimen (Elias 1989) for sarcomas a Agent Mesna Doxorubicin Ifosfamide Dacarbazine
Dose 2
2.5 g/m
20 mg/m
2
2
2.5 g/m
300 mg/m
2
Route
Mode
Timing
i.v.
24-h infusion
Days 1, 2, 3, 4
i.v.
24-h infusion
Days 1, 2, 3
i.v.
24-h infusion
Days 1, 2, 3
i.v.
24-h infusion
Days 1, 2, 3
Route
Mode
Timing
i.v.
24-h infusion
Day 1
i.v.
Shorttime
Day 1
Six 3-week cycles Table 48. Mesna, Adriamycin, ifosfamide (Steward 1993) a Agent Ifosfamide
Dose 5 g/m
2 2
Doxorubicin
75 mg/m
Mesna
3g
i.v.
24-h infusion
Day 1
1.5 g
i.v.
24-h infusion
Day 2
Six 3-week cycles See also Steward et al. (1997, 1999) and O'Byrne and Steward (1999)
a
Therapy Regimens for Renal Cell Cancer
Therapy Regimens for Renal Cell Cancer The survival of patients with renal cell cancers is closely correlated with surgical and histopathologically confirmed N0 stage and primarily negative M stage on radiological diagnosis. When regional lymph nodes (sentinel nodes) are cancer infiltrated it must be assumed that systemic spread to lung, brain, liver, and bone marrow has probably already occurred. However, it has not been possible to develop a uniform therapeutic concept for cases in which hematogenous metastatic spread has already been verified. In isolated cases spontaneous regression may indicate an endogenous, obviously immunologically based, defense mechanism. Individual strategies need to be developed in all cases. Such strategies include laser-guided surgery in cases with solitary or few lung metastases, or laser-mediated coagulation of liver metastases. The approach using electrohybridization of dendritic reticulum cells and renal cancer cells of the patient for specific immune stimulation is currently the subject of critical discussion.
Chemotherapy Agents used for adjuvant chemotherapy in this condition are vinblastine and 5-fluorouracil. No remission rates higher than 15% have been obtained with these preparations. At present the use of other drugs for single-agent chemotherapy cannot be expected to yield any improvement on these unsatisfactory results.
Immune Therapy In recent years there have been a great many attempts at immune therapy. · Cytokine therapies using interleukin (IL2) and interferon (IFNa), mostly combined with 5fluorouracil or vinblastine. Retinoids have also been used. · Trials of tumor-infiltrating lymphocytes (TIL) or lymphokine-activated killer cells (LAK). · Cellular vaccinations, peptide vaccinations, or use of dendritic reticulum cells loaded with lysates of cancer cells.
· Immune therapy trials using antibodies against cancer cell structures. · Gene therapy approaches with genetically modified cancer cell vaccines or genetically modified TIL. The scheme most frequently used recently in clinical protocols includes the administration of IL-2, interferon-a, and 5-fluorouracil. The remission rates (including both complete and partial remissions) were 20±40%, but the complete remission rate was under 10%.
Indications for Radiotherapy Radiotherapy is sometimes used in the treatment of bone and soft tissue metastases. When at least 50 Gy is used bone metastases can recede and the areas concerned can be recalcified. Experience has shown that in cases where there is a risk of fracture surgical intervention is indicated.
Studies in Progress and Preliminary Results After ineffective treatment of RCCs, primarily with IFN-a2 b, 5-FU and MCC, after intravenous IL2 therapy metastases disappeared (Nashikimi et al. 2004). Horiguchi and Uchida (2004) emphasize that after IFN-a and IL2 in a case with cancer progression regression of the metastastic process was induced by use of another IFN-a (OIF). Stadler et al. (2003) tested the survival status of 153 patients with metastatic RCC, treated with a combination of gemcitabine and 5-FU (phase I and phase II trials). They suggest that this regimen provides a modest improvement over the results obtained with historical chemotherapy approaches. The following statements have recently been made on IFN therapy for patients with metastatic RCC: 1) IFN-a in combination with IFN-c has no benefit (Dutcher et al. 2003) 2) A combined therapy regimen with IFN-a and IL-2 is no more effective than IL-2 alone (Tourani et al. 2003) 3) IFN-a in combination with thalidomide is active in advanced RCC, but the clinical benefit is small compared with that of IFN alone (Hernberg et al. 2003)
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
4) IL-2 is clinically more active at maximal doses, but does not produce any overall survival benefit (Yang et al. 2003) 5) Subcutaneous IL-2, IFN-a2 b, and 5-FU can be used as second-line treatment after failure of previous immunotherapy (Ravaud et al. 2003; phase II-trial). Genetic heterogeneity of the primaries and formation of different subclones in single RCCs are partly responsible for the low response rates obtained with all adjuvant and palliative therapy regimens used. Therefore, the identification of prognostic factors, that would allow improved individual adjustment to the chosen therapy regimen in each case, is essential (see also Sternberg 2003). For instance, controls of proliferative activity (Ki67, S-Phase etc.) in excised metastatic cancer tissue, with comparison of this with the average proliferative activity in the primary, can give an indication of how successful a therapy might be (Donskov et al. 2004). Antiangiogenic therapy regimens (bevacizumab) have recently been tried in advanced RCC cases (Yang et al. 2003; Sonpavde 2003; Verheul and
Pinedo 2003; Mariani 2003). These studies were started because it was known that mutations in the tumor suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell RCCs. Bevacizumab significantly prolonged the time to disease progression, but the studies of Yang et al. (2003), for example, were stopped after the interim analysis, which met the criteria for early stopping. Preliminary results of a phase III study (Gingras et al. 2001) have shown that AE 941 (Neovastat), which occurs naturally and can be extracted from cartilage, has antiangiogenic properties, even after oral administration (Bukowski 2003). AE 941 inhibits several steps of the angiogenesis process, including matrix metalloproteinase activities, and VEGF signaling pathways. The substance induces endothelial cell apoptosis and tissue-type plasminogen activator activity; thus, it can be suggested that it is a multifunctional antiangiogenic drug (see also Boivin et al. 2002). Among RCC patients, the median survival was significantly longer in those receiving high doses of AE 941 than in those treated with low doses.
Therapy Regimens for Prostate Cancer
Therapy Regimens for Prostate Cancer The standard therapy for prostate cancer is medical ablative hormone therapy with GnRH analogues. Additional antiandrogenic therapy is recommended before the start of medication, as there may be a transitory increase in testosterone levels (ªflare-upº) at the beginning of medication (orchiectomy is an alternative, but is usually not the therapy of first choice, for psychological reasons). Therapy can be given in 3-month or in 1-month cycles (Table 49). Radiation therapy with curative intent would require too-high doses and has been discussed as a cause of serious lesions. At present the ablative and goserelin therapy regimens seem to be the most efficient.
New Reports on Androgen Deprivation Therapy Regimens Akaza (2004) studied the efficacy of adjuvant goserelin either alone or combined with nonsteroidal antiandrogen, in patients with localized or locally advanced prostate cancer. The study included 3500 patients in 5 trials; the follow-up was 4.8±7.1 years. Administration of goserelin resulted in significant improvements in disease-free survival (P £ 0.004) and a decrease in disease-related mortality (DRM). The author concludes that adjuvant goserelin therapy may offer greater clinical benefits than neoadjuvant hormonal treatment.
In a phase III trial (Hanks et al. 2003) concerned with locally advanced carcinoma of the prostate (RTOG 92-02), the addition of long-term adjuvant androgen deprivation (AD) to short-term androgen deprivation (STAD) combined with radiotherapy (RT) for T2c±4 prostate cancers was of significant benefit. In the exploratory subset analysis of patients with Gleason scores of 8±10 long-term adjuvant AD resulted in a survival advantage. Similar experiences concerning survival benefits were recorded by Wachter et al. (2003) in RTOG 8610 and RTOG 8531 for patients with Gleason scores of 6 or lower after short-term neoadjuvant hormonal therapy combined with RT. Lorente et al. (2003) reported that failure of primary surgical treatment is frequently related to cancer-positive surgical margins and/or extracapsular extension. However, neoadjuvant combined androgen blockade (CAB) withdrawal therapy over 6 months can affect tumor volume (TV) and surgical margin status. Pisansky, at the Mayo Clinic (2003), also reports that the combination of neoadjuvant and adjuvant therapeutic regimens with RT reduces TV even in cases with large primaries. This may be helpful in cases with advanced and node-positive prostate cancer. In a phase III study comparing whole-pelvis versus prostate-only RT and neoadjuvant versus adjuvant combined androgen suppression, conducted by the Radiation Therapy Oncology Group 9413 (Roach et al. 2003), neoadjuvant therapy plus whole-pelvis RT had the best results seen in the median follow-up period of 59.5 months. The results are shown in more detail in Table 50. Improvement was achieved in 15% of patients with a
Table 49. Standard therapies for prostate cancer Agent
Dose
Route
Days administered
Goserelin
10.8 mg
s.c.
Day 1, every 3 months
Flutamide
3 ´ 250 mg
p.o.
1 week before start of goserelin
Leuprorelin
10.72 mg
s.c.
Day 1, every 3 months
Flutamide
3 ´ 250 mg
p.o.
1 week before start of leuprorelin
3-Monthly schemes
Monthly scheme (same dosage) Goserelin
3.6 mg
s.c.
Day 1, monthly
Flutamide
3 ´ 250 mg
p.o.
1 week before start of goserelin
533
534
Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types Table 50. Results of phase III study conducted by the Radiation Therapy Oncology group (Roach et al. 2003) Therapy
Progression-free
Neoadjuvant androgen depression vs
52%
Adjuvant androgen depression
49%
Whole-pelvis RT plus neoadjuvant therapy
60%
Prostate-only RT plus neoadjuvant therapy
44%
Whole-pelvis RT plus adjuvant androgen depression
49%
Prostate-only RT plus adjuvant androgen depression
50%
risk of lymph node involvement. However, so far no data indicative of a survival advantage have been presented. All specifications demonstrate that many study results cannot easily be compared. For instance, in a study on 507 patients (Martinez et al. 2003), when external beam radiation therapy (EBRT) and a high dose rate (HDR) brachytherapy boost (transrectal ultrasound guided) were used, the addition of androgen suppression therapy (AST) did not appear to confer a 5-year therapeutic advantage. In addition, the Paris group (Peyromaure et al. 2003) suggests that patients who have a Gleason score of 7 or lower and do not undergo AD are more likely to benefit from salvage RT after radical prostatectomy. In a phase I/II study program at the National Institute of Radiological Science Japan, Akakura and his group (2004) evaluated the efficiency of carbon ion therapy in T1±3 cases. Heavy ion beams possess high linear energy transfer components and a prominent Bragg peak in the human body, resulting in higher relative biological effectiveness and improved dose distribution. Three carbon ion beams were used for irradiation of prostate and seminal vesicles. The total dosage was adjusted to 66 GyE. The therapy blocks were: Stage T1b, T1c, T2a, N0, M0 T2b, T3, pN0 M0 T2b T3 N0/p N1 M0
Therapy Monotherapy Combination with neoadjuvant endocrine therapy Combination with neoadjuvant and adjuvant endocrine therapy
The rates obtained for 5-year overall, cause-specific, clinical recurrence-free, and biochemical recurrence-free survival were 87.7, 94.9, 90.0 and 82.6%. These results are in parts complemented and supported by studies at the Sloan Kettering Cancer Center, New York, from where multimodal treatment strategies combining neoadjuvant hormonal therapy and chemotherapy with radical prostatectomy in high-risk localized prostate cancer are reported. Eastham (2004) reports successful treatment of T3±4 tumors: chemotherapy followed by hormonal therapy has improved patient survival. However, the multimodal programs of neoadjuvant or adjuvant hormonal and/or chemotherapy followed by radical prostatectomy need further evaluation. In the course of a first analysis of the early prostate cancer program of the Prostate Cancer Trialist group (Medical College of Wisconsin, Milwaukee), bicultamide was tested as an immediate therapy regimen alone and as an adjuvant therapy complementing standard care of patients with localized or locally advanced prostate cancer. The drug was administered daily at a dose of 150 mg. Bicultamide led to a highly significant reduction of 42% in the risk of objective progression compared with standard care (P = 0.0001). The overall survival data are not yet complete. Follow-up studies will determine whether there is a clear-cut survival benefit of using bicultamide.
Therapy Regimens for Vulvar Cancer
Therapy Regimens for Vulvar Cancer In the early stages the area that has undergone malignant transformation is delineated in the periphery. The 3% acetic acid test or the Collins test (1% toluidine blue solution, followed by 2% acetic acid) should be used. The morphological diagnosis is made in cytological smears or punch biopsy specimens. Once the delineation is clear, intracutaneous administration of blue dye and/or 99mTc-nanocolloid is helpful in the search for SLNs.
Table 51. Therapy regimens by FIGO staging FIGO (T1)
PT: excision with 10-mm tumor-free margins plus excision of surrounding Vin areas N: complete inguinofemoral lymph node dissection SLN control: can help in decision between uni- or bilateral lymphadenectomy, or for nonradical surgery if SLNs are negative
FIGO II (T2) and III (T3) grade I, no lymphangiosis carcinomatosa (favorable prognosis)
PT: radical vulvectomy N: bilateral inguinofemoral lymphadenectomy
FIGO III (T2) with unfavorable prognosis and FIGO IV (T4a)
PT: preoperative radiotherapy N1: radical bilateral lymphadenectomy N2: radical bilateral inguinofemoral, and possibly also pelvic, lymphadenectomy
Therapy Regimens · Vulvar intraepithelial neoplasia (vin 3). Local excision with 10-mm tumor-free margins, basal histopathological control. · Microinvasive cancer (Ia/pT1a). Local excision with 10-mm tumor-free margins, basal histological control, primary lymphadenectomy. In these cases the SLN search may also detect SLNs in atypical locations. The regimen selected also depends on the FIGO stage of the disease (Table 51). Indications for Postoperative Radiotherapy · Involvement of two or more lymph nodes in metastasis · Breakout of cancer infiltration through lymph node capsule(s) · T3 and T4 cancer · RT extension to pelvic node groups in the presence of extensive inguinal node metastases · Omission of inguinal node dissection Indications for and Limitations of Chemotherapy. Administration of 5-fluorouracil, cisplatin, mitomycin C and bleomycin results in a few months' remission in 30% of patients concerned; in other words, chemotherapy is of only minor significance in vulvar cancer.
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Therapy Regimens for Cervical Cancer All treatment strategies depend on exact cancer staging. This statement can be referred to the extension of the primary and also to any lymph node involvement. The stage-related therapy regimens and N staging, possibly supported by SLN labeling, are summarized in Table 52. Radiotherapy Strategies. Combined contact [high dose rate (HDR) afterloading] radiotherapy with preceding or simultaneous percutaneous radiotherapy and chemotherapy with (for example) cisplatin is mostly used in advanced cervical cancers.
Chemotherapy. Chemotherapy is efficient in the treatment of both squamous cell cancers and adenocarcinomas. Cisplatin, carboplatin, and ifosfamide have all proved effective. These drugs can be combined with anthracyclines, bleomycin or taxanes. Curative effects have been obtained with chemotherapy only when it has been given in combination with radiotherapy. In recent years it has been clearly documented that in locoregional advanced cancer stages without distant metastases (M0) following initial radical surgery, additional combined radiochemotherapy is superior to postoperative radio- or chemotherapy alone, as stated/confirmed by the National Cancer Institute (NCI-USA), the American College of Obstetricians and Gynecologists (ACOG) (2002),
Table 52. Stage-related treatment of cervical cancer: use of SLN labeling in a working formulation Cancer stage
Therapy regimen
SLN labeling
Ia1: Early stromal invasion (£ 3 mm ± no unfavorable parameters, volume £ 400 mm3)
Hysterectomy when family complete
SLN labeling could be helpful to guarantee N negativity to exclude ªearly lymph node involvementº
Ia2: invasion > 3±5 mm: surface extension £ 7 mm
Hysterectomy without resection of parametria, but pelvic lymphadenectomy
SLN labeling and histo- and immunochemical examination might include N-staging
II a
Wertheim-Meigs radical hysterectomy with partial resection of the vagina (tumor-free zone in the circumference £ 2 cm)
SLN labeling can help in N-staging and surgical locoregional cancer clearance and in removal of atypical localized SLNs
II b
In the United States related to NIH Consensus Conference 1997 on Primary Radiation Therapy. In Europe and Japan mostly primary surgical therapy. Strategy: soft tissue plus lymph node removal up to the pelvic wall, and additional para-aortal lymphadenectomy if pelvic nodes are found to be involved on examination of frozen sections
Use of SLN search can help in detection of involved nodes and atypically localized lymph nodes
III
Radiotherapy is the method of choice
SLN search seems to have no significance
IV
Radiotherapy is the method of choice
SLN concept seems to have no significance
Therapy Regimens for Cervical Cancer
the Jefferson Hospital, Philadelphia, USA (2002), the Karolinska Hospital, Stockholm (Sweden) (Einhorn et al. 2003), the Petrov Research Institute of Oncology, Petersburg (2003) and the Neoadjuvant Chemotherapy Metaanalysis Collaboration group (2003). In 2002 Holtz and Dunton, working at Jefferson Hospital, USA, summarized their treatment strategies in the different stages as follows: Stage I A Conization in patients who desire continued fertility, or otherwise standard simple hysterectomy Stage I B, II A Radical hysterectomy or radiation therapy, depending on patient's health and preference
Risk factors after hysterectomy: bulky tumor, deep invasion, involved nodes and margins might warrant adjuvant radiation therapy or chemoirradiation Stage II B, III and IVA Chemoirradiation is current standard According to the experiences of the Hess group (see Weiss et al. 2003), for the combined treatment of pelvic and para-aortal lymph node basins the supine position and technique B (four-field box), or alternatively technique C, also with the supine position (three-field technique), should be preferred, despite the advantages of the prone position on a board for pelvic irradiation alone.
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
Therapy Regimens for Urinary Bladder Cancer Therapeutic strategies applied in the early stages of urinary bladder cancers require surgical and histopathological precision and patience in both doctors and patient, in view of the need for longterm monitoring. (Bear in mind that the entire urothelium can undergo transformation to preneoplastic, genetically based stages that are undetectable on histopathological examination at these early stages.) Therapeutic options that might be considered are summarized in Table 53. Cytostatic prophylactic treatment against intravesical recurrence can help to keep down the frequency of relapses. Especially in cancers with higher degrees of malignancy (grades 2±3), SLN labeling followed by open or laparoscopic node ex-
cision with consistent histopathological control supported by immunohistochemistry (to search for cytokeratin-positive cells) can help in the detection of early regional spread. Perusal of the guidelines of the German Cancer Society yields the list of indications compiled in Table 54. The dosages used in instillation therapy are summarized in Table 55. In cases with a low risk of cancer progression, immune therapy and chemotherapy seem to be equally successful; however, in high-risk cases (grade-3 cancers, lesions with recurrences) intravesical BCG therapy seems to be superior. Up to now there are no consistent standardization protocols. The key points for orientation are related to the induction phases of and maintenance of successful results.
Table 53. Therapeutic options in early stages of urinary bladder cancer Superficially spreading or minimally invasive cancers
Therapeutic strategies
Margins not free
Prognostic factors
Adjuvant instillation therapy
pTis
Electrosection after complete resection: marginal biopsy controls
In T1 stage second resection then cytopathological control
Grade of multifocality of malignancy accompanied by dysplasia accompanying Tis
Administration of immune modulators: BCG alternative doxorubicin, mitomycin
Table 54. Indications for instillation therapy Stage
Grade of malignancy
Primary recurrence
Adjuvant intravesical therapy
pTa
Grade 1
Primary Recurrence
Not indicated Indicated
Grades 2 and 3
Primary and recurrence
Indicated
pTis
Grade 3
Primary
Indicated
pT1
Grades 1 and 2
Primary and recurrence
Indicated
Grade 3
Primary
Indicated
Table 55. Time schedule and dosages for usable instillation therapy regimens Drug used
Dosage
Induction therapy (short term)
Long-term treatment regimens
Bacille Calmette-Gurin (BCG)
1±5 ´ bacilli per week
6 weeks
3 weeks after 3±6 months, then every 6 months for up to 3 years
Doxorubicin
40 mg per week
6±8 weeks
Monthly for 6±12 months
Mitomycin
20 mg per week
6±8 weeks
Therapy Regimens for Urinary Bladder Cancer
Primary nonpapillary carcinoma in situ is mostly grade-3 cancer. There is an 80% risk of recurrence or cancer progression. The primary local excision must therefore be followed by administration of BCG to induce long-term remission, which has been achieved in a maximum of 70% of patients. In most cases with deep muscle infiltration (pT2a) partial or radical cystectomy is the method of choice. It may be that SLN labeling before the operation can be helpful to improve the locoregional clearance. Radiotherapy is indicated in patients who are unsuitable for or refuse cystectomy. In such cases R0 resection must be aimed at. Radiochemotherapy administered before radiotherapy is started may improve the results of therapy in cases with residual cancer following the surgical operation. Adjuvant chemotherapy after radical cystectomy may improve the result of surgical treatment, especially in patients with N1 disease. Various chemotherapy regimens are used in Nand M-positive cases. Polychemotherapy with administration of methotrexate, vinblastine, Adriamycin and cisplatin (M-VAC) is most often used. In phase III studies comparing cisplatin against M-VAC the remission rates were significantly higher in patients treated with M-VAC, but the toxicity of M-VAC is high.
Table 56. Dosages of gemcitabine and cisplatin Gemcitabine Cisplatin
1000 mg/m2 70 mg/m
2
Days 1, 8, 15 Day 1
Four 28-day cycles (Meliani et al. 2003)
Alternatives are gemcitabine, cisplatin, cisplatin + taxol and carboplatin + taxol. Combinations of cisplatin with doxorubicin are used as the first-line regimen. The results of animal experimental research and of preliminary experience in the treatment of human patients with advanced urinary bladder cancer have also led to the use of combinations of cisplatin with gemcitabine (Table 56). In the last few decades many clinical trials have been conducted in the hope of improving the success of therapy in advanced urinary bladder cancer. The main efforts have been concentrated on replacing the frequently used MVAC regimen with new regimens containing gemcitabine, taxanes, and cisplatin. These international investigations are still in progress, so that only the basic schemes and preliminary results are briefly documented in Table 57.
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types Table 57. Preliminary results obtained with new regimens in urinary bladder cancer Reference
Therapy regimen
Result
Segal et al. (2002)
The Canadian Genitourinary Cancer Care Group: use of MVAC and CMV in a randomized trial in deep muscle-invasive bladder cancer
No benefit in overall survival after cystectomy
Rçbben and Otto (2001)
Treatment of T2±4 N0M0 cases with methotrexate vinblastine, Adriamycin, cisplatin (MVAC)
In locally advanced cases no survival advantage after cystectomy and lymphadenectomy. In neoadjuvant treatment some improvement
Winquist et al. (2004)
Neoadjuvant cisplatin in stages II and III
Benefit 6.5%: improved overall survival of patients with muscle-wall-infiltrating cancers
Patton et al. (2002)
Gemcitabine-cisplatin compared with neoadjuvant methotrexate, vinblastine, doxorubicin, cisplatin
Gemcitabine-cisplatin is equally efficacious with less toxicity
Meliani et al. (2003)
pT2b±4 N0±2: Gemcitabine 1000 mg/m2 on days 1, 8, and 15; cisplatin 70 mg/m2 on day 1 of each 28day cycle for four cycles
Well tolerated regimen; no results in terms of overall survival
Culine et al. (2003)
Gemcitabine 1500 mg/m2 oxaliplatin 85 mg/m2 with 2-week interval (G0 regimen)
Safe protocol; no results at time of writing
Sousa-Escadon et al. (2002)
Neoadjuvant treatment of infiltrating urinary bladder cancer with paclitaxel 175 mg/m2 and cisplatin 75 mg/m2 Phase II trial, new cycle every 21 days
Achievement of a vesicle-preservation rate of 52%
Sherif et al. (2002)
T2±4a Nx, M0: cisplatin-methotrexate
Estimated 5-year survival 53%; no statistical survival benefit
de Wit for European Organization for Research and Treatment (2003)
Comparison of different US and European study results with cisplatin, methotrexate, vinblastine (976 cases)
10% absolute improvement in survival; trial results 5.5% survival difference at 3 years in chemotherapy arm
Pectasides et al. (2002)
Docetaxel 35 mg/m2 plus gemcitabine 800 mg/ m2, and cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks
Highly effective treatment protocol for advanced TCC. Further phase III study recommended
Meluch et al. (2001)
Phase II trial of the Minnie Perl Cancer Research Network on unresectable cancer: paclitaxel 200 mg/m2 i.v. over 1 h; gemcitabine 1000 mg/m2 i.v. days 1, 8, 15 repeated every 21 days (six courses)
Regimen active and well tolerated; response rates and duration compare favorably with those of other active, first-line regimens
Sternberg et al. (2001)
Gemcitabine 2500±3000 mg/m2 and paclitaxel 150 mg/m2 every 2 weeks
Regimen is highly active, produces objective and lasting responses Two-week schedule is well tolerated
Hagan et al. (2003)
Phase I±II selective bladder conservation using TURBT, followed by methotrexate, cisplatin, vinblastine (MCV) plus twice-daily accelerated irradiation
Complete response 75%; adjuvant CT poorly tolerated Overall survival comparable to that with other regimens
Kaasinen et al. (2003)
One year of BCG (120 mg) monotherapy compared with alternating BCG and mitomycin (4 mg)
Monotherapy with BCG for 1 year superior to alternating regimen
New Approaches to Halting Cancer Cell Spread by Immunological Blockade of Neoangiogenesis
Adjuvant Therapy for Prevention of Severe Neutropenia, Possibly Followed by Infections
New Approaches to Halting Cancer Cell Spread by Immunological Blockade of Neoangiogenesis
Most cytostatic therapy regimens cause bone marrow depression, in some cases with severe granulocytopenia, which can be followed by upcoming infectious diseases. Therefore, 24±48 h after administration of cytostatics, Neupogen (r-met-HuG-CSF, filgrastim) is usually given by s.c. injection to stop the drop in granulocytes; in total 4±5 injections of Neupogen (0.5 million units (5 lg) per kilogram of bodyweight per day) are necessary. Two years ago the successor drug to Neupogen, Neulasta (pegfilgrastim), produced and dealed by Amgen, became available in the US, and it is now also on the market in Europe. This drug induces granulopoiesis with normalization of the peripheral values with administration of a single dose (6 mg, supplied ready for injection in a one-way syringe) by reaching maximal plasma concentration within 72 h. The drug has a longlasting depot effect. It is not excreted via the kidneys, but degraded by receptor-mediated endocytosis. Degradation of Neulasta (internalization) occurs on neutrophil granulocytes with intracellular destruction. During phases of granulocyte depression special caution care must be taken to treat infection, and especially upcoming pulmonary and urinary tract infections, with adequate antibiotics, if possible after resistance analysis.
Approaches in recent years have revealed that the VEG-blocking substance Avastin, produced by Roche, stops neoangiogenesis, especially during the progression of colorectal cancers. In contrast, it has not been possible to demonstrate this blocking effect clearly in breast cancer cases. It is still not known in which other cancer types this neoangiogenesis-blocking substance can be successfully used for adjuvant and palliative treatment.
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types Pisters KM (2001) Adjuvant and neoadjuvant therapy for early stage non-small cell lung cancer. Semin Oncol 28(4 Suppl):23 Pisters KM, Ginsberg RJ, Giroux DJ, Putnam JB Jr, Kris MG, Johnson DH, Roberts JR, Mault J, Crowley JJ, Bunn PA Jr (2000) Induction chemotherapy before surgery for earlystage lung cancer: a novel approach. J Thorac Cardiovasc Surg 119(3):429±439 Piver MS, Rutledge F, Smith JP (1974) Five classes of extended hysterectomy for women with cervical cancer. Obstet Gynecol 44:265±272 Polee MB, Hop WC, Kok TC, Eskens FA, van der Burg ME, Splinter TA, Siersema PD, Tilanus HW, Stoter G, van der Gaast A (2003) Prognostic factors for survival in patients with advanced oesophageal cancer treated with cisplatinbased combination chemotherapy. Br J Cancer 89(11): 2045±2050 Poon MA, O'Connell MJ, Wieland HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Maillieard JA (1991) Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9(11): 1967±1972 Pottgen C, Eberhardt W, Bildat S, Stuben G, Stamatis G, Hillejan L, Sohrab S, Teschler H, Seeber S, Sack H, Stuschke M (2002) Induction chemotherapy followed by concurrent chemotherapy and definitive high-dose radiotherapy for patients with locally advanced non-small-cell lung cancer (stages III a/III b): a pilot phase I/II trial. Ann Oncol 13(3):403±411 Potti A, Hille R, Koch M (2003) Immunohistochemical determination of HER-2/neu in malignant melanoma. Anticancer Res 23(5A):4067±4069 Ravaud A, Trufflandier N, Ferriere JM, Debled M, Palussiere J, Cany L, Gaston R, Mathoulin-Pelissier S, Bui BN (2003) Subcutaneous interleukin-2, interferon alpha-2b and 5-fluorouracil in metastatic renal cell carcinoma as second-line treatment after failure of previous immunotherapy: a phase II trial. Br J Cancer 89(12):2213±2218 Reboul FL (2004) Radiotherapy and chemotherapy in locally advanced non-small-lung cancer: preclinical and early clinical data. Hematol Oncol Clin North Am 18(1):41±53 Recchia F, Sica G, DeFilippis S, Rosselli M, Saggio G, Guerriero G, Pompili P, Rea S (2000) Cisplatin, vindesine, mitomycin-C and 13-cis retinoic acid in the treatment of advanced non small cell lung cancer. A phase II pilot study. Anticancer Res 20(3 B):1985±1990 Reck M, von Pawel J, Macha HN, Kaukel E, Deppermann KM, Bonnet R, Ulm K, Hessler S, Gatzemeier U (2003) Randomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristine in patients with small-cell lung cancer. J Natl Cancer Inst 95(15):1118±1127 Renard A, Noel G, Mazeron JJ (2000) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non small-cell lung cancer. Cancer Radiother 4(4):317±318 Roach M 3rd (2003) Hormonal therapy and radiotherapy for localized prostate cancer: who, where and how long? J Urol 170(6 Pt 2):S35±40; discussion S40±41 Rosell R (2002) Multicenter Trial of the Spanish Lung Cancer Study Group and the SAKK (Swiss Cancer Society)
(arm A: preoperative, arm C: adjuvant). Personal announcement; see also Rosell et al (2002) Rosell R, Gomez-Codina J, Camps C, Maestre J, Padille J, Canto A, Mate JL, Li S, Roig J, Olayabal A et al (1994) A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with nonsmall-cell lung cancer. N Engl J Med 330(3):153±158 Rosell R, Martin C, Balana C (1999) Ifosfamide in nonsmall-cell lung cancer. Ann Oncol 10(Suppl 5):S25±28 Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemassani A, Bogaerts J, Gallant G (2002) Phase III randomised trial comparing paclitaxel/ carboplatin with paclitaxel/cisplatin in patients with advanced non small cell lung cancer: a comparative multinational trial. Ann Oncol 13(10):1539±1549 Ross PJ, Rao S, Cunningham D (1998) Chemotherapy of oesophago-gastric cancer. Pathol Oncol Res 4(2):87±95 Ross PJ, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickish T, Lofts F, Norman A (2002) Prospective randomized trial comparing mitomycin, cisplatin, and protracted venousinfusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20(8):1996±2004 Rougier P, Mitry E (2000) Chemotherapy in the treatment of neuroendocrine malignant tumors. Digestion 62(Suppl 1):73±78 Rougier P, Mitry E (2001) Review of the role of CPT-11 in the treatment of colorectal cancer. Clin Colorectal Cancer 1(2):87±94 Rçbben H, Otto T (2001) Locally advanced or metastatic bladder carcinoma. Current aspects of therapy. Urologe A 40(6):464±467 Ruszniewski P, Ducreux M, Chayvialle JA, Blumberg J, Coarec D, Michel H, Raymond JM, Dupas JL, Gouerou H, Jian R (1996) Treatment of the carcinoid syndrome with long acting somatostatin analogue lanreotide: a prospective study in 39 patients. Gut 39:279±283 Sabel MS, Sondak VK (2003) Is there a role for adjuvant high-dose interferon-alpha-2b in the management of melanoma? Drugs 63(11):1053±1058 Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343(13):905±914 Schachter J, Brenner B, Fenig E, Gutman R, Sulkes A, Gutman H (2003) Patterns of failure in patients with malignant melanoma treated with high-dose interferon-alpha 2b in the adjuvant setting. Melanoma Res 13(1):93±96 Schiller JH, Harrington D, Sandler A, Belani C, Langer C, Krook J, Johnson DH (2000) Randomized phase III trial of four chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). ASCO 2000: abs 2 Schiller JH (2001) Current standards of care in small-cell and non-small-cell lung cancer. Oncol 61(Suppl 1):3±13 Schull B, Kornek GV, Schmid K, Raderer M, Hejna M, Lenauer A, Depisch D, Lang F, Scheithauer W (2003) Effective combination chemotherapy with bimonthly docetaxel and cisplatin with or without hematopoietic growth factor support in patients with advanced gastroesophageal cancer. Oncology 65(3):211±217
References and Recommended Further Reading Sculier JP, Lafitte JJ, Berghmans T, Thiriaux J, Lecomte J, Efremidis A, Ninane V, Paesmans M, Mommen P, Klastersky J (2000) A phase II trial testing gemcitabine as second-line chemotherapy for non small cell lung cancer. The European Lung Cancer Working Party. Lung Cancer 29:67±73 Scully RE, Bonfiglio TA, Kurman RJ, Silverberg SG, Wilkinson EJ (1994) Histological typing of female genital tract tumours, 2nd edn (WHO International histological classification of tumours). Springer, Berlin Heidelberg New York Segal R, Winquist E, Lukka H, Chin JL, Brundage M, Markman BR (2002) Cancer Care Ontario Practice Guidelines Initiative Genitourinary Cancer Disease Site Group: Adjuvant chemotherapy for deep muscle-invasive transitional cell bladder carcinoma ± a practice guideline. Can J Urol 9(5):1625±1633 Sherif A, Rintala E, Mestad O, Nilsson J, Holmberg L, Nilsson S, Malmstrom PU on behalf of the Nordic Urothelial Cancer Group (2002) Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer ± Nordic Cystectomy Trial 2. Scand J Urol Nephrol 36(6):419±425 Shields AF, Zalupski MM, Marshall JL, Meropol NJ (2004) Treatment of advanced colorectal carcinoma with oxaliplatin and capecitabine: a phase II trial. Cancer 100(3): 531±537 Shiga H, Rasmussen AA, Johnston PG, Langmacher M, Baylor A, Lee M, Cullen KJ (2002) Prognostic value of c-erb B2 and other markers in patients treated with chemotheray for recurrent head and neck cancer. Head Neck 22(6):599±608 Shimizu Y, Kato M, Yamamoto J, Nakagawa S, Tsukagoshi H, Fujita M, Hosokawa M, Asaka M (2004) EMR combined with chemoradiotherapy: a novel treatment for superficial esophageal squamous-cell carcinoma. Gastrointest Endosc 59(2):199±204 Siena S, Piccart MJ, Holmes FA, Glaspy J, Hackett J, Renwick JJ (2003) A combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily filgrastim in patients with stage II±IV breast cancer. Oncol Rep 10:715±724 Skogseid B (2001) Nonsurgical treatment of advanced malignant neuroendocrine pancreatic tumors and midgut carcinoids. World J Surg 25(6):700±703 Slamon et al (abstract) (1999) Cited in Cobleigh (2000) Results from the pivotal anti-HER2 therapy chemotherapeutic combination study. ECCO, abs 1261 Smith JA (2003) Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. Roach M 3rd, De Silvio M, Lawton C, Uhl V, Machtay M, Seider MJ, Rotman M, Jones C, Asbell SO, Valicenti RK, Han S, Thomas CR Jr, Shipley WS, Radiation Therapy Oncology Group 9413, University of California San Francisco, San Francisco, CA. J Clin Oncol 21:1904±1911. Urol Oncol 21(6):482 Smith SR, Som P, Fahmy A, Lawson W, Sacks S, Brandwein M (2000) A Clinicopathological study of sinonasal neuroendocrine carcinoma and sinonasal undifferentiated carcinoma. Laryngoscope 110(10 Pt 1):1617±1622 Sonpavde G (2003) Bevacizumab in renal-cell cancer. N Engl J Med 349(17):1674
Sousa-Escandon A, Vazquez S, Quintero-Aldana G, Picallo JA, Neira J, Garcia-Novio F, Mateo A, Rico M, Mel JR (2002) Neo-adjuvant treatment of infiltrating transitional-cell carcinoma of the bladder with paclitaxel and cisplatin: a phase II trial. Int J Urol 9(3):162±166 Spencer S, Wheeler R, Peters G, Meredith R, Beenken S, Nabel L, Wooten A, Soong SJ, Salter M (2003) Phase 1 trial of combined chemotherapy and reirradiation for recurrent unresectable head and neck cancer. Head Neck 25(2):118±122 Sporn RJ, Greenberg BR (1990) Empiric chemotherapy in patients with carcinoma of unknown primary site. Am J Med 88(1):49±55 Stadler WM, Huo D, George C, Yang X, Ryan CW, Karrison T, Zimmermann TM, Vogelzan NJ (2003) Prognostic factors for survival with gemcitabine plus 5-fluorouracil based regimen for metastatic renal cancer. J Urol 170(4 Pt 1):1141±1145 Sternberg CN (2003) Metastatic renal cell cancer treatments. Drugs Today (Barcelona) 39(Suppl C):39±59 Sternberg CN, Calabro F, Pizzocaro G, Marini L, Schnetzer S, Sella A (2001) Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer 92(12):2993±2998 Steward WP (1997) Chemotherapy for metastatic soft tissue sarcomas. Cancer Treat Res 91:157±172 Steward WP, Verweij J, Somers R, Spooner D, Kerbrat P, Clavel M, Crowther D, Rouesse J, Tursz T, Tueni E et al (1993 a) The use of recombinant human granulocytemacrophage colony-stimulating factor with combination chemotherapy in the treatment of advanced adult softtissue sarcomas: early results from the EORTC Soft-Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 31(Suppl 2):S241±244 Steward WP, Verweij J, Somers R, Spooner D, Kerbrat P, Clavel M, Crowther D, Rouesse J, Tursz T, Tueni E et al (1993) Granulocyte-macrophage colony-stimulating factor allows safe escalation of dose-intensity of chemotherapy in metastatic adult soft tissue sarcomas: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 11(1):15±21 Terando A, Sabel MS, Sondak VK (2003) Melanoma: adjuvant therapy and other treatment options. Curr Treat Options Oncol 4(3):187±199 The ATAC (Armidex, Tamoxifen Alone or in Combination) Trialists' Group (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. The Lancet Vol 359, June 22, www.thelancet.com Thomas M, Rube C, Semik M, von Eiff M, Freitag L, Macha HN, Wagner W, Klink F, Scheld HH, Willich N, Berdel WE, Junker K (1999) Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer. J Clin Oncol 17(4):1185 Tonato M (2002) Consensus conference on medical treatment of non-small cell lung cancer: adjuvant treatment. Lung Cancer 38(Suppl 3):S37±42 Tourani JM, Pfister C, Tubiana N, Ouldkaci M, Prevot G, Lucas V, Oudard S, Malet M, Cottu P, Ferrero JM, Mayeur
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Chapter 33 Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment of the Discussed Tumor Types D, Rixe O, Sun XS, Bernard O, Andre T, Tournigand C, Muracciole X, Guilhot J (2003) Subcutaneous Administration Propeukin Program Cooperative Group: Subcutaneous interleukin-2 and interferon alpha administration in patients with metastatic renal cell carcinoma: final results of SCAPP III, a large, multicenter, phase II, nonrandomized study swith sequential analysis design. J Clin Oncol 21:3987±3994 Treat J (2003) Weekly topotecan in the management of lung cancer. Lung Cancer 41(Suppl 4):S27±31 Trump DL (2002, 2003) Biculatamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program. See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, Chodak G, Montie J, Tyrrell C, Wallace DM, Delaere KP, Vaage S, Tammela TL, Lukkarinen OM, Persson BE, Carroll K, Kolvenbag GJ, Casodex Ear Prostate Cancer Trialist Group, Medical College of Wisconsin, Milwaukee, WI. J Urol 168:429±435, 2002. Urol Oncol 21(5):408±409 Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, Wagner H, Aisner S, Johnson DH (1999) Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340(4): 265±271 Urba SG, Chansky K, Van Veldhuizen PJ, Pluenneke RE, Benedetti JK, Macdonald JS, Abbruzzese JL for the Southwest Oncology Group (2004) Gemcitabine and cisplatin for patients with metastatic or recurrent esophageal carcinoma: a Southwest Oncology Group Study. Invest New Drugs 22(1):91±97 Urba SG, Orringer MB, Ianettonni M, Hayman JA, Satoru H (2003) Concurrent cisplatin, paclitaxel, and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma. Cancer 98(10):2177±2183 Valentino J, Spring PM, Shane M, Arnold SM, Regine WF (2002) Interval pathologic assessment in patients treated with concurrent hyperfractionated radiation and intraarterial cisplatin (HYPERRADPLAT). Head Neck 24(6): 539±544 Verheul HM, Pinedo HM (2003) Vascular endothelial growth factor and its inhibitors. Drugs Today (Barcelona) 39(Suppl C):81±93 Vogel CL, Franco SX (2003) Clinical experience with trastuzumab (herceptin). Breast J 9(6):452±462 Vogel C, Cobleigh M, Tripathy D, Harris L, Fehrenbacher L, Slamon D, Ash M, Novotny W, Stewart S, Shak S (2000) First-line non-hormonal treatment of women with Her2overexpressing metastatic breast cancer with herceptin (Trastuzumab, humanized anti-HER2-antibody). ASCO meeting 2000, Aventure, Fla, abstract 275 Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in firstline treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719±726 Vose J, Crump M, Lazarus H, Emmanouilides C, Schenkein D, Moore J, Frankel S, Flinn I, Lovelace W, Hackett J, Liang BC (2003) Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol 21(3): 514±519
Wachter S, Wachter-Gerstner N, Potter R (2003) Neoadjuvant hormonal treatment and radiotherapy for prostate cancer. Oncology 65(Suppl 1):29±33 Wagner G (ed) (1993) Tumorlocalisationsschlçssel, 5th edn. Springer, Berlin Heidelberg New York Waldherr C, Schumacher T, Pless M, Crazzolara A, Maecke HR, Nitzsche EU, Haldemann A, Mçller-Brand J (2001) Radiopeptide transmitted internal irradiation of non-iodophil thyroid cancer and conventionally untreatable medullary thyroid cancer using. Nucl Med Commun 22(6):673±678 Waldherr C, Schumacher T, Meacke HR, Nitzsche EU, Mçller-Brand J (2001) Radionuclide therapy of somatostatinreceptor-positive tumors using (90-Y-DOTA)-D-Phe1Tyr3-octreotide (90Y-DOTATOC): the Basle experience. Schweiz Krebs Bull 21:65±68 Weiss E, Richter S, Hess CF (2003) Radiation therapy of the pelvic and paraaortic lymph nodes in cervical carcinoma: a prospective three-dimensional analysis of patient positioning and treatment technique. Radiother Oncol 68(1):41±49 Weissbach L, Miller K (eds) (1998) Diagnostische und therapeutische Standards in der Urologischen Onkologie. Zuckschwerdt, Munich Berne Vienna New York Weissbach L, Miller K (1998) Leitlinien zur Diagnostik und Therapie des Harnblasenkarzinoms. Urologe (A) 37:440± 457 Wheatley K, Ives N, Hancock B, Gore M (2002) Interferon as adjuvant treatment for melanoma. Lancet 360(9336): 878 Wieder HA, Brucher BL, Zimmermann F, Becker K, Lordick F, Beer A, Schwaiger M, Fink U, Siewert JR, Stein HJ, Weber WA (2004) Time course of tumor metabolic activity during chemotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 22(5):900±908 Wilke H, Achterrath W, Schmoll HJ, Gunzer U, Preusser P, Lenaz L (1988) Etoposide and split-dose cisplatin in small-cell lung cancer. Am J Clin Oncol 11(5):572±578 Winer EP, Hudis C, Burstein HJ, Bryant J, Chlebowski RT, Ingle JN, Edge SB, Mamounas EP, Gelber R, Gralow J, Goldstein LJ, Pritchard KI, Braun S, Cobleigh MA, Langer AS, Perotti J, Powles TJ, Whelan TJ, Browman GP (2003) American Society of Clinical Oncology: Technology assessment working group update: use of aromatase inhibitors in the adjuvant setting. J Clin Oncol 21(13): 2597±2599 Winer EP, Hudis C, Burstein HJ, Chlebowski RT, Ingle JN, Edge SB, Mamounas EP, Gralow J, Goldstein LJ, Pritchard KI, Braun S, Cobleigh MA, Langer AS, Perotti J, Powles TJ, Whelan TJ, Browman GP (2002) American Society of Clinical Oncology: Technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol 20(15):3317±3327 Winquist E, Kirchner TS, Segal R, Chin J, Lukka H for Genitourinary Cancer Disease Site Group, Cancer Care Ontario Program in Evidence-based Care Practice Guidelines Initiative (2004) Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. J Urol 171(2 Pt 1):561±569 Wittekind C, Wagner G (1997) TNM-Klassifikation maligner Tumoren, 5th edn. Springer, Berlin Heidelberg New York
References and Recommended Further Reading Wong JY, Shibata S, Williams LE, Kwok CS, Liu A, Chu DZ, Yamauchi DM, Wilczynski S, Ikle DN, Wu AM, Yazaki PJ, Shively JE, Doroshow JH, Raubitschek AA (2002) A Phase I trial of 90 Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer. Clin Cancer Res 9(16 Pt 1):5842±5852 Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349(5):427±434
For inquiries and to obtain contact details of speakers who presented papers at ASCO Meetings and their coauthors contact ASCO Publication Inquiries (Tel.: 888-2733508 (within the USA) or +1-703-5191430 (from outside the USA); Fax: +1-703-5188157; e-mail:
[email protected]; websites: ASCO: www.asco.org; JCO: www.jco.org)
Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Roger-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA (2003) Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21(16):3127±3132 Yanik GA, Levine JE, Matthay KK, Sisson JC, Shulkin BL, Shapiro B, Hubers D, Spalding S, Braun T, Ferrara JL, Hutchinson RJ (2002) Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. J Clin Oncol 15, 20(8):2142± 2149
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Subject Index
A ABBI device 169±173, 188 ± advantages 173 ± control instrument 174 ± puncture device 172 AC scheme (anthracycline / anthraquinone) 505 acinic cell cancer 296 ACO II (adriamycin, cyclophosphamide, vincristine) 513 acoustics, quality criteria of gamma probes 113, 118 acquisition protocol 34 ACR (American College of Radiology), BI-RADS lexicon 183±188 adenoid cystic cancer 293, 295 adenolymphoma 293, 295 adenoma, pleomorphic 293 adenosis, sclerosing 163 ADH (atypical ductal hyperplasia) 137, 188 adjuvant treatment, therapy regimens used in 503±541 ± adjuvant systemic treatment 504 adrenal gland 426 adrenalectomy 484 adrenal-sparing surgery 492 adriamycin 328 ± combined therapy modalities ± ± adriamycin, cyclophosphamide and paclitaxel 508 ± ± adriamycin, cyclophosphamide and vincristine (ACO II) 513 ± ± mesna, adriamycin and ifosfamide 530 AEG scheme 372 albumin, 99mTc-colloidal 44, 49, 60 allergic reaction 90 American Joint Committee on Cancer Staging 360 amifostine ± prevention of nephrotoxicity 503 ± reduction of toxicity 516 amyloid, neuroendocrine 266, 274 anaphylactic reaction 92 anaplastic cancer, salivary gland tumors 297 anastrozole / letrozole 504, 506 ± c-erb B1 and B2 overexpressing cases 504
± effectiveness 506 ± phase-shifted contralateral breast cancer 506 ± in postmenopausal advanced breast cancer 506 ± superior to tamoxifen 507 ± tamoxifen vs. letrozole: c-erb B1 and / or B2-positive cancer cases 507 androgen ± combined androgen blockade (CAB) 533 ± short term androgen deprivation (STAD) 533 angiogenesis, breast cancer, enhancing factors 220, 222 angiolipoma 493 anthracyclin containing regimen 504 ± AC scheme (anthracycline / anthraquinone) 505 anti-HER2-therapy 507 ± combined therapy modalities, antiHER2 plus cytostatics 507 ± immunoresponse stimulation 507 ± inhibiting tumorgrowth 507 ± results with first-line anti-HER2monotherapy 507 ± study programs 507 antiangiogenic drugs in combination with chemotherapeutica 516 antibodies, used for special diagnosis ± anti-CEA 426 ± anti-pancytokeratin (MNF 116) 147 ± CD20 89 ± 9G6, directed to extracellular domain of p185 27 ± labeled 26 ± monoclonal 68, 394, 395 ± polyclonal 101 ± somatostatin receptor 24, 102 antihormon therapies, neuroendocrine tumors 522 antimony sulfide colloid 98 aorto-pulmonary window 321, 322 APAAP technique 230 APUD cells 401 areola, eczema 227 aspergillosis 306
Assmann foci, in lung tuberculosis 302 ATAC-tamoxifen studies 506 attenuation correction 33 avastin, VEG-blocking substance 541 Augsburg group 86 axillary lymph node ± involvment 52 ± preoperative diagnosis 155±159 ± revision, axillary 26, 182, 244 ± ± avoidance 4, 48, 93, 129, 130 ± ± complications 39, 178 ± ± extended 95 ± ± preoperative decision 158 B background count, mean 127 balanced pressure, guarantee, SLN concept 133 basalioma, pigmented 331 battery-supported device, gamma probe 91 benefit, sentinel lymph node investigation 247 berry picking in thyroid cancer clearance 278, 280 bevacizumab, antiangiogenic therapy regimen 532 BIO PSYS puncture system 163, 165, 166 biopsy ± aspiration 42 ± core needle 134±136 ± ± automated percutaneous 136 ± ± selective use 133 ± ± stereotactic (SCNB) 132, 136 ± ± vacuum-assisted 132, 134, 164 ± endoscopic 311 ± instrumentation, advanced 132 ± minimally invasive excision 169±173 ± punch 42 ± sonographically guided 258 ± stereotactic 131 ± stereotactic / excision, ratio 129 ± systems 162±169 ± techniques, comparison 136±138 ± tru-cut 74 ± ultrasound-guided 456, 457 ± video-assisted thoracoscopic 302
554
Subject Index ± zylinder ± ± extraction, steps 161 ± ± radiographic examination 167 BI-RADS (Breast Imaging Reporting and Data System) ± ACR lexicon 183±188 ± categories 183 ± ± III / IV 162 ± ± V 208 ± and histological result 184 Birch-Hirschfeld, nephroblastoma 427 bladder cancer (see urinary bladder cancer) 17, 481±483, 538±539 blaukernige kindliche Tumoren 427 bleeding, avoidance 93 blocking plates 94 blood vessel, iatrogenic opening 65 blue dye 5, 12, 39, 42, 81, 327 ± injection technique 62±64 ± isosulfan 15 ± malignant melanoma 340, 351±353 ± mapping, critical points 90 ± staining method, timing 91 ± thyroid cancer 257 ± vulva cancer 433 bombesin 425 Bonadonna, classical CMF regimen 504 bone marrow ± smears 54 ± toxicity 503 bourgeonnement in early stage of carcinoid development 401 Bowen's disease 440 breast ± cancer 11, 23, 44, 71±76, 500, 504±508 ± ± actual concept, alternatives 248 ± ± anastrozole (see there) 506 ± ± ± in breast cancer prevention 506 ± ± ± in early stages of breast cancer 506 ± ± ± in postmenopausal advanced breast cancer 506 ± ± bilaterality 195, 209, 212 ± ± centrally localized primary 239 ± ± classification according to risk factors 504 ± ± comedocarcinoma 221, 226 ± ± deep seated primary 240 ± ± development, sentinel lymph node concept 177 ± ± diagnosis ± ± ± before sentinel node labeling 131±138, 189 ± ± confirmation 74 ± ± principles in diagnosis 140 ± ± diffusely growing 73 ± ± ductal carcinoma in situ (DCIS) 137, 179, 188, 220±228 ± ± ± sentinel node labeling 190, 191
± ± ductal invasive 213, 216 ± ± early cancer 73 ± ± ethical aspects in treatment 249, 250 ± ± fine-needle aspiration cytology 131, 132 ± ± grading 194, 196 ± ± hematogenous spread 137 ± ± Indian file pattern 131, 195 ± ± inflammatory 47, 191 ± ± injection principles 73, 74 ± ± International Breast Cancer Intervention Study (IBIS-1) 506 ± ± intraductal 73 ± ± invasive lobular 74, 131, 197 ± ± large-cell 131, 192, 197 ± ± large primary 244±246 ± ± lateral quadrant 236 ± ± legal aspects 249, 250 ± ± lobular 195, 236 ± ± local disease, progress 219 ± ± lymphatic spread, figure 66 ± ± MAGE-A3 marker function 46 ± ± medullary 195, 217, 218, 221, 225 ± ± metastases ± ± ± detection, immunohistochemical markers 200±205 ± ± ± rate, table 53 ± ± microcarcinoma 73, 74, 171, 216 ± ± ± sentinel node labeling 190, 191 ± ± micropapillary low-grade 193 ± ± mucinous 193 ± ± multicentricity 181, 195, 205± 220, 228, 236±239 ± ± multifocality 181, 195, 205±220, 228, 236±239 ± ± multilocular 212 ± ± noninvasive 181 ± ± oncogene activity 197, 198 ± ± palpable / nonpalpable 72, 73, 139, 236 ± ± papillary intraductal 191, 224 ± ± PET screening for sentinel lymph node and metastasis 182, 183 ± ± phase-shifted contralateral breast cancer 507 ± ± preoperative detection, multifocality / multicentricity 133 ± ± primary, examination 191, 192 ± ± prognostic factors, unfavorable 250 ± ± radiodiagnostic systems 179, 180 ± ± recurrence, reduction 219 ± ± regional lymph node, involvment 52±54 ± ± retroareolar 48 ± ± retromammillary 74 ± ± risk factors 504 ± ± sentinel lymph node ± ± ± biopsy, indication 178
± ± ± investigation, false-negative results 248, 249 ± ± sharply delineated, differential diagnosis 243, 244 ± ± spicule-like extension 212 ± ± stage 179 ± ± staging, role of PET 181, 182 ± ± suppressor genes, mutated 197 ± ± treatment / therapy regimens 248±249, 504±508 ± ± ± chemotherapy and endocrine therapy regimens 504±507 ± ± ± tamoxifen, pros and contras for breast cancer prevention 506 ± ± triple diagnosis 72 ± ± tubular subtype 192 ± ± tumor typing 194, 195 ± ± ulcerated 211 ± ± unfavorable / incalculable prognosis 192±194 ± compression, adjustment in radioimaging 170 ± circumference 163 ± sentinel lymph node 177 Breslow stages / melanoma 23, 76, 501 ± prognostic risk groups 333 bronchoscopy 308 C cadherin, N-cadherin 490 calcitonin 266 ± immunohistochemical staining 272 calcitoninoma 414 Cameco, syringe 139, 259 cancer ± cell ± ± dissociation 234 ± ± drainage 52 ± ± necrotic / apoptotic 331 ± ± single, detection in lymph node 231 ± cell-like cell elements 234 ± Kettering, Sloan: Cancer Center, New York 534 ± with special ± ± localisation 512 ± ± oncogene overexpression and mutated suppressorgene expression (c-erb B2, p53) 512 capecitabine and docetaxel 518 carboplatin, combined therapy / radiochemotherapy 510 ± carboplatin plus paclitaxel 514 ± CEV (carboplatin, etoposide and vincristine) 513 ± 5-fluorouracil, cis- or carboplatin, mitomycin, and taxane 510 carcinoids 82, 306 ± bronchial system 402 ± colon 412 ± differentiated 313 ± epidemiology 401±403
Subject Index ± ± ± ± ± ± ± ± ± ± ± ±
gastrointestinal ± categories 402 ± treatment 413 ileum 424 lung 408, 415±418 malignancy, level 403, 404 origin, development, definition 401 pancreatic 408 small intestine 412 stomach 408 ± analysis 412 ± clinical / morphological correlations 411 ± ± detection, somatostatin receptor scintigraphy 410, 411 ± ± histopathology / immunohistochemical confirmation 409, 410 ± ± lymphogenic metastasis 409 carcinoma in situ, ductal (see DCIS) cardiotoxicity 503 CASS 200 machine 148 cathepsin D 198 CCNU 523 CD20 89 CEA 27, 101 ± expression 233 CEA-labeling 83 centers of excellence 39 c-erb B2 oncoprotein 27, 244, 373 ± amplification 200, 204 ± overexpression 137, 192, 194, 197±200, 380±386 cervical cancer 18, 86, 434, 435, 536±537 ± labeling solutions, local administration 435 ± prognosis factors 45 ± therapy regimens 536±537 ± ± neuroendocrine small-cell cancers of the cervix 524 ± ± radiotherapy strategies 536 ± ± stage-related treatment 536 cetuximab = erbitux 515 CEV (carboplatin, etoposide and vincristine) 513 chemotherapy regimens in breast cancer 298, 504±508 ± adjuvant 246, 504 ± ± efficacy 504 ± antiangiogenic drugs in combination with chemotherapeutica 516 ± for breast cancer 504±508 ± and endocrine therapy 504 ± new chemotherapy regimen 514 ± thyroid cancer 509 ± ± monotherapy with doxrubicin 509 childhood, cancers 427 C-11-choline as a radiopharmaceutical 33 chromogranin / CgA (chromogranin A) 313, 314, 405, 422 ± immunohistochemical staining 272
chylic vessel 490 CIR (conservative image reading) 181 cisplatin ± combined therapy / chemotherapy ± ± cisplatin plus etoposide 513 ± ± cisplatin plus gemcitabine 514 ± ± cisplatin plus vinorelbine 515 ± ± docetaxel and cisplatin 518 ± ± doxorubicin plus cisplatin or etoposide 509 ± ± mitomycin C, ifosfamid and cisplatin (MIC) 515 ± hyperradplat (hyperfractionated radiation and intraarterial cisplatin) 510 ± p53, tumor-suppressor gene activity marker for response to cisplatin 512 Clark-Level 333 classification ± histopathological 156 ± UICC 383 clearance concept, sentinel lymph node (SLCC) 333 closing remarks 499±502 CMF regimen (Cyclophosphamide, Methotrexate, 5-Fluorouracil) 504 ± classical CMF regimen according to Bonadonna 504 ± three versus six cycles 506 c-myc 383 CNS-relapses 529 cobalt-57 91 coccidioidomycosis 306 cold node, thyroid gland 260 colitis, radiation 86 collimation 61, 94, 108 collimator 43, 105, 236 colloid ± behavior in bloodstream 61 ± degradation, biological 61 ± nanocolloid (see there) ± quality 60±62 ± transport 61 colorectal cancer 14, 83±85, 386±393, 520±521 ± detection, FDG-PET 387, 388 ± monobloc resection technique 84 ± monoclonal antibodies 393 ± N-staging 388±390 ± SLN ± ± biopsy, results, table 15 ± ± detection / evaluation, pilot studies 391±393 ± ± labeling 391±392 ± therapy regimens 520±521 ± ± adjuvant 395, 396 ± ± chemotherapy regimens 520±521 ± ± radioimmunotherapeutical approach 521 comedo type, carcinoma in situ 220 comedocarcinoma 221, 226 Compton effect 108 concept, sentinel lymph node 11
condyloma, giant 440 consensus meeting 2003, St. Gallen 504 contrast ± media, quality 99 ± solution, routes 71 control unit, characteristics 119, 120 corticotropinoma 414 cross-sectional imaging technique 103 CUP (cancer of unknown primary) 184 ± cervical lymph nodes, infiltration 292±298 Cushing syndrome 302 cyclophosphamide 328, 505 ± combined therapy modalities ± ± adriamycin, cyclophosphamide and paclitaxel 508 ± ± adriamycin, cyclophosphamide and vincristine (ACO II) 513 ± ± CMF regimen (cyclophosphamide, methotrexate, 5-fluorouracil) 504 ± ± EPICO (epirubicin, cyclophosphamide and vincristine) 513 ± TAC scheme (docetaxel / doxorubicin / cyclophosphamide) 505 cystectomy, total 482 cystitis, prevention with Mesna 503 cystosarcoma phylloides 213, 216 cytoceratin 200 ± double-expression 264 ± positive cells 54 cytokeratin 487 ± pattern 24 ± staining 230 cytokines, breast cancer, enhancing factors 222 cytology ± exfoliative 289, 290 ± fine-needle aspiration (see FNAC) ± imprint 95 ± ± intraoperative 233, 234 cytoma, ovarian cancer 423 cytostatics, combined therapy modalities, anti-HER2 plus cytostatics 507 D DAR (differential absorption ratio) 33 DCIS (ductal carcinoma in situ) 137, 179, 188, 220±228 ± sentinel node labeling 190, 191 ± types, table 220 ± van Nuys-Holland-classification 129, 228 decision-making, individual 245 decontamination solution, radioactive 229 deep-seated tumors 64 definition, sentinel lymph node 3, 4 degeneration, fatty, node 94 degradation, colloids 61
555
556
Subject Index dendritic ± cell vaccines 529 ± reticulum cells 89 detection, primary, SLN 12, 39±49 ± accuracy 130 ± basic principles 3, 4 ± basic strategies 23±27 ± critical points 27 ± histo- / cytopathological diagnosis 44±46 ± improvement 40±43 ± inclusion / exclusion criteria 47, 48 ± intraoperative 43, 44 ± mediastinum 46, 47 ± methodical work-up 40±43 ± parasternal 72 ± pitfalls 94 ± precision 120 ± prescreening methods 24, 25 ± rates 113 ± ± dependence of pT-stages 130 ± requirements, operationoriented 106±108 ± technical conditions 129, 130 ± techniques 43 detector ± head, rectangular 103 ± performance 109, 110 ± sandwich detector 124 devices, combined radiological and histological cancer diagnosis 161±174 dextran ± cross-linked 26 ± 99mTc-labeled 98 diagnosis, combined radiological and histological, strategies / devices 161±174 display, quality criteria of gamma probes 113, 118 distribution, lateral sensitivity 114 DMSA (99mtechnetium-dimercaptosuccinic acid) 406 docetaxel 518 ± combined therapy ± ± docetaxel and capecitabine 518 ± ± docetaxel / doxorubicin / cyclophosphamide (TAC scheme) 505 ± ± docetaxel and cisplatin 518 ± ± docetaxel and epirubicin 518 ± single substance 518 double basin sentinel node implication 244 downstaging 246 doxorubicin 505, 509 ± combined chemotherapy ± ± doxorubicin plus cisplatin or etoposide 509 ± ± streptozotocin, 5-fluorouracil, and doxorubicin 523 ± monotherapy 509, 530 DTPA ± 111In-labeled (di-DTPA-TL) 426
± 99mTC 68, 155, 501 DTPA-D-Phe1-octreotide 425 DUR (differential uptake ratio) 33 dynamic image 32 E E 4296 (Eastern Cooperative Group) 521 ECF (epirubicin, cyclophosphamide and 5-fluorouracil), gastric cancer 518 eczema, areola 227 EGFR (epidermal growth-factor receptor) 199, 373, 380, 381 EIC (extensive intraductal component) 39, 137, 180, 238 electromedical safety, management 110 endobronchial sampling 305 endocrine ± oncology in University Hospital Uppsala 524 ± responsive and non-responsive, risk category 405 Endorem, liver-specific contrast agent 8 energy ± discrimination 113, 118 ± resolution 109 ± ± probe 61 ± window 108 enhancement, dynamic contrast 217 EORTC 333±335 ± questionaire 514 EPICO (epirubicin, cyclophosphamide and vincristine) 513 epirubicin and docetaxel 518 EPOS R system 146 c-erb B1 and B2 overexpressing cases, anastrozole and letrozole 504 erbitux = cetuximab 515 erlotinib = tarceva 515 erythroplasia of Queyrat 440 esophageal cancer 13, 371±372, 517 ± adenocarcinoma 371, 372 ± AEG (adenocarcinoma of the esophagogastric junction) scheme 372 ± cardia carcinoma 371, 372 ± differential diagnosis 317 ± FDG-PET, relative value 370, 371 ± South West Oncology Study Group: treatment of metastatic or recurrent esophageal cancer 517 ± superficial esophageal cancers 517 ± therapy regimens 517 ± ± chemoradiotherapy 517 ± ± chemoresistance 517 ± ± chemotherapeutic and combined treatment 517 ± ± radio-chemotherapy 517 esthesioneuroblastoma 512 estrogen, breast cancer, enhancing factors 222 Ethicon device 165
etoposide, combined therapy / chemotherapy ± CEV (carboplatin, etoposide and vincristine) 513 ± cisplatin plus etoposide 513 ± doxorubicin plus cisplatin or etoposide 509 European cancer centre Milan 11 evaluation, sentinel lymph node 24, 25 ± benefits 96 ± criteria 48, 49 ± secondary 93 Ewing sarcoma 427 experience, level of, detection and radiological imaging of SLN 40 F face, cancer 283±298 FDE regimen, neuroendocrine tumors 523 FDG-6-phosphate, intracellular 32 FDG-PET (see PET) FEC scheme according to Levine 505 female cancer 17, 18 fibroadenoma 163 ± breast 181, 188, 221 ± ± extracanalicular 223 ± ± intracanalicular 223 ± intracanalicular 217 fibrocystic disease 185, 187, 188 filament, anchoring 51 filgrastim 541 ± neulasta (pegfilgrastim) 541 Fischer-Imaging 162 FISH technique 198, 204 F-18-fluoride as a radiopharmaceutical 33 F-18-fluorodeoxyglucose as a radiopharmaceutical 33 F-18-fluoroethylthyrosine as a radiopharmaceutical 33 F-18-fluoromethyltyrosine as a radiopharmaceutical 33 F-18-fluoromisonidazole (FMISO) as a radiopharmaceutical 33 5-fluorouracil, combined therapy / radiochemotherapy ± cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen 504 ± 5-fluorouracil, cis- or carboplatin, mitomycin, and taxane 510 ± 5-fluorouracil and folic acid regimen 518, 520 ± streptozotocin, 5-fluorouracil, and doxorubicin 523 fluorothymidine 33 FNAC (fine-needle aspiration cytology) 24 ± breast cancer 131, 132, 134±136 ± ± stereotactic (see SFNAC) ± head and neck cancer 283, 289, 290
Subject Index ± thyroid cancer 258 ± ± syringe quality 259, 260 ± ± technique 260 FOLFOX, IROX and IFL, comparisons of 521 folinic acid ± 5-fluorouracil and folic acid regimen 518, 520 ± 5-fluorouracil and leucovorin 518 follow-up studies 77 foregut tumors 402 fractures, tamoxifen 507 full-groin dissection 439 FWHM (full width at half maximum) 114, 116 G 9G6 27 gamma c ± camera 26, 31 ± ± development 103, 104, 106 ± ± digital, operation 105 ± ± set-up and function 104, 105 ± probe 14, 41, 77 ± ± handling 228±250 ± ± intraoperative sentinel node detection 43, 44 ± ± minimal requirements 118 ± ± parameters, comparison 121±123 ± ± practical use 91±94 ± ± probe guided surgery 91, 113 ± ± protection 92 ± ± quality criteria, requirements and future developments 113±124 ± ± quality requirements 105, 106, 110 ± ± servicing 91±94 ± ± sterilization procedures 228±250 ± ± types 117 ± ray ± ± emitted annihilation 33 ± ± measurement 108, 109 gastrectomy ± laparoscopically assisted 14 ± partial 383 gastric cancer 82, 83, 372±386, 518±519 ± adenocarcinoma 376 ± advanced 374, 375, 378 ± c-erb B1±3 oncogene overexpression 380±386 ± depth of cancer infiltration, radioimmunolabeling strategies 379 ± early (EGC) 13, 372, 374, 377, 378 ± exophytic (polyp-like) 374, 375 ± signet-ring cancer 376 ± staging 383±386 ± ± N-staging 385, 386 ± ± stage pT2pN0 383 ± ± stage-related gastric surgery, classification 373±377
± subtypes 374±377 ± ± recommendations for treatment 377 ± TNM classification 385 ± treatment / therapy regimens 518 ± ± fluorouracil / folic acid regimen 518 ± ± neoadjuvant treatment of locally advanced gastric cancer 518 ± ± surgical, rules for extend 377±379 ± ± treatment of neuroendocrine tumors in the gastrointestinal tract 522 ± undifferentiated (lymphoid cell like) 152, 375 gastrinoma 403, 414, 419 gastrointestinal cancer 13, 44, 369±397 ± lymphatic network 373 ± N-staging 369, 370 ± prognosis factors 45 ± up-staging 393±395 GDDTPA-PGM 155 gefitinib = iressa 515 gemcitabine, combined therapy ± gemcitabine, and cisplatin 514 ± gemcitabine, and 5-fluorouracil 531 ± taxane, gemcitabine, and vinorelbine 514 ± topotecan, gemcitabine and vinorelbine 515 genitourinary cancer, sentinel node mapping 431 germ ± cell tumor 17 ± ± nonseminomatous (NSGCT) 444 ± trail 442 ghost cells 151 Giemsa staining 355 GiSCAD (Italian group for the study of digestive tract cancer) 518 glandular body, breast, topography 52 Gleason's grading system 449±451, 454 ± grading errors 456, 457 ± predictive value 456 glucagonoma 403, 414, 418 glucose transporter 32 gold-198 98 Gomori staining 401 goserelin, adjuvant 533 grading, breast cancer 194, 196 green, indocyanine 14 Grimelius staining 314, 401 growth activity, malignant melanoma 333 H half-live, physical 32 hamartoma 302 handheld probe 283 HAWKEYE radiomonographic measurement equipment 106
head and neck cancer 12, 80, 283±298, 511±512 ± intratumoral cisplatin epinephringel (CDD-epi-gel)-infiltration 512 ± laryngeal ± ± cancer 511 ± ± preservation 510 ± mass reduction of local tumorinfiltration 512 ± oropharyngeal cancer 511 ± PET, staging 284, 285 ± radical neck dissection 511 ± therapy regimens 510±512 ± ± combined radiochemotherapy 510±511 ± ± ± 5-fluorouracil, cis- or carboplatin, mitomycin, and taxane 510 ± ± radiotherapy 510 ± ± treatment of cancers with special localizations 512 ± ± intraoperative radiotherapy 510 ± voice preservation 511 hemangioma 331 hematogenous spread, cancer cells, danger 65 hepatotoxicity 503 HER2, palliative treatment of HER2positive cancer cases 508 heregulin 199 herceptin (see also trastuzumab; see also anti-HER2 therapy) 507 ± results with first-line anti-HER2monotherapy 507 heterozygosity, loss of (LOH) 336 high-precision work 40 hindgut tumors 402 histopathology / histopathological procedure 95, 96 ± lymphatic system 89 HMB45 24 HNSCC (head and neck squamous cell cancer) 283, 286 ± adjuvant therapy regime 292 Hodgkin's disease 308, 310, 315 Horner symptom complex 303 Hçrthle cell adenoma / carcinoma 265, 266, 271 hyperglycemia 34 hyperintense signal 156 hyperparathyreoidism 302 hyperplasia, atypical ductal (ADH) 137, 188 hyperradplat (hyperfractionated radiation and intraarterial cisplatin) 510 hypervascularization 217 hypopharynx cancer ± levels of metastasis 290±292 ± sentinel node 284 I IALT (International adjuvant lung cancer trial) 514
557
558
Subject Index IDEAL trial I and II (Iressa dose evaluation in advance lung cancer) 515 identification, learning stages 130 IFL, FOLFOX, and IROX, comparisons of 521 ifosfamide, combined therapy ± mesna, adriamycin and ifosfamide 530 ± mitomycin C and cisplatin (MIC) 515 immunoglobulins, 99mTc-labeled 60 immunohistochemistry (IHC) 3, 12, 59, 130 ± cost-intensive 95 ± detection rate 153 ± routine technique 145 ± ultrarapid 57, 95, 145±148 ± ± application, differences 148 ± ± methodical options 146 ± ± planning, future 148 ± ± preliminary experience 146, 147 ± ± technical procedure 146 in-breast recurrence 250 indian file pattern 131, 195 inguinal pick, male cancers 16, 439 injection in relation to primary site 5 ± circular 350 ± dermal 74±76 ± intratumoral 61, 62 ± modalities 42 ± perifocal 288 ± peritumoral 61±63, 65, 131, 173, 235, 274, 288 ± semicircular 350 ± subdermal 61±63, 75, 78±80, 131, 235 ± submucosal 85 ± technique, using 99mTc nanocolloids / blue dyes 62±64, 352, 353 Institute of Physical Sciences in Medicine (IPSM) 6 insulinoma 403, 414, 417, 418 International Breast Cancer Intervention Study (IBIS-1) 506 interferon (IFN) ± IFNa, combined with thalidomide 531 ± IFNa2b 338, 360, 361 ± adjuvant 529 ± malignant melanoma, interferon monotherapy 529 interleukin 2 (IL-2) in RCCtreatment 532 interpretation, standardization 157 intestinal cancer, SLNslabeling 391±392 intraductal component, extensive (EIC) 39, 137, 180, 238 iodine-125 101 iodine-129 42, 91 iodine-131 101, 509 ± nonstorage of iodine, local radiotherapy 509
± standard activity 5±8 GBq iodine-131 509 IORT (intraoperative electron beam radiotherapy) 510 iressa = gefitinib 515 irinotecan (CPT-11) 520±521 ± combination with oxaliplatin 521 IROX, FOLFOX, and IFL, comparisons of 521 isointense signal 156 Italian ± group for the study of digestive tract cancer (GiSCAD) 518 ± trial (ALPI) 514 K key lymph node 177 Ki67 383 kidney (see renal cell cancer) L labeling procedure ± breast cancer, technique 75 ± CEA 83, 101 ± different cellular compartments, lymph node 89, 90 ± false 64 ± figure 56 ± incorrect 242 ± main technique 5±8 ± orientation of labeling procedure on the wrong substance, breast cancer 240, 241 ± peritumoral 217 ± pitfalls 94 ± probability 55 ± of the SLNs by analogy with Tsioulias 383 ± specific developments 59±68 ± 99mTc-nanocolloids 241±243 laparoscopic evaluation, probe use 124 larynx / laryngeal cancer 80, 81, 511 ± chemotherapy and larynx preservation 512 ± head and neck cancer, laryngeal preservation 510 ± levels of metastasis 290±292 ± sentinel node 284 LAS (lymphatic outflow scintigraphy) 347 lateral quadrant, breast cancer 236 Leeds cancer centre 520 anastrozole / letrozole 504, 506 letrozole (see anastrozole / letrozole) 504, 506 leucovorin and 5-fluorouracil 518 Levine, FEC scheme according to 505 Lindsay tumor 266 line of sight, SLNs 93 linear attenuation coefficient 108 line-of-sight technique 110 linitis plastica 375
liposomes, radioimaging 65±68, 98, 101 ± long-circulating (LCL) 67 ± use 68 lobectomy 304 localization, sentinel lymph node ± determination 92, 93 ± different node groups 188, 189 ± multifocal / multicentric breast cancer 205±220 ± outside the axilla 177 Lorad MultiCare 169 lumpectomy 39 lumped constant (LC), glucose metabolism based on FDG uptake 33 lung cancer 13, 44, 81, 301±328, 513±516 ± adeno-cell 301 ± Italian trial (ALPI) 514 ± bronchoalveolar 304 ± diagnosis / diagnostic strategy 308±317, 320 ± ± stage-adapted 305 ± extensive disease 319 ± five-year survival rate 318 ± giant-cell 301 ± grading 309 ± IALT (International adjuvant lung cancer trial) 514 ± IDEAL trial I and II (Iressa dose evaluation in advanced lung cancer) 515 ± immunohistochemical lymph node analysis 316 ± laboratory investigations 301 ± limited disease 319 ± locoregional spread 82 ± mediastinal lymph node dissection 304, 323 ± metastasis 308 ± multicentricity, primary 304, 305 ± N-level-dependent survival 317±321 ± node staging by means of USPIO 159 ± non-small-cell (NSCLC) 301, 313, 514±516 ± ± approaches to block neoangiogenesis in NSCLC 516 ± ± lymph node sampling 325, 326 ± ± operability 319, 328 ± ± prognosis factors 45 ± peripheral (scar) 302±304 ± PET-CT-MRI pre-evaluation 307±310 ± PET staging ± ± N-staging 306, 307 ± ± significancy 305 ± ± T-staging 306 ± polymorphous cellular 313 ± sentinel lymph node detection, preoperative, difficulties 326, 327
Subject Index ± serological parameters 301, 302 ± small-cell (SCLC) 301, 308, 312, 513±514 ± ± differential diagnosis 315 ± skip metastasis 323 ± squamous cell 301 ± subtyping 309 ± therapy regimens 513±516 ± ± new therapeutic approaches 515 ± ± non small-cell (NSCLC) 514±516 ± ± planning 309 ± ± small-cell (SCLC) 513±514 ± tumor shadow disappearance rate 302 ± UK trial (big lung trial) 514 lymph node ± axillary (see there) ± dissection ± ± elective 337±339 ± ± limited 13 ± ± mediastinal 13 ± ± pelvic, radioisotope-guided 17 ± ± selective 511 ± iliacal 473 ± intercalar 473 ± investigation ± ± detection 230±232 ± ± histopathological investigation, technical procedures 232, 233 ± ± practical conclusions 235 ± jugular chain 286 ± junctional 286 ± key lymph node 177 ± mastoid 286 ± mediastinal 322 ± occipital 286 ± obturatoric 473 ± parasternal 177, 249 ± praecardial 322 ± preauricular deep parotid 286 ± retrorectal 389 ± retromammillary 239 ± spinal accessory chain 286 ± structure, figure 90 ± submandibular 286 ± superficial cervical 286 lymphadenectomy 278 ± bilateral pelvic 16, 18 ± complete 463 ± early, benefit 332 ± elective versus uncontrolled 76±78 ± inguino-femoral 18, 431 ± pelvic 86 ± retroperitoneal 491, 492 lymphangiography, X-ray 8 lymphangiosis carcinomatosa 47, 74, 207 lymphatic ± drainage ± ± block 191, 237 ± ± intrathyroidal 257 ± ± to sentinel lymph node 51±57 ± ± ± time schedule 51, 52
± flow 62 ± ± bypass 94 ± fluid 51 ± sinus network 89 ± vessel 51 Lymphazurin 15 lymphedema 77 lymphography 3 ± MR lymphography 8 lymphoma 308, 310, 427 lymphoscintigraphy 54, 278 ± radiopharmaceuticals 339 M M0l+ in immunhistochemical staging 151 macrocalcifications 184 macrophage, siderin deposits 331 MAGE-A3 46 magnetic resonance imaging (MRI) 3 ± contrast enhanced 206 ± dynamic, standardized 180 ± guide-lines 180 ± ¹International Investigation Project on Diagnostic Parameters in Contrast-enhanced MRI of the Breastª 180 ± practical procedures 207 ± preoperative axillary lymph node diagnosis, using USPIO 155±159 ± value, breast cancer detection 179, 180 MAID regimen 530 male cancer 16, 17 malignant / malignancy ± melanoma (see there) 529±530 mammaria interna group 23 ± lymph nodes 210 mammography 164, 190 ± MR 208 ± X-ray 208 Mammomat 3000 165, 168, 169 Mammotest Pluss 171 mapping, intraoperative 81, 82 ± blue dye, critical points 90 marker / marking ± MAGE-A3 46 ± neuroendocrine 24 ± post-puncture 166 ± three-dimensional 166 MART-1 (clone M2±7C10) 24 MCF, gastric cancer 518 MCM2 (minichromosome maintenance protein) 316 mean, multiple counts 127 mediastinal lymph node dissection 13, 304, 323 mediastinoscopy 13, 305, 319 ± value for staging 318 Melan A (clone A103) 24 melanoma, malignant 11, 23, 44, 76±80, 286 ± ABCD formula 331
± acrolentiginous (ALM) 334, 335 ± actual status, present opinions 359, 360 ± amelanotic 344 ± anal circle 342 ± apoptotic 25 ± atypical localisation 342 ± Breslow, prognostic risk groups 333 ± Clark-Level 333 ± classification 348 ± detection rates 113 ± development, stages 337±339 ± diagnosis ± ± dysplastic nevi / early invasive 343 ± ± historical overview 339, 340 ± ± improvement, immunological supported methods 356±359 ± ± undetected primary 343±345 ± diagonal metastatic spread 61 ± early invasive 343 ± electrophoresis 359 ± en bloc excision, lymphoscintigraphy-guided 347 ± follow-up control studies, nonradioactive imaging 359 ± head and neck 287 ± injection technique 78±80 ± lentigo maligna (LMM) 334 ± lymphadenectomy, elective versus uncontrolled 76±78 ± macroscopic criteria 331, 332 ± metastasis 331 ± ± atypical 335, 336 ± ± in transit 335, 336 ± ± interval 336 ± ± satellite 335 ± necrotic 25 ± nodular (NM) 334, 338 ± penile skin 439 ± primary, searching 341, 342 ± prognosis factors 45 ± rectum 342 ± recurrence, risk 332 ± sentinel node ± ± detection, experiences 347±360 ± ± investigation, technique 354, 355 ± ± localization 348, 349 ± sequencing 359 ± staging ± ± clinical 333±335 ± ± locoregional T- and N-staging 346, 347 ± ± system, recommendation, American Joint Committee on Cancer Staging 360 ± statistics 359 ± superficial spreading (SSM) 334, 337 ± survival ± ± labeling 350 ± ± rates, overall 349
559
560
Subject Index ± ± risk 332 ± ± 5-years 334 ± systemic disease, exclusion 345±347 ± treatment / therapy regimens 360±363, 529±530 ± ± interferon monotherapy 529 ± underestimation 137 ± tumor progression, risk 332 ± types 334 ± tyrosinase transcripts in blood 356±359 ± ultrarapid immunohistochemistry 148 ± vulva 433 Memorial Sloan Kettering Cancer Center 523 menopause, anastrozole in postmenopausal advanced breast cancer 506 Merkel cell cancer (MCC) 14, 23, 80, 422, 524 ± chemotherapy 524 ± radiation therapy 524 mesna (preventing cystitis) 503 ± combined sarcoma therapy: mesna, adriamycin and ifosfamide 530 metalloprotease 198 metastases ± brain 36 ± cross-metastasis 81 ± hematogenous 4, 347 ± ± danger 65 ± ± direct / secondary 54, 55 ± ± propagation 133 ± liver 55 ± lung 55 ± malignant melanoma 335, 336 ± micrometastases 12, 23, 113, 151±153, 230±233, 257 ± occult 4, 15 ± PET diagnosis 35 ± regional node, exclusion / verification 23±27 ± silent 346 ± skip 15, 80, 96, 179, 232, 323, 389, 431 ± transit 40 C11-methionine (MET), radiopharmaceuticals 33, 36, 483 methotrexate, 5-fluorouracil, cyclophosphamide (CMF) regimen) 504 MiBI 383 MIBG, 123I / 124I 428 microcalcifications 163, 167, 184 ± biopsy 164 ± line-like 187 ± monomorphous 185 ± opaque (¹dust-likeª) densities 206 ± polymorphous 186 ± retromamillary 184 ± small groups 205
± subtypes 205 ± Y-like arrangement 205 microcarcinoma 73, 74, 171, 216 ± sentinel node labeling 190 microinvolvement versus micrometastases 151±153 Microlite 98 MicroMark clip 164 micrometastases 12, 23, 113, 230±233, 257 ± significance, table 152 ± versus microinvolvement 151±153 microwave, styptic in partial nephrectomy 494 midgut tumors 402 Milan group 60 Millenium VG device 106 mimicry ± epithelial cancer cell 231 ± sentinel lymph node 239, 240 minithoracotomy 309 MION (monocrystalline iron oxide nanoparticles) 26 mitomycin, combined therapy / radiochemotherapy 510 ± 5-fluorouracil, cis- or carboplatin, mitomycin, and taxane 510 ± mitomycin C, ifosfamid and cisplatin (MIC) 515 MNF 116 (anti-pancytokeratin antibody) 147 molybdenum-98 96 monobloc resection technique 84 mucin 200 mucoepidermoid cancer 293, 296 multicenter study, local 40 multicentricity in breast cancer 23, 47, 48, 60, 73, 181 ± definition 207 ± phase-shifted 190 multifocality 23, 47, 48, 60, 73, 181, 190 ± definition 207 musculoskeletal disorders and fractures, tamoxifen 507 myopathy 302 N N0 151 N0(mol+) 151 Nabholtz, TAC scheme according to 505 Nanocis 98 Nanocoll 60, 98 nanocolloidals, 99mTc 5, 44, 77, 81, 241±243, 277, 423, 440±443, 474 ± advantages, table 17 ± injection technique 62±64 ± quality 60±62 ± vacuum vials 501 nanoparticle, iron oxide 8, 26 ± MION (monocrystalline iron oxide nanoparticles) 26
± USPIO (ultrasmall paramagnetic iron oxide particles) 26, 42, 81, 89, 155±159, 326, 489 nasopharyngeal cancer 44 National Cancer Institute of the United States 501 National Radiological Protection Board (NRPB) 5 National Surgical Adjuvant Breast and Bowel Project no. 4 177 natural killer cells 491 NAVIGATOR GPS 14 NCAM (neural cell adhesion molecule) 301 neck ± cancer 12, 80, 283±298 ± ± PET, staging 284, 285 ± dissection 257, 511 ± ± bilateral 280 ± ± neo-selective 12 ± ± selective 12 ± ± unilateral 280 necrosis factors, breast cancer, enhancing factors 222 neoadjuvant treatment, therapy regimens used in 503±541 neoangiogenesis 221, 541 ± blockade of 541 neoprobe 2000 102 nephrectomy ± laparoscopic 484 ± partial 484, 494 ± radical 494 nephroblastoma (Wilms, Birch-Hirschfeld) 427 nephrotoxicity 503 ± prevention with Amifostine 503 neulasta (pegfilgrastim) 541 neupogen 541 neuregulin 199 neuroblastoma ± differential diagnosis, table 428 ± sentinel lymph node approach 426±428 ± treatment / therapy regimens 429, 526±528 neuroendocrine cancer 14, 44, 82, 83, 401±429, 522±528 ± amyloid, neuroendocrine 266, 274 ± application of sentinel node concept 404 ± blood chromogranin, clinical significance 405 ± carcinoids (see there) ± cervical region 421 ± degree of malignancy, biological features, table 420 ± duodenum 414, 415 ± 111In-pentetreotide 404, 405 ± gastrointestinal tract 407±408, 522 ± ± discrimination 407, 408 ± ± FDG-PET staging 406 ± hindgut carcinoids 522
Subject Index ± lung 408, 415±418 ± ± preoperative sentinel node imaging 418 ± marker, neuroendocrine 24 ± metastases ± ± detection, developments 425 ± ± search 423, 424 ± midgut carcinoids 522 ± N-staging, PET 405, 406 ± neuroendocrine cells, in carcinomas 423 ± origin, development, definition 401 ± pancreas 414, 415, 522 ± PNET (peripheral neuroendocrine tumor) 403, 421±423 ± prevertebral thoracic 421 ± prognosis factors 45 ± retroperitoneum 421 ± SNEC (sinonasal neuroendocrine carcinoma) 524 ± subtype, characterization 404 ± therapy regimens 522±528 ± ± adjuvant 425 ± ± antihormone therapy 522 ± ± classic therapeutic regimens and newer approaches 523±524 ± ± neuroendocrine small-cell cancers of the cervix 524 ± ± neuroendocrine tumors in the gastrointestinal tract 522 ± ± somatostatin-receptor-sczintigraphy (SRS-scan) positive neuroendocrine tumors 522 ± ultrarapid immunohistochemistry 148 neuropathy, peripheral 302 neurotoxicity 503 neutron irradiation 96 neutropenia followed by infections 541 nevus cell ± dysplastic 341, 343 ± nonneoplastic 25 ± preneoplastic 331 nipple ± bleeding 221 ± secretion, cytological examination 191 node ± cold in thyroid gland 260 ± intraoperative node evaluation 383 noncomedo type, carcinoma in situ 220 nonsystemic therapy concept, breast cancer 54 nose, cancer 283±298 NSCLC (non-small-cell lung cancer; see also lung cancer) 301, 313, 514±516 ± approaches to block neoangiogenesis in NSCLC 516 NSE (neuron-specific enolase) 301, 405
NSGCT (nonseminomatous germ cell tumors) 444 nurse, scrub nurse 7 O occult lesion of breast cancer, radioguided localization (ROLL) 42 octreotide scan 405 oncocytoma 265, 271, 272, 281 Opdima digital imaging 165 operating room, radiation protection 5±7 oral cavity, cancer 283±298 ± examples 288, 289 oropharyngeal cancer 12, 511 ± levels of metastasis 290±292 ± prognosis factors 45 ± sentinel node 284 osteosarcoma, small-cell 427 ototoxicity, caused by cytostatics 503 ovarian cancer 18, 435±437 ± development 435 ± diagnosis / staging, role of FDG-PET 436 oxaliplatin 520 ± irinotecan (CPT-11), combined with oxaliplatin 521 P p53 137, 198, 244, 383, 481, 490 ± tumor-suppressor gene activity marker for response to cisplatin 512 p105 protein 205 p185 protein 27, 83, 197, 198, 199, 380, 381 paclitaxel, combined therapy modalities ± adriamycin, cyclophosphamide and paclitaxel 508 ± carboplatin plus paclitaxel 514 ± trastuzumab plus paclitaxel 508 Paget's disease 221, 227 Pancoast cancer 292, 303 pancreatic cancer 391±392, 523 ± EPT (endocrine pancreatic tumor) 523 ± SLNs-labeling 391±392 Papanicolaou smears 434 papillary lesion, breast 221 papilloma 188, 224 papulosis, bowenoid 440 paraganglioma, malignant 286, 403, 421 parasternal basins 210 parotid gland cancer 284±293, 297, 298 particle of labeling solution ± nanoparticle (see there) ± size 97 pathologist, responsibility 95 pathology laboratory, radiation protection 8, 229, 230
PCR (polymerase chain reaction) 3, 201, 202 ± reverse transcriptase (RT-PCR) 24, 25, 42, 78 pegfilgrastim (neulasta) 541 penile cancer 16, 85, 86 ± clinical / histopathological results 85 ± prognosis factors 45 penile cancer ± labeling, sentinel lymph node, 99mTc-nanocolloid 440±442 ± sentinel node identification 439, 440 ± treatment strategies 440 Pennsylvania project 245, 246 percentage of positive cancer cells and staining intensivity: grade I and grade II 506 pericytoma 493 peritoneotomy, inverted-V 463 PET (positron emission tomography) 3, 7, 26, 31±36, 177 ± brain metastases, exclusion 36 ± clinical application 34 ± data acquisition 31 ± false-positive lesions 183, 285, 306 ± head and neck tumor staging 284, 285 ± imaging principles 31, 32 ± limitations 35, 36 ± locoregional recurrence, significance 285 ± lymph node metastases, diagnosis 35 ± patient preparation 34 ± predictive value 182 ± primary tumors, diagnosis 34, 35 ± properties, system-immanent 36 ± prostate cancer 477 ± recurrence 183 ± scanner 32 ± screening, for sentinel lymph node and metastasis 182, 183 ± sensitivity PET, axillary lymph node dissection 182 ± spatial resolution 182 ± staging 35 ± ± breast cancer 181, 182 ± ± germ cell tumors 446 ± ± renal cell cancer 493, 494 ± ± thyroid cancer 257, 258 ± ± urinary bladder cancer 483 ± therapy, monitoring 35 ± transaxial 181 ± whole-body 183 phantom studies 34 pharynx, cancer 283±298 ± levels of metastasis 290±292 phase III study 157 pheochromocytoma 403, 421, 493 photo-multiplier tube 43 placlitaxel 505
561
562
Subject Index PNET (peripheral neuroendocrine tumor) 403, 421±423 pneumectomy 304 poor spatial resolution 109 primary ± systemic disease concept 53 ± tumor ± ± diagnosis by PET 34, 35 ± ± type / localization 11±18 processing protocol 34 prognosis factors, table 45 proliferation activity 288 prostate ± cancer 86, 113, 533±534 ± ± anaplastic 455 ± ± Augsburg research group, experiences 473, 474 ± ± biopsy, ultrasound-guided 456, 457 ± ± capsule perforation 459 ± ± degree of malignancy 454 ± ± ± and number of biopsies, N-staging 458 ± ± ± Gleason's grading system 449±451, 454, 456, 457 ± ± detection of sentinel nodes, approach 470±473 ± ± dysplasia, relation to cancer 455 ± ± FDG-PET, helpful in detection and N-staging 477 ± ± gold standard 449 ± ± grade II (WHO), division 456 ± ± high-risk group 466 ± ± labeling procedure ± ± ± animal experimental studies 477 ± ± ± performance 474 ± ± low-risk group 466 ± ± metastatic nodes, side differences 460 ± ± metastatic spread, lymphogenous / hematogenous 457, 458 ± ± microcarcinoma 455 ± ± miocrometastasis 465, 470, 471 ± ± minimal lesions 455 ± ± moderately differentiated 454 ± ± molecular biological / clinical parameters 451, 452 ± ± multifocality 467 ± ± N-stage 459±463 ± ± ± intraoperative and postoperative staging 463, 464 ± ± ± laparoscopic lymph node staging 463, 465 ± ± ± Whitmore's staging scheme 464±466 ± ± organ limited stage 459 ± ± pelvic node metastasis, incidence 459 ± ± predictive values 457 ± ± primary cancer detection 459 ± ± prognosis factors 45
± ± prostate-specific antigen (PSA), serum values 449 ± ± seminal vesicle infiltration 459 ± ± survival rate 467±469 ± ± ± versus lymph node metastasis 460 ± ± therapy regimens 533±535 ± ± ± androgen deprivation therapy regimens 533 ± ± ± anti-androgen therapy 533 ± ± ± standard therapy 533 ± ± tumor stage, sentinel lymph node concept 466, 467 ± ± tumor volume, significance in treatment 455 ± ± ultrarapid immunohistochemistry 148 ± ± well-differentiated 454 ± hyperplasia 451 prostatectomy 466 ± radical 469 psammoma body 257, 265 puncture ± techniques 136 ± three-dimensional guidance 163 Q quality parameters 113, 124 Queyrat, erythroplasia 440 R radiation ± dose ± ± breast 6 ± ± calculation 6 ± ± staff 6 ± exposure ± ± internal / external 5 ± ± legislative limits 5 ± ± surgical staff, values 6 ± protection ± ± operating room 5±7 ± ± pathology laboratory 8, 229, 230 ± therapy, postoperative 177 radiation-detecting systems 101±110 ± detector, performance 109, 110 ± gamma camera (see there) ± quality, preconditions 102, 103 ± steps in development 101, 102 radioactivity monitoring 7 radiochemotherapy 504, 510±511 ± combined 510 radiocolloidal sizing technique 97 radiodiagnosis, preoperative 24 radiograph, specimen 164 radioimmunolabeling 3 radioiodine therapy (RIT) 509 ± execution of 509 ± guidelines of radiation control laws 509 ± locoregional recurrence 509 ± painfull swelling of thyroid gland tissue 509
± side effects 509 radioisotope, positron emitting 31 radionuclides ± in conventional / routine nuclear medicine 59, 60 ± physical properties 59, 102 radiopharmacy 32, 33, 339 ± quantitative measurement 33, 34 ± radiopharmaceuticals, table 33, 42 radiotherapy 247 ± accelerated 510 ± adjuvant 210 ± conformational 515 ± external-beam 258 ± hyperfractionated 510 ± IORT (intraoperative electron beam radiotherapy) 510 ± with 4500 cGy 518 random error, detection counts 127 recurrences, locoregional 39 regeneration cancer 371 region of interest (ROI) 156 reliability, measurement 127 renal cell cancer 531 ± adrenal-sparing surgery 492 ± clear-cell 297 ± cytology 487 ± lymph drainage, laterality 485±487 ± lymph node investigation, possible methods 489±491 ± lymphadenectomy, retroperitoneal 491, 492 ± lymphatic basins 486 ± metastases, rate of 484 ± nephrectomy, radical / partial 494 ± operative principles 484 ± prognosis, locoregional lymph node dissection 483, 484 ± prognostic factors, significance for treatment strategies 490, 491 ± sentinel lymph node ± ± detection, cancer-specific immune response 491 ± ± labeling 492 ± stages, figure 487 ± staging 487, 488 ± ± before surgical treatment 484, 485 ± ± N-staging, FDG-PET 493, 494 ± ± Robson system 484 ± ± TNM system 484 ± studies in progress and preliminary results 531 ± survival rates 490 ± therapy regimens 531±532 ± ± adjuvant therapy regimens 494 ± ± chemotherapy 531 ± ± immune therapy 531 ± ± radiotherapy 531 ± ± studies in progress and preliminary results 531±532 reirradiation 512
Subject Index resolution ± probe 61 ± spatial 113, 114 ± ± good / bad 116 rhabdomyosarcoma 18, 362, 427 risk ± category, endocrine responsive and non-responsive 405 ± factors, classification according 504 ± ± average 504 ± ± minimal 504 Robson system 484 ROLL (radioguided occult lesion, localization) 42 Rotterdam Breast Cancer Research Group 40, 48 round cell picture 422 S S-100 ± protein 422 ± reaction 338 safety standard protocol 110 salivary gland cancer 284±293 ± special subtypes 297 Santa Monica Conference 499 sarcoidosis-like granuloma 443 sarcoma ± Ewing sarcoma 427 ± osteosarcoma, small-cell 427 ± rhabdomyosarcoma 18, 362, 427 ± synovial 17, 18 ± treatment / therapy regimen 529 satellite ± concept 32 ± focus 208 scan, pre- / postcontrast 157 Schmincke cancer 292 schwannoma, malignant 337 scintigraphy ± 131I 258 ± external scintigraphic radiation detector 31 ± 111indiumoctreotide 424 ± lymphatic outflow scintigraphy (LAS) 347 ± lymphoscintigraphy 54, 278, 339 ± somatostatin receptor 410, 411, 423 ± 99mtechnetium 2-methoxyisobutylisonitrile (MIBI) 258 ± thallium-201 258 ± whole body 258 scintillation crystal 43 SCLC (small-cell lung cancer; see also lung cancer) 301, 308, 312, 513±514 SCNB (stereotactic core needle biopsy) 132 ± disadvantage 136 screening programs, breast cancer 205 seborrheic verrucae, pigmented 331 selectivity, spatial 113
seminoma 17, 442±444 sensitivity 113, 115, 157 ± probe 61 ± radial distribution 114 ± regular sensitivity testing 91 sentinel node / lymph node ± definition 3, 4 ± pseudosentinel 94 ± SNNS (sentinel node navigation surgery) 82 ± substitute 94 sestamibi, 99mTc-sestamibi 7 SFNAC (stereotactic fine-needle aspiration cytology) 132 ± cytological findings ± ± correlation with histological findings 141 ± ± table 140 ± false-negative rate 139 ± quality of sampling 139±142 ± statistical evaluation 142 shape, probe 113, 118 shielding 113, 115 shields 94 shinethrough phenomen 93 SIADH (inappropriate antidiuretic hormone production) 302 sialadenitis 509 side effects 509±510 signal ± box, intraoperative 93 ± 18F 32 ± intensity ratio (SIR) 156 silicon implants, examination of the breast 206 Simon apical foci in lung tuberculosis 302 Sinerem 8, 26 ± method 283 SIR (sensitive image reading) 181 skin, nonmelanoma lesions 331 skip metastasis 15, 80, 96, 179, 232, 323, 389, 431 SLNs ± of colorectal cancers 392±393 ± false-negative rate 391 ± labeling ± ± of gastrointestinal cancer, labeling by analogy with Tsioulias 383 ± ± of intestinal cancer 391±392 ± ± of pancreatic cancer 391±392 ± ± in a working formulation 536 ± up-staging 391 SNEC (sinonasal neuroendocrine carcinoma) 524 SNNS (sentinel node navigation surgery) 82 SNUC (sinonasal undifferentiated carcinoma) 524 soft tissue tumors, therapy regimens 530 somatostatin ± analoga 522
± receptor 406, 407, 424 ± ± antibody 24, 102 ± ± scintigraphy 410, 411, 423 somatostatin-receptor-scintigraphy (SRS-scan) positive neuroendocrine tumors 522 somatostatinoma 414 South West Oncology Study Group: treatment of metastatic or recurrent esophageal cancer 517 spatial resolution 35, 110 SPDP (N-succinimidyl 3(2'pyridyldithio)propionate) 26 specificity 157 SPECT (single photon emission computed tomography) 425 SPET (single photon emission tomography) 103 spilling over 378 spillover 71, 107, 108 ± high 41 ± vulvar cancer 433 squamous cell cancer ± head and neck (HNSCC) 283, 286 ± ± adjuvant therapy regime 292 St. Gallen consensus meeting 2003 504 staging ± downstaging 246 ± intraoperative 55±57, 232 ± M-staging 141 ± N-staging 177 ± PET 35, 181 ± primary 16 ± upstaging 15, 84 staining ± cytokeratin 230 ± Giemsa 355 ± Gomori 401 ± Grimelius 314, 401 ± immunohistochemical (see immunohistochemistry) standard deviation 127 statistics / statistical evaluation 127 sterilization, gamma probe 228±250 steroidhormone receptor expression, threshold of 506 strategies, combined radiological and histological cancer diagnosis 161±174 streptozotocin, 5-fluorouracil, and doxorubicin 523 stroma invasion, early 220 subareolar circle 75 substance P 425 suitability, minimally invasive diagnostic methods 136 sulfur colloid 98 Sulphur Colloid 60 Sunbelt Melanoma Clinical Trial 340 SUR (standardized uptake ratio) 33 surgeon, pregnant female 7
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Subject Index surgical investigation, techniques 89±98 ± blue dye ± ± combined use with 99mTc labeling 92 ± ± mapping, critical points 90 ± complete surgical removal 120 ± evaluation, sentinel node, benefits 96 ± gamma probe, practical use / servicing 91±94 ± histopathology, lymphatic system 89 ± ± procedure 95, 96 ± labeling ± ± contrast solution, choice 96±99 ± ± different cellular compartments, lymph node 89, 90 ± ± pitfalls 94 ± probe guidance 91 ± radiodiagnostic technique 96 SUV (standardized uptake value) 33 Swedish multicenter breast cancer trial 500 Sydney Melanoma Unit 499 syndromes / diseases (names only) ± Bowen's disease 440 ± Cushing syndrome 302 ± Hodgkin's disease 308, 310, 315 ± Horner symptom complex 303 ± Paget's disease 221, 227 synovial sarcoma 362 synthesis, time of 32 syringe ± Cameco 139, 259 ± computed guided 171 ± quality, FNAC 259, 260 systemic basin involvement 80 T TAC scheme according to Nabholtz 505 tamoxifen 504±507 ± alternatives to 506 ± anastrozole, superior to tamoxifen 507 ± ATAC-tamoxifen studies 506 ± better with respect to musculoskeletal disorders and fractures 507 ± cerebrovascular events 507 ± endometrium carcinoma development 507 ± no inhibitory effect 529 ± pros and contras for breast cancer prevention 506 ± vaginal bleeding 507 ± venous thrombosis 507 ± versus letrozole: c-erb B1 and / or B2-positive cancer cases 507 tarceva = erlotinib 515 taxane, combined therapy / radiochemotherapy
± 5-fluorouracil, cis- or carboplatin, mitomycin, and taxane 510 ± taxane, gemcitabine, vinorelbine 514 teacup phenomen 184 technetium (99mTc) 42 ± nanocolloidals (see there) ± 99mTc-colloidal albumin 44, 49, 60 ± 99mTc-dextran 98 ± 99mTC DTPA 68, 501 ± 99mTc-labeled immunoglobulins 60 ± 99mTc MIBI 44, 258 ± 99mTc-sestamibi 7 technical news 501, 502 Tec-Probe 2000 92 temozolomide (TMZ) 362 ± in combination with IFNa 362 ± in combination with thalidomide 362 teratoma 423 ± ovarian 342, 423 ± testicular 442 testicular cancer ± biological prognostic factors 444, 445 ± combined type 442 ± macroscopic / microscopic features 442, 443 ± N-staging, FDG-PET 446 ± nonseminomatous 442, 444 ± retroperitoneal node labeling, approach 445 ± seminomatous 442 ± stage-related surgical treatment 445, 446 thalidomide 362 ± in combination with IFNa 531 ± in combination with temozolomide (TMZ) 362 therapy regimens used in adjuvant and neoadjuvant treatment 503±541 ± adjuvant treatment (see there) 503±504 ± anti-HER2-therapy 507 ± breast cancer 504±508 ± cervical cancer 536±537 ± colorectal cancers 520±521 ± esophageal cancer 517 ± gastric cancer 518 ± head and neck cancers 510±512 ± lung cancer, chemotherapy regimens 513±516 ± malignant melanoma 529 ± neuroendocrine tumors 522±528 ± prostate cancer 533±535 ± renal cell cancer 531±532 ± soft tissue tumors 530 ± tested and international tested regimens 503 ± thyroid cancer 509 ± urinary bladder cancer 538±539 third generation drugs 515 thoracic duct 55
three-field dissection 13 thrombosis ± prophylaxis 506 ± renal vein 485 thymoma 308, 310, 315, 317 thyroid cancer 101, 509 ± atypically located nodes, pitfalls 262 ± detection rates 259 ± diagnosis, preoperative 262±274 ± FDG-PET, T- / N-staging 257, 258 ± FNAC 258±260 ± follicular 262, 267±270, 278 ± ground-glass nuclei 265 ± investigation, strategies 279 ± labeling strategy, choice 274 ± level-related grouping 276 ± low-differentiated 262 ± lymph node groups 276 ± lymphatic drainage, main basins 275 ± lymphatic spread, regional 262 ± medullary 266, 272, 274, 403 ± ± N-staging 406 ± ± spindle-cell differentiated 266 ± multifocality 265 ± oncocytoma 265, 271, 272, 281 ± papillary 257, 262 ± ± in childhood 263 ± ± oncocytic type 267 ± ± sentinel node labeling 280 ± ± squamous cell metaplasia 266 ± perforation of capsule 266 ± practicability of sentinel node concept 257 ± primaries, properties 258±281 ± pT classification 260, 261 ± risk factors 259 ± RIT (thyroid gland tissue), painfull swelling, 509 ± sentinel node ± ± concept, value 280, 281 ± ± labeling 278 ± ± search 275±280 ± small-cell anaplastic 264 ± targeting 426 ± therapy regimens 281, 509 ± ± chemotherapy 509 ± ± dependence of sentinel lymph node status 281 ± ± radioiodine therapy 509 ± undifferentiated 262, 281 ± vascular invasion 263, 266 thyroidectomy, subtotal 277 tinea nigra 331 tissue sampling 167 TNM-classification, renal cell cancer 484, 485 tongue, cancer 287 ± sentinel lymph node investigation 288 topotecan, gemcitabine and vinorelbine 515
Subject Index tracer ± administration, precision 64, 65 ± application modality 43 ± experimental studies 49 ± injection site 7 ± most frequently used 25±27 ± resorption 51 ± storage 51 ± usage, harmonization 43 transferrin 26 trastuzumab (herceptin) 507, 529 ± block cell cycle progression 507 ± combined therapy modalities ± ± adriamycin, cyclophosphamide and paclitaxel 508 ± ± paclitaxel plus trastuzumab 508 ± payment by insurance companies for adjuvant treatment of breast cancer 508 ± HER2-receptor down regulation 507 triple diagnosis, primary 48 Tsioulias (Research group, Calif., USA 383 tuberculoma 306 tumor (see also cancer) ± cells, single, intraoperative search 145 ± clearance, improvement 426 ± shadow disappearance rate (TDR) 302 two-step operation procedure 244 tyrosinase, mRNA coding 331 U UK trial (big lung trial) 514 ultrasonography / ultrasound ± endoscopic (EUS) 370 ± guidance labeling 64 upstaging 15, 84 uranium-235 96 urinary
± ± ± ± ±
bladder cancer 17, 481±483, 538±539 ± carcinoma in situ 481 ± long term survival 481 ± papillary exophytic 481 ± sentinel node, detection rate 482 ± ± staging, PET 483 ± ± therapy regimens 538±539 ± ± ± early stages, therapeutic options 538 ± ± ± guidelines of the German Cancer Society 538 ± ± ± indications of installation therapy 538 ± ± tumor associated antigens 483 ± trakt ± ± renal cell cancer 483±494 ± ± urogenital cancer 85±86 USPIO (ultrasmall paramagnetic iron oxide particles) 26, 42, 81, 89, 326, 489 ± preoperative axillary lymph node diagnosis 155±159 ± ± value, evaluation 157, 158 V vaginal cancer 17 ± prognosis factors 45 van Nuys-Holland-classification 129, 228 vascular permeability 220 vascularization, local 90 VEG-blocking substance: avastin 541 vein, opening 4 venous angle 55 vimentin 487 ± double-expression 264 vincristine 328 ± combined therapy / chemotherapy ± ± adriamycin, cyclophosphamide and vincristine (ACO II) 513
± ± CEV (carboplatin, etoposide and vincristine) 513 ± ± epirubicin, cyclophosphamide and vincristine (EPICO) 513 vinorelbine, combined therapy ± cisplatin plus vinorelbine 515 ± taxane, and gemcitabine 514 ± topotecan, gemcitabine and vinorelbine 515 vipoma 414, 419 Virchow gland 292 visualization, lymphatics 41 voice preservation, head and neck cancers 511 vulvar cancer 17, 18, 86, 431±434 ± acceptance, sentinel node concept 434 ± local recurrence, depression 434 ± prognosis factors 45 ± sentinel node ± ± detection 433 ± ± mapping 432 ± therapy regimens 535 ± ± chemotherapy, limitations 535 ± ± by FIGO staging 535 ± ± postoperative radiotherapy 535 W wait and see strategy 16, 281, 466 wallpaper cancer 81 Warburg theory 34 wash-out effect 206 water as a radiopharmaceutical 33 Whitmore's staging scheme 464±466 Wilms, nephroblastoma 427 Y Y-shaped configuration 184 Z ZD-6474 project 516 Zçrich research group
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