Recent Advances in Liver Surgery

MEDICAL INTELLIGENCE UNIT

Renzo Dionigi DIONIGI MIU

Recent Advances in Liver Surgery

Recent Advances in Liver Surgery

Medical Intelligence Unit

Recent Advances in Liver Surgery Renzo Dionigi, MD, FACS, FRCS Department of Surgical Sciences University of Insubria Varese, Italy

Landes Bioscience Austin, Texas USA

Recent Advances In Liver Surgery Medical Intelligence Unit Landes Bioscience Copyright ©2009 Landes Bioscience All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the USA. Please address all inquiries to the publisher: Landes Bioscience, 1002 West Avenue, Austin, Texas 78701, USA Phone: 512/ 637 6050; Fax: 512/ 637 6079 www.landesbioscience.com ISBN: 978-1-58706-317-6 While the authors, editors and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Library of Congress Cataloging-in-Publication Data Recent advances in liver surgery / [edited by] Renzo Dionigi. p. ; cm. -- (Medical intelligence unit) Includes bibliographical references and index. ISBN 978-1-58706-317-6 1. Liver--Surgery. I. Dionigi, Renzo. II. Series: Medical intelligence unit (Unnumbered : 2003) [DNLM: 1. Liver--surgery. 2. Liver Neoplasms--surgery. 3. Liver Transplantation. WI 770 R295 2009] RD546.R383 2009 617.5'562--dc22 2009003812 .

"The superior man is modest in his speech, but exceeds in his actions" —Confucius (551 BC-479 BC The Confucian Analects)

About the Editor...

Renzo Dionigi is Professor of Surgery and Rector of the University of Insubria in Varese, Italy. His main research interests include identification of high risk surgical patients, surgical immunobiology, cancer, nutrition and immunocompetence, whereas his major interests in clinical surgery are esophageal, pancreatic and liver surgery, and kidney and pancreas transplantation in HIV patients. He is honorary and ordinary member of numerous national and international scientific organizations, including the American College of Surgeons (ACS), the Royal College of Surgeons of Edinburgh (Honorary), the European Society for Surgical Research (President in 1982), the International Surgical Group (President in 1992). He is a member of the editorial boards of several major scientific journals, and has been invited as Visiting Professor in the most prestigious universities of the five continents. He is author or co-author of more than 700 scientific articles, 41 chapters in medical and surgical textbooks, 13 textbooks on surgical topics. http://www.renzodionigi.com

CONTENTS Preface........................................................................................................ xxi 1. Liver Surgery: A Historical Account............................................................1 Renzo Dionigi, Giulio Carcano, Gianlorenzo Dionigi and Francesca Rovera Renaissance .................................................................................................................2 Early Sporadic Liver Resections .............................................................................8 Elective Surgery .......................................................................................................11 In-Flow Vascular Occlusion ..................................................................................14 Anatomic Surgery and Intraoperative Sonography .........................................16 2. Genetics of Hepatocellular Carcinoma ......................................................20 Andreas Teufel and Peter R. Galle Chromosomal Aberrations .................................................................................. 20 p53 ...............................................................................................................................21 Wnt Signalling Pathway ....................................................................................... 22 TGFβ Pathway ........................................................................................................ 23 Ras Signalling .......................................................................................................... 24 PDGF Signalling .....................................................................................................25 Rb ............................................................................................................................... 26 Genome-Scale Analysis of Gene Expression in HCC.................................... 26 Altered DNA Methylation in HCC .................................................................. 27 Databases of Genetics of HCC ........................................................................... 28 3. Staging Algorithms for Patients with HCC and Prognostic Indicators ....35 Christos S. Georgiades Staging Systems ....................................................................................................... 36 Prognostic Variables............................................................................................... 40 Staging Algorithms .................................................................................................41 4. Staging Systems to Predict Survival in Hepatocellular Carcinoma ...........49 Sonia Pascual and Miguel Pérez-Mateo Staging System in Hepatocellular Carcinoma ..................................................51 TNM ..........................................................................................................................52 Okuda ........................................................................................................................52 CLIP...........................................................................................................................52 BCLC ........................................................................................................................ 54 JIS............................................................................................................................... 54 Other Prognostic Staging Systems ..................................................................... 56 5. Virtual Liver Surgery: Computer-Assisted Operation Planning in 3D Liver Model .......................................................................60 Hauke Lang, Milo Hindennach, Arnold Radtke and Heinz Otto Peitgen Technology ...............................................................................................................61 Clinical Experience .................................................................................................61 Outlook .....................................................................................................................65 Practical Guide and Summary ............................................................................ 66

6. Transection Techniques in Liver Surgery ...................................................68 Luigi Boni, Gianlorenzo Dionigi, Mario Diurni and Renzo Dionigi Circumferential Hepatic Compression ............................................................. 68 “Finger-Fraction” and “Crush-Clamp” Technique ..........................................69 Water-Jet Parenchymal Transection ...................................................................69 Ultrasonic Energy ...................................................................................................70 Radiofrequency Assisted Hepatic Resection ................................................... 72 Heat Conducting Technique............................................................................... 72 Surgical Staples ........................................................................................................74 Results of Different Types of Transection Techniques...................................75 7. Vascular Isolation Techniques in Liver Resection ......................................80 Jacques Belghiti, Safi Dokmak and Catherine Paugam-Burtz Anatomic Basis for Vascular Control .................................................................81 Surgical Aspects of Vascular Clamping..............................................................81 Hemodynamic Response to Different Types of Clamping............................91 Anesthetic Considerations ................................................................................... 92 8. Preoperative Portal Vein Embolization for Hepatocellular Carcinoma ....98 Taku Aoki, Hiroshi Imamura, Takuya Hashimoto, Norihiro Kokudo and Masatoshi Makuuchi Preoperative PVE for HCC ................................................................................. 98 Sequential TACE and PVE.................................................................................. 99 Indications for Preoperative PVE in Patients with HCC ............................. 99 Technique of PVE ................................................................................................ 101 Approach ................................................................................................................ 101 Embolization Materials ...................................................................................... 102 Portal Venous Pressure after PVE..................................................................... 105 Clinical Course after PVE.................................................................................. 105 Volumetric Changes after PVE ......................................................................... 105 Histological Changes after PVE ....................................................................... 107 Effect of PVE on Hepatic Functional Reserve .............................................. 107 Results of Hepatic Resections following PVE ............................................... 107 9. Vascular Embolotherapy in Hepatocellular Carcinoma ..........................112 Saad M. Ibrahim, Gianpaolo Carrafiello, Robert J. Lewandowski, Robert K. Ryu, Kent T. Sato, Reed A. Omary and Riad Salem Technique............................................................................................................... 112 Transarterial Embolization ................................................................................ 113 Transarterial Chemoembolization ....................................................................114 Yttrium-90 Radioembolization .........................................................................115 Drug Eluting Beads ...............................................................................................117 10. Sequential Arterial and Portal Vein Embolization before Right Hepatectomy in Patients with Cirrhosis and Hepatocellular Carcinoma ...122 Jacques Belghiti, Béatrice Aussilhou and Valérie Vilgrain Rationale ................................................................................................................ 122 History .................................................................................................................... 124

Hospital Beaujon’s Experience .......................................................................... 124 Complications ....................................................................................................... 126 11. Intraoperative Ultrasonic Examination in Liver Surgery.........................129 Junichi Arita, Norihiro Kokudo, Keiji Sano and Masatoshi Makuuchi History .................................................................................................................... 130 Transducer ............................................................................................................. 130 Intraoperative Surveillance ................................................................................ 131 Guidance for Hepatic Resection ....................................................................... 133 Contrast-Enhanced IOUS .................................................................................134 12. Perioperative Blood Transfusion in Hepatocellular Carcinomas ............141 Gianlorenzo Dionigi, Salvatore Cuffari, Giovanni Cantone, Alessandro Bacuzzi and Renzo Dionigi Allogeneic Blood Transfusion ........................................................................... 142 Intraoperative Autotransfusion ........................................................................ 142 Preoperative Autologous Blood Donation ..................................................... 144 Intraoperative Isovolemic Hemodilution ....................................................... 145 Discussion .............................................................................................................. 146 13. Inferior Vena Cava Resection for Infiltrating Hepatic Malignancy .........153 Gabriele Piffaretti, Gianlorenzo Dionigi, Matteo Tozzi, Patrizio Castelli and Renzo Dionigi Surgical Anatomy ................................................................................................. 154 Diagnosis .................................................................................................................155 Treatment ............................................................................................................... 158 Discussion .............................................................................................................. 160 14. Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement ......................................................................166 Tsuyoshi Sano and Yuji Nimura General Preoperative Examination for Liver Functional Reserve ............ 167 HCC with Tumor Thrombus in the Main Portal Trunk or Major Portal Vein Branches ...................................................................................... 167 Right Anterior Sectionectomy .......................................................................... 167 Hemihepatectomy ................................................................................................ 169 HCC with Tumor Thrombus in the Biliary Tree ......................................... 173 HCC with Tumor Thrombus in the Hepatic Vein and/or Inferior Vena Cava (IVC) ............................................................................................. 176 15. Surgical Strategies and Technique for Hilar Cholangiocarcinoma .........187 Tsuyoshi Sano and Yuji Nimura Preoperative Staging of Hilar Cholangiocarcinoma .................................... 189 Preoperative Management.................................................................................. 192 Surgery .................................................................................................................... 194 General Procedures in Resectional Surgery for HC..................................... 194 Left Hemihepatectomy with Caudate Lobectomy ....................................... 196 Right Hemihepatectomy with Caudate Lobectomy....................................200 Portal Vein Resection and Reconstruction ....................................................204 Right Trisectionectomy with Caudate Lobectomy ......................................204

Left Trisectionectomy with Caudate Lobectomy .........................................207 Hepatopancreatoduodenectomy....................................................................... 212 Hepatic Arterial Resection and Reconstruction during Hepatobiliary Resection ........................................................................................................... 212 16. Resection of Noncolorectal Cancer Liver Metastases..............................214 Cristina R. Ferrone and Kenneth K. Tanabe Noncolorectal Hepatic Metastases ................................................................... 214 Neuroendocrine Tumors .................................................................................... 214 Noncolorectal Nonneuroendocrine Hepatic Metastases.............................215 Breast Cancer ........................................................................................................ 216 Sarcoma................................................................................................................... 217 Melanoma .............................................................................................................. 217 Noncolorectal Gastrointestinal Tumors ......................................................... 218 Genitourinary and Reproductive Tract Primary Tumors........................... 218 17. Current Role of Laparoscopic Surgery for Liver Malignancies ...............221 Andrew A. Gumbs and Brice Gayet Indications ............................................................................................................. 221 Preoperative Work-Up ........................................................................................222 Operating Room Set-Up .....................................................................................222 Trochar Placement ...............................................................................................223 Mobilization of the Liver....................................................................................224 Isolation and Transection of the Hepatic Inflow.......................................... 225 Isolation of the Hepatic Outflow .....................................................................226 Transection of the Hepatic Parenchyma ......................................................... 229 Transection of the Hepatic Outflow................................................................ 229 The Lateral Approach .......................................................................................... 231 Post Operative Management ............................................................................. 231 18. Loco-Regional Ablative Therapies for Colorectal Metastases .................234 Riccardo Lencioni, Laura Crocetti and Dania Cioni Eligibility Criteria ................................................................................................234 Technique............................................................................................................... 235 Complications ....................................................................................................... 238 Clinical Outcomes ............................................................................................... 241 Other Ablative Therapies.................................................................................... 241 19. Sepsis after Liver Resection: Predisposition, Clinical Relevance and Synergism with Liver Dysfunction ....................................................245 Gennaro Nuzzo, Ivo Giovannini, Felice Giuliante, Francesco Ardito and Carlo Chiarla General Predisposing Factors ............................................................................ 245 Underlying Diseases and the Disease Requiring Liver Resection .............246 Liver Resection (the Operation) ....................................................................... 247

Microbiology .........................................................................................................248 Prevention of Sepsis .............................................................................................248 Bile Leaks as the Cause of Sepsis ...................................................................... 249 Postoperative Recognition of Sepsis................................................................. 249 Synergism between Sepsis and Liver Insufficiency ....................................... 249 Synergism of Sepsis and Liver Dysfunction on Blood Chemistries .......... 250 Impact of Postoperative Sepsis on Long-Term Outcome ............................ 254 20. Percutaneous Treatment of Surgical Bile Duct Injury .............................260 Gianpaolo Carrafiello, Domenico Laganà, Monica Mangini, Federico Fontana, Massimiliano Dizonno, Andrea Ianniello, Elisa Cotta, Riad Salem and Carlo Fugazzola Classification ......................................................................................................... 261 Leak ......................................................................................................................... 262 Imaging ................................................................................................................... 263 Biloma ..................................................................................................................... 267 Stricture .................................................................................................................. 270 Arteriobiliary or Venousbiliary Fistula (Hemobilia) ................................... 275 21. Response Evaluation Criteria in Hepatocellular Carcinoma (Moving beyond the RECIST) .................................................................282 Carlo Fugazzola, Gianpaolo Carrafiello, Chiara Recaldini, Elena Bertolotti, Tamara Cafaro, Maria Gloria Angeretti, Paolo Nicotera and Domenico Lumia Dimensional Criteria...........................................................................................282 Functional Criteria ..............................................................................................284 Contrast Enhancement .......................................................................................287 Follow-Up of HCCs Treated with TACE ......................................................288 Follow-Up of HCCs Treated with Radiofrequency Ablation ................... 293 Follow-Up of HCCs Treated with Radioembolization .............................. 299 22. One Liver for Two: Split and Living Donor Liver Transplantation for Adult and Pediatric Patients ...............................................................305 Bruno Gridelli, Salvatore Gruttadauria, Angelo Luca, Marco Spada, Riccardo Volpes, Wallis Marsh and Amadeo Marcos Living Donor Liver Transplantation: Donor Selection and Outcomes......306 Split Liver Transplantation: The Sharing of a Cadaver Liver .....................307 Left Lateral Segment Transplantation in Children: Technique and Results ........................................................................................................309 Live-Donor Hepatectomy: Technical Aspects ..............................................309 LDLT: Technical Aspects of the Recipient Operation ................................ 310 Imaging in Planning LDLT and Treatment of Post-Operative Complications .................................................................................................. 310 LDLT: Recipient Outcomes .............................................................................. 312 The Small-For-Size Syndrome............................................................................ 313 LDLT: Special Considerations ...........................................................................315

23. Radiological Intervention for Treatment of Complications after Liver Transplantation .......................................................................319 Giovanni Gandini, Maria Carla Cassinis, Dorico Righi, Andrea Doriguzzi-Breatta, Maria Cristina Martina and Maria Antonella Ruffino Vascular Complications ...................................................................................... 321 Biliary Complications ......................................................................................... 324 24. Hepatocyte Transplantation: A New Approach to Treat Liver Disorders .........................................................................................331 Javed Akhter, Loreena A. Johnson and David L Morris A Brief History of Animal Hepatocyte Transplantation Research .......... 332 Clinical Sources of Hepatocytes ....................................................................... 333 Split-Liver ............................................................................................................... 334 Foetal Hepatocytes .............................................................................................. 334 Stem Cells .............................................................................................................. 334 Immortalized Hepatocyte Cell Lines.............................................................. 334 Xenogenic Hepatocytes ...................................................................................... 335 Hepatocytes from Resected Livers ................................................................... 335 Isolation, Functionality and Preservation of Hepatocytes ......................... 336 Hepatocyte Viability and Function ................................................................. 338 Preservation of Isolated Hepatocytes .............................................................. 338 Engraftment and Proliferation Adjuncts ........................................................340 Encapsulation ........................................................................................................341 Hepatocyte Cellular Mass Required for Transplantation ..........................342 Routes of Hepatocyte Implantation ................................................................342 Human Hepatocyte Transplantation Experience ........................................344 25. Liver Transplantation in HIV-Infected Individuals ................................352 Paolo Antonio Grossi The Need: Liver Disease in HIV-Infected Individuals ................................ 353 Referral for Transplant Evaluation and Selection Criteria ......................... 353 Immunosuppression, HAART and Drug Interactions............................... 354 Management of HCV and HBV Recurrence after Transplantation ........ 355 Worldwide Experience of Liver Transplantation in the HAART Era .... 355 Appendix. Partial Hepatectomy after Liver Transplantation: Inclusion Criteria, Timing of Surgery and Outcome...............................359 Franco Filipponi and Franco Mosca Partial Hepatectomy after Liver Transplantation: Inclusion Criteria, Timing of Surgery and Outcome ................................................................. 359 Materials and Methods .......................................................................................360 Results .....................................................................................................................360 Index .........................................................................................................363

EDITOR Renzo Dionigi

Department of Surgical Sciences University of Insubria Varese, Italy Email: [email protected] Chapters 1, 6, 12, 13

CONTRIBUTORS Note: Email addresses are provided for the corresponding authors of each chapter. Javed Akhter Department of Surgery St. George Hospital Sydney, Australia Email: [email protected]

Béatrice Aussilhou Department of HPB Surgery University of Paris Hospital Beaujon Paris, France

Maria Gloria Angeretti Department of Radiology University of Insubria Varese, Italy

Alessandro Bacuzzi Department of Anesthesiology Azienda Ospedaliera-Polo Universitario Varese, Italy

Taku Aoki Department of Surgery Graduate School of Medicine University of Tokyo Tokyo, Japan Chapter 8

Jacques Belghiti Department of HPB Surgery University of Paris Hospital Beaujon Paris, France Email: [email protected]

Francesco Ardito Department of Surgery Catholic University of the Sacred Heart School of Medicine Rome, Italy

Elena, Bertolotti Department of Radiology University of Insubria Varese, Italy

Chapter 24

Chapter 21

Chapter 19

Junichi Arita Department of Surgery Graduate School of Medicine University of Tokyo Tokyo, Japan Email: [email protected] Chapter 11

Chapter 10

Chapter 12

Chapters 7, 10

Chapter 21

Luigi Boni Department of Surgical Sciences University of Insubria Varese, Italy Email: [email protected] Chapter 6

Tamara Cafaro Department of Radiology University of Insubria Varese, Italy Chapter 21

Giovanni Cantone Department of Anesthesiology Azienda Ospedaliera-Polo Universitario Varese, Italy Chapter 12

Giulio Carcano Department of Surgical Sciences University of Insubria Varese, Italy Chapter 1

Gianpaolo Carrafiello Department of Radiology University of Insubria Varese, Italy Chapters 9, 20, 21

Maria Carla Cassinis Department of Radiology University of Turin San Giovanni Battista Hospital Turin, Italy Chapter 23

Patrizio Castelli Department of Surgical Sciences University of Insubria Varese, Italy Chapter 13

Carlo Chiarla Department of Surgery Catholic University of the Sacred Heart School of Medicine Rome, Italy Chapter 19

Dania Cioni Department of Oncology, Transplants, and Advanced Technologies in Medicine University of Pisa Pisa, Italy Chapter 18

Elisa Cotta Department of Radiology University of Insubria Varese, Italy Chapter 20

Laura Crocetti Department of Oncology, Transplants, and Advanced Technologies in Medicine University of Pisa Pisa, Italy Chapter 18

Salvatore Cuffari Department of Anesthesiology Azienda Ospedaliera-Polo Universitario Varese, Italy Chapter 12

Gianlorenzo Dionigi Department of Surgical Sciences University of Insubria Varese, Italy Chapters 1, 6, 13

Mario Diurni Department of Surgical Sciences University of Insubria Varese, Italy Chapter 6

Massimiliano Dizonno Department of Radiology University of Insubria Varese, Italy Chapter 20

Safi Dokmak Department of HPB Surgery University of Paris Hospital Beaujon Paris, France Chapter 7

Andrea Doriguzzi-Breatta Department of Radiology University of Turin San Giovanni Battista Hospital Turin, Italy Chapter 23

Cristina R. Ferrone Instructor of Surgery Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA Chapter 16

Franco Filipponi Department of General Surgery and Transplantation University of Pisa Pisa, Italy Email: [email protected] Appendix

Federico Fontana Department of Radiology University of Insubria Varese, Italy Chapter 20

Carlo Fugazzola Department of Radiology University of Insubria Varese, Italy Email: [email protected] Chapters 20, 21

Peter R. Galle Department of Internal Medicine Johannes Gutenberg University Mainz, Germany Chapter 2

Giovanni Gandini Department of Radiology University of Turin San Giovanni Battista Hospital Turin, Italy Email: [email protected] Chapter 23

Brice Gayet Department of Digestive Diseases Instiut Mutualiste Montsouris University René Descartes Paris, France Email: [email protected] Chapter 17

Christos S. Georgiades Fellowship Program Director Vascular & Interventional Radiology Johns Hopkins Hospital Baltimore, Maryland, USA Email: [email protected] Chapter 3

Ivo Giovannini Department of Surgery Catholic University of the Sacred Heart School of Medicine Rome, Italy Chapter 19

Felice Giuliante Department of Surgery Catholic University of the Sacred Heart School of Medicine Rome, Italy Chapter 19

Bruno Gridelli Mediterranean Institute for Transplantation and Advanced Specialized Therapies University of Pittsburgh Medical Center in Italy Palermo, Italy Email: [email protected] Chapter 22

Paolo Antonio Grossi Department of Clinical Medicine University of Insubria Varese, Italy Email: [email protected]

Hiroshi Imamura Department of Surgery Graduate School of Medicine University of Tokyo Tokyo, Japan

Salvatore Gruttadauria Mediterranean Institute for Transplantation and Advanced Specialized Therapies University of Pittsburgh Medical Center in Italy Palermo, Italy

Loreena A. Johnson Department of Surgery St. George Hospital Sydney, Australia

Chapter 25

Chapter 22

Andrew A. Gumbs Division of Upper GI and Endocrine Surgery Columbia University College of Physicians and Surgeons New York, New York, USA Chapter 17

Takuya Hashimoto Department of Surgery Graduate School of Medicine University of Tokyo Tokyo, Japan Chapter 7

Milo Hindennach MeVis Bremen, Germany Chapter 5

Andrea Ianniello Department of Radiology University of Insubria Varese, Italy Chapter 20

Saad M. Ibrahim Division of Radiology Northwestern University Chicago, Illinois, USA Chapter 9

Chapter 8

Chapter 24

Norihiro Kokudo Department of Surgery Graduate School of Medicine University of Tokyo Tokyo, Japan Chapters 8, 11

Domenico Laganà Department of Radiology University of Insubria Varese, Italy Chapter 20

Hauke Lang Department of General and Visceral Surgery University Hospital Mainz, Germany Email: [email protected] Chapter 5

Riccardo Lencioni Department of Oncology, Transplants, and Advanced Technologies in Medicine University of Pisa Pisa, Italy Email: [email protected] Chapter 18

Robert J. Lewandowski Division of Radiology Northwestern University Chicago, Illinois, USA Chapter 9

Angelo Luca Mediterranean Institute for Transplantation and Advanced Specialized Therapies University of Pittsburgh Medical Center in Italy Palermo, Italy Chapter 22

Domenico Lumia Department of Radiology University of Insubria Varese, Italy Chapter 21

Masatoshi Makuuchi Department of Surgery Japanese Red Cross Medical Center Tokyo, Japan Email: [email protected]. or.jp Chapter 8

Monica Mangini Department of Radiology University of Insubria Varese, Italy Chapter 20

Amadeo Marcos Thomas Starzl Transplantation Institute University of Pittsburgh Medical Center Pittsburgh, Pennsylvania, USA Chapter 22

Wallis Marsh Thomas Starzl Transplantation Institute University of Pittsburgh Medical Center Pittsburgh, Pennsylvania, USA Chapter 22

Maria Cristina Martina Department of Radiology University of Turin San Giovanni Battista Hospital Turin, Italy Chapter 23

David L. Morris Department of Surgery St. George Hospital Sydney, Australia Chapter 24

Franco Mosca Department of General Surgery and Transplantation University of Pisa Pisa, Italy Appendix

Paolo Nicotera Department of Radiology University of Insubria Varese, Italy Chapter 21

Yuji Nimura Division of Gastroenterological Surgery Aichi Cancer Center Hospital Nagoya, Japan Chapters 14, 15

Gennaro Nuzzo Department of Surgery Catholic University of the Sacred Heart School of Medicine Rome, Italy Email: [email protected] Chapter 19

Reed A. Omary Division of Radiology Northwestern University Chicago, Illinois, USA Chapter 9

Sonia Pascual Unidad Hepática Hospital General Universitario de Alicante Alicante, Spain Email: [email protected] Chapter 4

Catherine Paugam-Burtz Department of HPB Surgery University of Paris Hospital Beaujon Paris, France Chapter 7

Heinz Otto Peitgen MeVis Bremen, Germany Chapter 5

Miguel Pérez-Mateo CIBERehd Instituto de Salud Carlos III Madrid, Spain Universidad Miguel Hernández, Elche Alicante, Spain Chapter 4

Francesca Rovera Department of Surgical Sciences University of Insubria Varese, Italy Chapter 1

Maria Antonella Ruffino Department of Vascular and Interventional Radiology University of Turin San Giovanni Battista Hospital Turin, Italy Chapter 23

Robert K. Ryu Division of Radiology Northwestern University Chicago, Illinois, USA Chapter 9

Gabriele Piffaretti Department of Surgical Sciences University of Insubria Varese, Italy

Riad Salem Department of Radiology Northwestern University Medical School Chicago, Illinois, USA

Arnold Radtke Department of General and Visceral Surgery University of Hospital Mainz, Germany

Keiji Sano Gastroenterological Surgery Division Aichi Cancer Center Hospital Nagoya, Japan

Chapter 13

Chapter 5

Chapters 9, 20

Chapter 11

Chapter 21

Tsuyoshi Sano Hepato-Biliary and Pancreatic Surgery Division Aichi Cancer Center Hospital Nagoya, Japan Email: [email protected]

Dorico Righi Department of Radiology University of Turin San Giovanni Battista Hospital Turin, Italy

Kent T. Sato Division of Radiology Northwestern University Chicago, Illinois, USA

Chiara Recaldini Department of Radiology University of Insubria Varese, Italy

Chapter 23

Chapters 14, 15

Chapter 9

Marco Spada Mediterranean Institute for Transplantation and Advanced Specialized Therapies University of Pittsburgh Medical Center in Italy Palermo, Italy Chapter 22

Kenneth K. Tanabe Division of Surgical Oncology Massachusetts General Hospital Harvard Medical School Email: [email protected] Chapter 16

Andreas Teufel Department of Internal Medicine Johannes Gutenberg University Mainz, Germany Email: [email protected] Chapter 2

Matteo Tozzi Department of Surgical Sciences University of Insubria Varese, Italy Chapter 13

Valérie Vilgrain Department of HPB Surgery University of Paris Hospital Beaujon Paris, France Chapter 10

Riccardo Volpes Mediterranean Institute for Transplantation and Advanced Specialized Therapies University of Pittsburgh Medical Center in Italy Palermo, Italy Chapter 22

PREFACE For many years liver surgery has been considered major surgery, which has been often associated with a high complication rate. Although evidence suggests that better results are achieved in specialized centers with a high volume of procedures, nevertheless liver resections are now carried out in most of the general surgery divisions. Beside the fact that I still believe that liver surgery should be a field of trained specialists, in editing this book I have attempted to cover for the general surgeon all the main topics of liver surgery and to review the very latest innovative developments. Eminent surgeons from different countries agreed to contribute their own views, opinions and results in the management of primary and secondary liver tumours. The book covers most of the topics which are essential elements in modern liver surgery: applied anatomy of the liver with its radiological demonstration, prognostic indicators and staging systems, portal vein embolization, vascular occlusion, intraoperative ultrasonic guided surgery, different transection techniques. I thought necessary to give space to the radiologists in an effort to outline the extraordinary advances of interventional radiology, which have taken place in recent years. Particular consideration has been given to the aspect of avoiding and managing complications. There are also new specific contributions such as partial hepatectomy after transplantation, genetics of hepatocellular carcinoma, hepatocyte transplantation, and computer-assisted operations. Since the first report of a laparoscopic liver resection, hepatic resection using minimally invasive surgery has become increasingly more common; therefore emphasis has been given to this alternative approach. Recently introduced innovative contributions in liver transplantation are also described. In conclusion, I have attempted to take into consideration and discuss most of the innovative developments related to different aspects of liver surgery, and I hope that the book will be of value not only to the experienced surgeon, but also to specialists of different areas. I also wish that some of the contributions, due to their originality, could generate constructive discussion, which could inspire further studies and investigations. Renzo Dionigi, MD, FACS, FRCS Varese, Italy

Acknowledgements An edited work such as this is only as good as the efforts of its contributors and production staff. The Editor is deeply grateful to all those who participated in and supported this project.

Chapter 1

Liver Surgery: A Historical Account

Renzo Dionigi,* Giulio Carcano, Gianlorenzo Dionigi and Francesca Rovera

Abstract

T

his introductory chapter, which includes a list of references for the interested reader, reviews the accomplishments of the past, on which twenty first century surgery of the liver depends on. The first relevant descriptions of the anatomy of the liver appeared with the renditions of Herophilus and Erasistratus. Although military surgeons had occasionally removed fragments of liver protruding through wounds since ancient times, it was not until after the development of anesthesia and antisepsis that formal liver resections have been performed during the late 1800s. The history of liver surgery has been mainly the history of controlling bleeding and in this essay emphasis is given to the vascular occlusion principles that had been developed to control hemorrhage. Moreover, the 20th century studies about the functional anatomy of the liver represent one of the major advancements in the evolution of liver resection techniques. These and many other remarkable advances in the techniques of liver resections, consent to perform elective liver surgery much more safely, if experience of the surgeons and proficiency of the centers are assured. The histories of biliary reconstruction, portal hypertension, treatment of ascites, liver transplantation and laparoscopic liver resection will not be touched upon.

Introduction

The history of liver surgery originates in the civilizations of antiquity, it is fascinating and for many aspects unique since from ancient times till 17th century is principally based on mythological features and eventually on friable evidences. The speculations of Babylonian, Egyptian, Greek and Roman societies, from time immemorial, considered the liver as the noble organ, the organ of life, mainly because it was observed to contain the most blood.1,2 The earliest medically relevant reports of the anatomy of the liver came from the Alexandrian Herophilus of Calcedon (305-283 BC). Sometimes called “the father of anatomy”, Herophilus was a Greek physician who practiced in Alexandria, where human dissections were permitted and he had the opportunity to perform some in public. His findings, included the differentiation between sensory and motor nerves and was one of the first to throughly study the human internal anatomy.3 Herophilus wrote at least nine works, including a commentary on Hippocrates, a book for midwives and treatises on anatomy and the causes of sudden death, all lost in the destruction of the library of Alexandria (AD 272). We know of his findings from Galen citations of his anatomic work. Another Greek anatomist, who continued the methodical investigation of the anatomy of the liver begun by Herophilus, was Erasistratus of Chios (310-250 B.C.) (Fig. 1). He coined the term “parenchyma” (“something poured in beside”) and was the first to propose the nature of an intrahepatic capillary bed.4 Three cenuries later the theories of Galen of Pergamum (AD 129-ca 200 or 216), the celebrated ancient Greek physician, dominated Western medical science for over a millennium. *Corresponding Author: Renzo Dionigi—Department of Surgical Sciences, Azienda Ospedaliera-Polo Universitario, Via Guicciardini, 21100, Varese, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

2

Recent Advances in Liver Surgery

Figure 1. Herophilus and Erasistratus. Detail of a woodcut depicting ancient herbalists and scholars of medical lore “Herophilus and Erasistratus”, in Laurentius Fries, Spiegel der artzney, vor zeyten zu nutz unnd trost den Leyen gemacht, (Balthazar Beek), (Strasburg), 1532 (Courtesy of Wellcome Library, London).

It was Galen (Fig. 2) who persuaded the scientific community that the liver was the principal organ of the human body, arguing that it came into view first of all the organs in the formation of a fetus. “The liver is the source of the veins and the principal instrument of sanguification,” he observed in On the Usefulness of the Parts of the Body. For Galen, it was the liver rather than the heart where blood was most actively formed; it was a warm, soggy organ. If all veins exchanged fluids through the liver, connecting only tenuously to the heart in order to provide a tiny amount of blood to mix with spirit in the arteries, then the liver was the center of the circulation of material substances in the body. Galen’s knowledge was so great, his work so encompassing and his writings so prolific that their fame inhibited further medical progress for thirteen centuries. Paulus Aegineta (Aegina, 625?-690?), a 7th-century Byzantine Greek physician, was the only one to shed a little light during those dark times by writing the medical encyclopaedia Medical Compendium in Seven Books (Fig. 3).5 For many years in the Byzantine Empire, this work contained the sum of all Western medical knowledge and was unrivaled in its accuracy and completeness. The work became a standard text throughout the Arabic World for the next 800 or so years. It was the most complete encyclopaedia of all medical knowledge at the time. Paulus was not only a scribe but also a highly capable surgeon and he gave us descriptions of the débridement of portion of liver protruding from spear and arrow wounds.

Renaissance

The dogmatic influence of Galenic theories retarded the rapid advancement of hepatic anatomy during the Middle Ages through the early Renaissance. Few cadaver dissections were performed and they proved to be too sporadic to submerge the past 1000 years of scholarship. Despite these circumstances, several anatomists cautiously reported inconsistencies and disclosed a few dissentions. Many advances came from Italy about the time of the Renaissance. Antonio Benivieni (1443-1502), a Florentine physician who pioneered the use of the autopsy, published a treatise

Liver Surgery: A Historical Account

3

Figure 2. Claudius Galen, Recetario. Title page of Claudius Galen, Recetario de Galieno optimo e probato a tutte le infermita che acadeno a homini e a donne de dentro e di fuora alli corpi humani, Traduto in vulgare per Maestro Zuane Saracino, Venice: G. de Rusconi, 1518 (Courtesy of Wellcome Library, London).

entitled De Abditis Morborum Causis (“The Hidden Causes of Disease”),6 which is now considered one of the first works in the science of pathology and the first record of special reference to biliary tract disease and its clinical manifestations (Fig. 4). Jacopo Berengario da Carpi (1460-1530) was an Italian physician. His book Anatomia Carpi published in 1523,7 made him the most important anatomist before Andreas Vesalius and, about the liver he claimed that “it has five lobes, sometimes four or three, sometimes two” (Fig. 5).8 The spanish physician Andres Laguna in 1535 wrote of the liver: “It is very rarely divided into five lobes, more frequently into four, most frequently into three lobes”.9 The first great challenge to Galenic orthodoxy in the description of the human body came with the flamish born Andreas Vesalius (1514-1564), described as the ‘most commanding figure in European medicine after Galen and before Harvey’ (Fig. 6). At fifteen Vesalius enrolled at the University of Louvain to study the liberal arts and in 1533 he traveled to Paris to pursue the study of medicine and anatomy under Jacobus Sylvius and Johann Guinther, both exponents of the Galenic school. In the preface of the De humani corporis fabrica, he states that during his studies at Paris he had himself dissected a corpse in the presence of undergraduates. Owing to the war between France and the forces of the Emperor, he was obliged to leave France and returned to Louvain where he conducted an anatomical demonstration before the medical and other faculties. Vesalius completed his medical training at Padua, the famous center of medical education during the Renaissance, where in 1537, after due examination, he was appointed as teacher in surgery and anatomy, a position he held until 1544.

4

Recent Advances in Liver Surgery

The pubblication of Vesalius’ De Humani Corporis fabrica in 1543 marked the advent of a new scientific spirit in anatomy and physiology. In his revolutionary work, Vesalius provided to his contemporaries the most precise description of human anatomy they had ever seen. The woodcuts in this volume, among the most beautiful and most famous of all anatomical drawing, include a naturalistic landscape backdrop of the Paduan countryside. They are usually attributed to Jan Stephan van Calcar (or Kalkar), one of Titian’s pupils in Venice, but there is still some question about whether they were done by him or some other artist of the Titian school. However, they were drawn under the supervision of Vesalius and are therefore anatomically accurate. Vesalius intended this work to be a textbook and so he accompanied this publication with an epitome for students, Suorum de humani corporis fabrica librorum epitome. In the Epitome, the drawings are larger and the text is limited. Because the pages are removable, many copies of the Epitome are incomplete today, making intact copies very rare . Vesalius Tabulae Anatomicae Sex, published in 1538, illustrated a liver with five lobes spread equally around a central point. It is interesting to note that an upper inset on the same figure showed a two-lobed liver. Whether this inset is an inconsistency or just a flattened five-lobed liver is uncertain. The Tabulae incorrectly noted that the venous system originated in the liver, a long hepatic vein existed and portal vein transporting chyle divided into five branches entering the liver, so the latter is more aptly supported.10

Figure 3. Paulus Aegineta, Pauli Aeginetae Medici Opera. Title page of Paulus Aegineta, Pauli Aeginetae Medici Opera, Apud Gulielmum Rovillium, 1589 (Courtesy of Wellcome Library, London).

Liver Surgery: A Historical Account

5

Figure 4. Antonio Benivieni, Libellus de abditis. Page from Antonio Benivieni, Antonii Benivenii Libellus de abditis nonnullis ac mirandis morborum and sanitationum causis, (Parisiis): Prostant ... apud Christianû Wechel, 1528 (Courtesy of Wellcome Library, London).

Later in De Humani Corporis fabrica Libri Septem (1543) Vesalius rectified some of his original errors and provided the most erudite challanges to Galen’s descriptions of the liver. Pictorial interpretations showed a recognizable asymmetric, two-lobed human liver with a small left lobe and larger right lobe. He also noted that the vena cava originated in the heart. He found that the portal vein still divided into five branches, and the liver’s lobular plane of symmetry seemed to be the falciform ligament. Nevertheless, Vesalius guided his contemporary scientists in a new era of medical discovery based on a growing interest in human anatomy. Anatomic studies significantly increased in all areas, especially in relation to human vasculature. William Harvey (1578-1657) was an English physician, who is credited with being the first to correctly describe, in exact detail, the systemic circulation and properties of blood being pumped around the body by the heart.11 Harvey was born in Folkestone, Kent, England (the nearest hospital to Folkestone (in Ashford) is named after him) and educated at The King’s School, Canterbury, at Gonville and Caius College, Cambridge, from which he received a BA in 1597 and at the University of Padua, where he studied under Hieronymus Fabricius and the Aristotelian philosopher Cesare Cremonini, graduating in 1602. He returned to England, where he became a doctor at St Bartholomew’s Hospital in London (1609-43) and a Fellow of the Royal College of Physicians. After his time at St Bartholomew’s he returned to Oxford and became Warden (head of house) of Merton College.

6

Recent Advances in Liver Surgery

Harvey’s discovery of the general circulation of blood helped to displace the liver from its central role in Galenic physiology. His concept of hepatic function, however, followed the teachings of his predecessors. Harvey described the structure of the liver accurately and he insisted on an unidirectional flow of blood in the liver, rejecting the traditional idea of bidirectional movement. Among his many studies, Harvey noted the gross appearance of a range of hepatic diseases. He gave one of the earliest accounts of cirrhosis as a clinical-pathological entity.12 Although his contributions had enormous importance to anatomy and physiology, their impact on the practice of medicine was limited since the notions and knowledge of disease were little advanced by his demonstrations. However, after Harvey’s evidences that a person’s blood was continually recycling, the question of whether to bleed a patient from the same or opposite side of a disorder became irrelevant. Medicine adjusted to the circulation of the blood but still thought in terms of humors and of therapeutics, relying on bleeding, purging and vomiting. Harvey’s work was an important confirmation of the new mechanical science and the principles of experimental and quantitative analysis. His work formed a common front with that of Galileo, Kepler, Newton, Boyle, Borelli, Malpighi and others. In his lecture notes Harvey compared the heart to a water bellows or a pump, which helped support the growing success of mechanistic philosophy. How was Harvey’s work received by his fellows? For twenty years after the publication of On the Movement of the Heart and Blood in Animals, controversy argued over its conclusions. In this

Figure 5. Jacopo Berengario da Carpi, Isagogae. Title page of Jacopo Berengario da Carpi, Isagogae breves, perlucide ac uberrime, in anatomiam humani corporis a communi medicorum academia usitatam, a Carpo in almo Bononiensi Gymnasio ordinariam chirurgiae docere, ad suorum scholasticorum preces in lucem datae, (Bologna, 1523) (Courtesy of University of Insubria Medical Library).

Liver Surgery: A Historical Account

7

Figure 6. Andreas Vesalius. Portrait of Andreas Vesalius bruxellensis anatomicorum facile princeps, by Philippe Galle, in Virorum doctorum de disciplinis bene merentium effigies XLIIII, P. Galle, Antuerpiae, 1572 (Courtesy of Wellcome Library, London).

initial period many medical men ignored him, including those who had observed his demonstrations. For some of these men—surgeons concerned with achieving a respectable status denied them by the fraternity of physicians—adhering to Galenism made them more acceptable (Fig. 7). Although Harvey’s work on the circulation added much to the collective knowledge of medicine, the most important contributions to hepatic anatomy came from scientists studying the intrahepatic vasculature of the liver. Among these contributions, the work of the Dutch physician Johannis Walaeus ( Jan de Waal, 1604 -1648) deserves special attention. Walaeus was the first to confirm and amplify by original experiments and observations Harvey’s discovery of the circulation of the blood. In 1640, Walaeus reported the discovery of the vasculobiliary sheath surrounding the portal pedicles when he stated: “…(usually) the smallest arteries distributing to the tissues have a single tunic, just like the veins. In the liver there are as many branches of the celiac artery as there are branches of the portal vein and also as many branches of the choledocus duct: all those branches have been considered up to now by Anatomists as branches of the portal vein, because a common tunic surrounds those three kinds of vessels within the liver.” 13

Francis Glisson (1597-1677) was a British physician, anatomist and writer on medical subjects. He did important work on the anatomy of the liver and is considered one of the most respected representatives of medicine in the seventeenth century. Liver was his chief field of interest. In his

8

Recent Advances in Liver Surgery

Figure 7. William Harvey, Exercitatio anatomica. Title page of Harvey, William, Exercitatio anatomica de motu cordis et sanguinis in animalibus, G. Fitzer, Frankfurt, 1628 (Courtesy of Wellcome Library, London).

book Anatomia hepatis (1654)14 he gave the first description of the capsule of the liver and described its blood supply, so much more accurate than any which had been published (Fig. 8). Thenceforward his name has been inseparably connected with the capsule, under the designation “Glisson’s capsule.” Glisson was the first to mention a sphincteric mechanism around the orifice of the common bile duct.15 In its time, the Anatomia hepatis was the most important treatise thus far on the physiology of the digestive system. In this work he also described splints and orthopaedic measures for the management of bony deformities. His studies on the intrahepatic vasculature stand out as monumental. He started by obtaining a liver and cooking it for an hour. This phase was followed by careful dissection, removing the parenchyma with small sticks. What he concluded was that the liver vasculature was distributed throughout the liver, branching from both the hepatic and portal veins. He also deduced the flow of blood through the portal veins traversing the capillaries into the vena cava. Glisson was one of the first to seriously discuss the topography of the intrahepatic vessels and his work served as the channel between the anatomic studies of his colleagues and the hepatic surgeons.

Early Sporadic Liver Resections

The earliest recorded successful surgical treatment of liver wounds was performed by Wilhelm Fabry in the early 17th century. Wilhelm Fabry (also William Fabry, Guilelmus Fabricius Hildanus,

Liver Surgery: A Historical Account

9

Figure 8. Francis Glisson, Anatomia Hepatis. Title page of Glisson, Francis, Anatomia hepatis. Cui praemittuntur quaedam ad rem anatomicam universe spectantia. Et ad calcem operis subjiciuntur nonnulla de lymphae-ductibus nuper repertis, Amstelaedami, Sumptibus Joannis Ravesteinii, 1659 (Courtesy of Wellcome Library, London).

or Fabricius von Hilden) (1560-1634), is often called the “Father of German surgery” (Fig. 9). He was the first educated and scientific German surgeon and author of 20 medical books. His Observationum et Curationum Chirurgicarum Centuriae, published in 1606,16 is the best collection of case records of the century and gives a clear perception of the variety and methods of his surgical practice. Here is his contribution to liver surgery: “a young man fell and accidentally stabbed himself in the upper abdomen with a knife he was carrying: a large piece of liver protruded from the wound and there was a massive haemorrhage. Hildanus excised the piece of liver and the patient survived. Three years later the patient died and postmortem revealed scar tissue on the liver and the absence of part of the liver, while the remainder was healthy”.17 The military surgeon and medical writer John Macpherson wrote in 184618 that Blanchard’s Anatomia practica rationalis (Fig. 10), published in Amsterdam in 1688, had contained an account

10

Recent Advances in Liver Surgery

Figure 9. Gulielmus Fabricius Hildanus. Frontispiece portrait of Gulielmus Fabricius Hildanus, in Observationum et curationum chirurgicarum centuriae, nunc primum in unum opus congestae, Lyons, J.A. Huguetan, 1641 (Courtesy of Wellcome Library, London).

of a soldier who had a small piece of liver protruding from a sword wound removed with forceps.19 An almost identical event has been attributed to Berta in 1716. In our opinion the contribution of Berta, who has been accredited in most of the historical accounts of this surgical accomplishment, should be declined until a better defined evidence will be provided. According to the most recent reports the Italian Giovanni Battista Berta in 1716 successfully débrided prolapsed liver after a psychopath self-inflicted a knife wound in the right hypochondrium. This information is given by Blumgart,20 Chen,4 Fagarasanu,21 Foster,22 Lau,23 McClusky,24 Li25 and a few others, all of them citing directly or indirectly a presentation given by Raffaele Paolucci di Valmaggiore (1892-1958) at the 16th Congress of the International Society of Surgery held in Copenhagen in 1955. Paolucci, professor of clinical surgery at the University of Rome in the 1940s, in the anglo-saxon accounts is always cited incorrectly as Di Valmaggiore P. and, anyway, in his presentation gives a very timid personal opinion, without elucidating about the source of his information: “In campo umano credo che il primo intervento di exeresi sia quello praticato da Giovanni Battista Berta nel 1716 su un demente che, in un tentativo di suicidio, si era prodotto una ferita da arma bianca all’ipocondrio destro con fuoriuscita del fegato. Il chirurgo asportò la parte procidente.26 I believe that the first human (liver) resection has been performed by Giovanni Battista Berta in 1716 on a person suffering of dementia, who tried to commit suicide self-inflicting a knife wound in the right hypocondrium. The surgeon removed the protruded portion”.

Liver Surgery: A Historical Account

11

Figure 10. Steven Blankaart, Anatomia practica rationalis. Engraving, Allegorical depiction of the futility of uroscopy etc.; deceased patients being interred or dissected after uroscopy, in Anatomia practica rationalis, sive rariorum cadaverum morbis denatorum anatomica inspectio. Accedit item tractatus novus de circulatione sanguinis per tubulos deque eorum valvulis, etc. (Steven Blankaart), Amsterdam, C. Blankard, 1688 (Courtesy of Wellcome Library, London).

Paolucci’s “I believe” in his presentation is quite weak for Berta to stand in liver history, unless we will be able to find the original description of the surgeon’s procedure, which we haven’t be able to achieve up to now. In 1888 the Swiss surgeon Carl Garrè (1857-1928) reported that his mentor Victor von Bruns (1812-1883), professor of surgery at the University of Tübingen, in 1870, during the last days of the FrancoPrussian war, operated on a soldier with a gunshot wound of the liver. He resected the involved part of the organ and the patient rejoined his regiment within 2 months. In another patient von Bruns successfully excised a small metastatic tumor from the edge of the liver with a cautery in a emaciated 50-year-old man with diffused carcinomatosis.27

Elective Surgery

The first appropriate well-documented description of intentional laparotomy to excise a solid tumor was published by Antonio Lius, assistant of Dr. Teodoro Escher, chief of surgery at the Civico Ospedale of Trieste (Fig. 11). Surgery was performed on a 67-year-old woman on January, 15th, 1886 by Escher, who in 45 minutes removed a 15.5 × 13 × 11.5 cm adenoma that hung down on a pedicle from the edge of the left lobe of the liver. Escher had to face an important hemorrhage during the procedure, he tried to suture the stump of the severed pedicle, but he failed because the stitches could not be secured due to the softness of the liver. The patient woke up after ether anesthesia, she received morphin and marsala (!), but she passed after a few hours.28

12

Recent Advances in Liver Surgery

Figure 11. Antonio Lius, Di un adenoma del fegato. Title page of the article published by Antonio Lius in the Gazzetta delle Cliniche (Courtesy of University of Insubria Medical Library).

About this same period several factors, including the description of liver’s functional reserve and its regenerative capacity, anesthesia, asepsis and laparotomy for trauma provided sufficient evidence for the rationalization of elective liver resection.4 Experimental studies by Tillmanns and Ponfick (Fig. 12), showed that transection of liver substance was possible29 and 75% of the liver could be resected successfully with the healthy liver regenerating close to its original weight.30 Remarkable contributions on liver regeneration have been provided almost at the same time (1883-1884) by eminent Italian pathologists, who presented their results in the original language, so restricting the merit of their accomplishments to local, even if prestigious Academies.31-35 As a matter of fact much of the development of knowledge in liver anatomy, physiology and surgery was concentrated in the most traditional Italian Universities since the 17th century when Giuseppe Zambeccari (1655-1728), a pupil of Francesco Redi (1627-1729), professor of anatomy at the University of Pisa, a pioneer in experimental surgery, made successful experimental excision of the spleen, kidneys, gallbladder, pancreas and he carried out on a dog, with the help of Stefano Bonucci and Bernardino Ciarpaglini the first liver resection in the form of a lobectomy.36 In the last two decades of the 19th century several European surgeons performed operations on the liver. Trauma, tumor and Echinococcus cysts were the preeminent indications.

Liver Surgery: A Historical Account

Figure 12. Emil Ponfick.

13

Figure 13. Carl Johan August von Langenbuch.

The first successful planned resection for liver tumor was performed on January 13, 1887 at the Lazarus Kranckenhause in Berlin by Carl Johan August von Langenbuch (1846-1901), the same audacious surgeon who in 1882 performed the world’s first cholecystectomy (Fig. 13). Langhenbuch excised a 370-g pedicled tumor of the left lobe of the liver in a 30-year-old woman who had had years of abdominal soreness. He attributed the tumor to compression by tight corsets. Upon laparotomy he transfixed the pedicle and removed the mass. The operation seemed to be a success, until a massive secondary hemorrhage occurred owing to a bleeding hilar vessel. The abdomen was reopened after a few hours, the vessel was ligated and the patient survived.37 The Surgical School at the University of Bologna has been remarkably active in this field in the 1880s and two surgeons of this University performed the first two liver resections for Echynococcus cyst: Pietro Loreta on August, 26, 1887 (Fig. 14)38 and Giuseppe Ruggi on December 8, 1888 (Fig. 15).39 Other than for the skin incision, they both applied the same technique: excision of the cyst including a thick margin of liver parenchyma secured by overlapping sutures and fixation of the transected stump with the remaining cavity to the skin (marsupialization). In both cases wound healing was delayed by a long-lasting biliary fistula (100 days). Based on the studies of Kousnetzoff and Pensky,40 the techniques used in the last part of the 19th century to resect liver and control hemorrhage were mainly based on transfixing and interlocking sutures and cauterization. The widespread adoption of this modus operandi allowed resection of benign and malignant tumors. Cysts and abscesses were drained, lacerations were resected and from Europe liver surgery enthusiasm spread to United States. Who was the first surgeon to perform liver resection in the United States? It’s not so explicit. In fact Louis McLane Tiffany, when professor of surgery at the University of Maryland in Baltimore reported the removal of a liver tumor in 1890.41 But, in his short description it appears that the tumor was formed by biliary stones and debris suggesting that it was not a neoplasia. About this issue, quite severe is James H. Foster’s “sentence”, who asserted “Whether he actually resected any

14

Recent Advances in Liver Surgery

Figure 14. Portrait of Pietro Loreta, professor of clinical surgery in Bologna (Courtesy of Foto Archivio Storico, Università di Bologna).

liver parenchyma is doubtful. However, his lack of personal experience did not stop him from publishing another report42 in 1890, in which he expressed confidence and enthusiasm about liver resection”. William Williams Keen (1837-1932) of Philadelphia, professor of clinical surgery at the Jefferson Medical College, acclaimed “Dean of American Medicine”, performed his first liver resection in October 1891.43 Keen’s first patient was a young lady with a cystoadenoma hanging from the right lobe, which was dissected using his thumbnail, due to troubles with the cautery. His second resection was performed in March 1897 and both were successful. In 1899, Keen published a paper on Annals of Surgery, presenting a table of 76 known resection cases with a mortality of 17%. Keen’s paper indicated the beginning of elective hepatic surgery and liver resections were carried out and reported from many institutions in the Western world in the decades after 1880.

In-Flow Vascular Occlusion

Despite this flourishing fervor, the history of liver surgery at the beginning of the 20th century was still the history of controlling bleeding. The technical achievement which represents the milestone of a safer resectional surgery is the in-flow vascular occlusion which still takes the eponym of “Pringle manoeuvre”. J. Hogarth Pringle (born 1863 in Parramatta, New South Wales, Australia—died 1941) graduated as a doctor in 1885 from Edinburgh University, Scotland. After working throughout Europe, he returned to work with the famous William Macewen in Glasgow, Scotland. From 1896 to 1923 he worked in the Glasgow Royal Infirmary. When he was Lecturer on Surgery in Q ueen Margaret College in 1908 he published an article on the arrest of hepatic hemorrhage due to trauma,44 listing his experience of treating eight patients who were hemorrhaging because of liver trauma. The Pringle idea to interrupt bleeding was to digitally occlude the portal triad with his finger and thumb. Here are some of the expressions he used in his report to describe the technique used on his patients: (…) after opening the abdomen an assistant held the portal vein and the hepatic artery between a finger and thumb and completely arrested all bleeding

Liver Surgery: A Historical Account

15

Figure 15. Giuseppe Ruggi, Dell’epatectomia parziale. Title page of the work of Giuseppe Ruggi, Dell’epatectomia parziale (Courtesy of University of Insubria Medical Library).

(…) two patients with rupture of the liver have been operated by me and in each case the hepatic and portal vessels were grasped between fingers and thumb as soon as the abdomen was opened (…) rapidity of operating and this will be favored by the immediate arrest of the active hemorrhage that is going on, by seizing the portal vessels as soon as the abdominal cavity is opened Pringle’s in-flow-occlusion principle was promptly adopted as an effective expedient to control hemorrhage and reduce the incidence of complication in liver surgery. The modern method of applying the Pringle manoeuvre is to clamp the portal triad using a tape or a noncrushing clamp.45 The human liver can tolerate continuous porta hepatis clamping for up to 1 h if the patient is normotensive,46,47 although some surgeons practice using clamping/declamping sequence at different intervals of time. The fact that the eponym “Pringle pinch” is still in use today demonstrates the Pringle’s lasting impact on surgical technique. Pringle’s new procedure modified surgical technique and correlated with the new acquisitions on the vascular anatomy of the liver clarified in Germany in 1888 by Rex48 and in England in 1897 by Cantlie.49 Rex using corrosion studies on several mammalian was able to show that right and left

16

Recent Advances in Liver Surgery

branches of the portal vein had a similar distribution and their secondary branches contributed to form two separate lobes. Cantlie continued the debate and reported: “the present anatomical division of the liver into right and left lobes is unscientific and consequently untrue and untenable”. According to his studies the right and left lobes were of equal size, divided by a plane of simmetry passing through the bed of the gallbladder and the groove of the inferior vena cava. The new information provided by Pringle, Rex and Cantlie encouraged a new generation of surgeons to pay greater attention on vascular occlusion and perform resections along possible avascular planes to control intraoperative bleeding. In 1910, Wendell intentionally and successfully ligated and divided the right hepatic artery and right hepatic duct before resecting a large “adenoma” from a 44-year-old woman:50 this was the prelude to the most formidable tool available to liver surgeons: the anatomic resection.

Anatomic Surgery and Intraoperative Sonography

The segmental classification of Couinaud represents the most remarkable contribution in fostering more selective and limited resections without risk for the remaining liver. Francis Sutherland and Julie Harris have provided in 2002 a complete and detailed information about the extraordinary studies of Claude Couinaud in the understanding of intrahepatic anatomy.51 The French surgeon and anatomist started his experiments in 1952, when he was 30 years old. He refined the technique of the injection casts using polyvinyl acetone injected into the common bile duct, hepatic artery, or portal vein and allowed to harden for 12 hours. The liver tissue was then dissolved with a dilute solution of hydrochloric or nitric acid. This immediately made the liver transparent and displayed the intrahepatic anatomy. In the ’50s he performed a huge number of liver casts, which allowed him to outline his concept of the segmental anatomy of the liver. He first described the distribution of the vessels and biliary ducts in the liver parenchyma.52 ‘‘Hepatectomies Gauche Lobaire et Segmentaires”53 published in 1952, details the segmental anatomy of the left liver (segments I-IV) and in his 1953 publication, “Les Hepato-colangiostomies Digestive”,54 he delineates the complete segmental anatomy of the liver (Fig. 16).

Figure 16. Couinaud’s classification of liver segments.

Liver Surgery: A Historical Account

17

Much of today’s success in elective liver resections relates to meticulous attention to the vascular anatomy of the inflow and outflow tracts and to the segmental anatomy as described by Couinaud. This basic anatomic knowledge and our ability to carry a patient through difficult surgical procedures due to major advances in anesthesia, intensive care, antibiotics, metabolic, hemodynamic and respiratory support, have been the starting point for a drastic reduction of complications: mortality rates have dropped from around 20% during the mid-1960s to 2% to 3% during the early 1990s.55-57 Techniques and tools for the division of liver parenchyma are still evolving and they will be treated in a specific chapter. Nevertheless of the most recent technical innovations one has found its definitive place in liver surgery history: intraoperative ultrasonography to define vascular anatomy and to identify occult tumor deposits. Liver surgery has been remarkably safer and more accurate in the last few decades because of the development of intraoperative ultrasonography (IOUS), an imaging modality which has become essential for hepatic resection. Pioneer in the development of this technique has been Masatoshi Makuuchi, who proposed and developed this technique in the early 1980s, when he was chief of surgery at Shinshu University in Matsumoto, Japan. Two are the major roles of intraoperative ultrasonography: the first role is to verify and validate with higher resolution preoperative data, the second role is to guide the direction of the transection plane during hepatic resection. Current advances have been recently reported on the development of contrast-enhanced ultrasonography, the rapid evolution of contrast materials and related detection systems. The progress of three-dimensional ultrasonography has been also anticipated. Clinical applications and evaluations of B-mode IOUS systems started in the late 1970s and early 1980s. IOUS with real-time B-mode imaging was first applied to liver surgery by Makuuchi and his colleagues.58 A small side-viewing probe, consisting of electronic linear-array transducers and dedicated for IOUS scanning of the liver, was invented and quickly became popular in Japan. Through the 1980s, the clinical use of IOUS gradually increased and the benefits of IOUS were defined.59 Using IOUS, the stage and resectability of tumors could be determined more accurately than with preoperative studies. Intraoperative localization of nonpalpable tumors and precise screening for liver metastasis also became possible using IOUS.60

Conclusions

The development of liver surgery is mainly based on the understanding of liver anatomy and physiology, appreciation of liver regeneration and improvements in the control of hemorrhage. It could seem obvious to underline the relevance of anatomy, but in the case of liver surgery understanding anatomy is not only important, is imperative. Every surgeon who operates in the abdomen must know the basics about the liver, i.e., how to stop the hemorrhage in an emergency situation, how to diagnose the disease and how to determine resectability. Nevertheless major procedures should be performed in centers with high volume of liver resections, by surgeons with specific experience and where all the most advanced techniques are available and adequately used. We allude especially to the innovative techniques such as intraoperative ultrasonography, which has greatly increased the practices of general surgeons by providing a realtime view of intrahepatic anatomy. Liver surgery is still a major operation that requires skilled hands, intense concentration and consummate competente and no amount of anatomic knowledge or refined equipment can make up for a lack of these abilities.

References

1. Kuss R, Bourget P. An illustrated history of organ transplantation. Rueil-Malmaison: Laboratoires Sandoz 1992. 2. Hardy K. Liver surgery: the past 2000 years. Aust NZ J Surg 1990; 60:811-7. 3. Mettler C. History of Medicine: A Correlative Text Arranged According to Subjects. Philadelphia: Blakiston, 1947. 4. Chen T, Chen P. Understanding the Liver: A History. Westport: Greenwood Press 1984. 5. Paulus A. De medica materia libri septem, totius fere artis medice breviarium. Quinque quidem primi septimusque Algano Torino ... interprete. Sextus vero De chirurgia, quem Germani non sunt interpretati a Joanne Bernardo Feliciano ... nunc primum Latinitate donatus. Venetiis: (In aedibus Lucaeantonii Juntae) 1532.

18

Recent Advances in Liver Surgery

6. Benivieni A. De abditis nonnvllis ac mirandis morborvm et sanationvm cavsis. Impressum Florentiae: Opera and impensa Philippi Giuntae 1507. 7. Berengario da Carpi J. Isagogae Breves, perlucid(a)e ac uberrim(a)e, in anatomia(m) humani corporis a co(m)muni medicoru(m) academia usitata(m)/a Carpo in almo Bononiensi Gymnasio ordinariam chirurgi(a)e doce(n)te, ad suorum scholasticoru(m) p(re)ces in lucem dat(a)e. Impressum and noviter revissum Bononi(a)e: Per Benedictum Hectoris bibliopolam Bononiensem anno virginei partus 1523 sub die xv. Iulii. 8. Berengario da Carpi J. Isagogae Breves, 15222 (A short introduction to anatomy), RR Lind, translator. Chicago: University of Chicago Press, 1959:59. 9. Laguna A. L’Anatomica methodus, di Andrés Laguna (1499-1560). (Con 4 tavole). (A cura di) Giorgio Rialdi (e) Ubaldo Ceccarelli. Pisa: Giardini 1968. 10. Vesalius A. The Illustrations from the Works of Andreas Vesalius of Brussels. With annotations and translations, a discussion of the plates and their background, authorship and influence and a biographical sketch of Vesalius by J.B. de C.M. Saunders and Charles D. O’Malley. Cleveland, New York: The World Publishing Co, 1950:43. 11. Harvey W. Exercitatio anatomica de motv cordis et sangvinis in animalibvs, Gvilielmi Harvei Angli: Sumptibus Gvilielmi Fitzeri, 1628. 12. Chen T, Chen P. William Harvey as hepatologist. Am J Gastroenterol 1988; 83(11):1274-7. 13. Walaeus J. quoted in Couinaud C: Surgical anatomy of the liver revisited. Paris: self-published 1989:30. 14. Glisson F. Anatomia hepatis. Londini: Impensis Octaviani Pullein, 1654:32. 15. Boyden E. The pars intestinalis of the common bile duct, as viewed by the older anatomists (Vesalius, Glisson, Bianchi, Vater, Haller, Santorini et al). Anat Rec 1936; 66:217. 16. Fabricius Hildanus W. Observationum and curationum chirurgicarum centuriae: in qua inclusae sunt viginti and quinque, antea seorsim aeditae, reliquae nunc cum nonnullis instrumentorum, ab autore inventorum delineationibus, in gratiam and utilitatem artis chirurgicae in lucem prodeunt : cum indice, Guilielmi Fabrici Hildan. Basileae: Sumptibus Ludovici Regis 1606. 17. Gurlt EJ. Geschichte der chirurgie und ihrer ausübung; volkschirurgie, alterthum, mittelalter, renaissance. Berlin: Hirschwald 1898. 18. Macpherson J. Removal of a portion of the liver from a human subject. London Med Gaz 1846; n.s. 2:112-113. 19. Blankaart S. Blancardi anatomia practica rationalis, sive rariorum cadaverum morbis denatorum anatomica inspectio. Accedit item tractatus novus de circulatione sanguinis per tubulos, deque eorum valvulis and c. Amstelodami: Ex officina Corn. Blancardi in Platea Vulgo de Warmoes Straat 1688;83. 20. Blumgart LH. Historical perspective. In: Blumgart LH, ed. Surgery of the Liver, Biliary Tract and Pancreas. Philadelphia: W B Saunders Company, 1907:xliii. 21. Fagarasanu I, Ionescu-Bujor C, Aloman D et al. Surgery of the Liver and Intrahepatic Ducts. St. Louis: W H Green, 1972:48. 22. Foster J. History of liver surgery. Arch Surg 1991; 126:381-387. 23. Lau WY. The history of liver surgery. J R Coll Surg Edinb 1997; 42:303-309. 24. McClusky DA, Skandalakis LJ, Colborn GL et al. Hepatic surgery and hepatic surgical anatomy: historical partners in progress. World J Surg 1997; 21:330-342. 25. Li AKC. Gray Turner Memorial Lecture. Changing role of liver surgeons. World J Surg 1999; 23:1-5. 26. Paolucci di Valmaggiore R. Le epatectomie. Parte introduttiva. In Proceedings of 16th Congress of the International Society of Surgery (Copenhagen): Imprimerie Medicale et Scientifique 1955:1009-1015. 27. Garré C. Contribution to surgery of the liver. Bruns Beitr Klin Chir 1888; 4:181. 28. Lius A. Di un adenoma del fegato. Gazzetta delle Cliniche 1886; 23(15):225-2 30. 29. Tillmanns H. Experimentelle un anatomische untersuchungen ueber wunden der leber und der niere. Virchow’s Arch bd. 1879; 78:437-465. 30. Ponfick E. Experimentelle beitrage zur pathologie der lebe. Arc path Anat 1889; 128:209-249. 31. Colucci V. Ricerche sperimentali e patologiche sulla ipertrofia e parziale rigenerazione del fegato. Memorie dell’Accademia di Scienze di Bologna. 1883; seduta 11 febbraio. 32. Tizzoni G. Studio sperimentale sulla rigenerazione parziale e sulla neoformazione del fegato. Atti della R Accademia dei Lincei 1883; seduta 19 marzo. 33. Griffini L. Studio sperimentale sulla rigenerazione parziale del fegato, comunicazione preventiva del professore Luigi Griffini. Torino: Vinc Bona, 1883:2-9. 34. Colucci V. Per una pretesa priorità di studio sperimentale sulla rigenerazione del fegato: osservazioni critiche del dott. Vincenzo Colucci, estr. da: Spallanzani, rivista di scienze mediche e naturali, fasc. 12., anno 13, se. 2. Modena: Tip. Vincenzi, 1884:21-28. 35. Corona A. Sulla rigenerazione parziale del fegato. Annali universali di medicina e chirurgia 1884; 267(803).

Liver Surgery: A Historical Account

19

36. Zambeccari G. Esperienze del dottor Giuseppe Zambeccari intorno a diverse viscere tagliate a diversi animali viventi, e da lui descritte, e dedicate all’illustrissimo signore Francesco Redi. In: Firenze: per Francesco Onofri, 1680:78-79. 37. Langenbuch C. Ein fall von resecktion eines linksseitigen schnurlappens del leber. Berl Klin Wosch 1888; 25:37-38. 38. Loreta P. Echinococco del fegato. Resezione del fegato. Escissione della cisti. Guarigione. Memoria del professor pietro loreta (letta nella sessione 11 Dicembre 1887), memorie della R. Accademia delle scienze dell’Istituto di Bologna, serie IV, tomo VIII. Bologna: Tipi Gamberini e Parmeggiani 1887:581-587. 39. Ruggi G. Dell’epatectomia parziale nella cura delle cisti d’echinococco. Bologna: Nicola Zanichelli, 1889:2-36. 40. Kousnetzoff M, Pensky J. Etudes cliniques et expérimentales sur la chirurgie du foie sur la resection partielle du foie. Rev Chir 1896; 16:954. 41. Tiffany L. The removal of a solid tumor from the liver by laparotomy. Maryland Med J 1890; 23:531. 42. Tiffany LM. Surgery of the liver. Boston Med Surg J 1890; 23:557. 43. Keen WW. On resection of the liver, especially for hepatic tumors. Boston Med Surg J 1892; 126:405. 44. Pringle JH. Notes on the arrest of hepatic haemorrhage due to trauma. Ann Surg 1908; 48:541-549. 45. Launois B, Jameison GG. Modern Operative Techniques in Liver Surgery. Edinburgh: Churchill Livingstone 1993:1-152. 46. Huguet C, Nordlinger B, Galopin J et al. Normothermic hepatic vascular exclusion for extensive hepatectomy. Surg Gynecol Obstet 1978; 147:689-93. 47. Dionigi R, Madariaga JR. New Technologies for Liver Resections. Basel, New York: Landes Systems, 1997:18-19. 48. Rex H. Beitrage zur morphologie der säugerlebe. Morph Jahrb 1888; 14:517. 49. Cantlie J. On new arrangement of right and left lobes of liver. In: Prooceedings of the Anatomical Society of Great Britain and Ireland 1897. J Anat physiol 1897-1898; 32:1-24, 4-6. 50. Wendell W. Beitrage zur chirurgie der leber. Arch Klin Chir 1911; 95:887. 51. Sutherland F, Harris J. Claude Couinaud. A passion for the liver. Arch Surg 2002; 137:1305-1310. 52. Couinaud C. Distribution intraparenchymateuse des vaisseaus hepatiques et des voies biliaires, 2: foie droit. C R Assoc Anat 1952; 39:318-323. 53. Couinaud C. Hepatectomies gauche lobaires et segmentaires. J Chir (Paris) 1952; 68(697-715). 54. Couinaud C. Lobes et segments hepatiques: notes sur l’architecture anatomique et chirurgicale de foie. Press Med 1954; 62:709-712. 55. Hemming AW, Scudamore C, Davidson A et al. Evaluation of 50 consecutive segmental hepatic resections. Am J Surg 1993; 165:621. 56. Ferid H, O’Connel T. Hepatic resections: changing mortality and morbidity. Am Surg 1994; 60:748. 57. Cunningham J, Yuman F, Shriver C et al. One hundred consecutive hepatic resections. Arch Surg 1994; 129:1050. 58. Makuuchi M, Hasegawa H, Yamazaki S. Intraoperative ultrasonic examination for hepatectomy. Ultrasound Med Biol 1983; (Suppl 2):493-497. 59. Makuuchi M. Abdominal Intraoperative Ultrasonography. Tokyo, New York: Igaku-Shoin, 1987. 60. Machi J, Isomoto H, Yamashita Y et al. Intraoperative ultrasonography in screening for liver metastases from colorectal cancer: comparative accuracy with traditional procedures. Surgery 1987; 101(6):678-684.

Chapter 2

Genetics of Hepatocellular Carcinoma Andreas Teufel* and Peter R. Galle

Introduction

H

epatocellular carcinoma (HCC) is among the most common malignancies worldwide. At present, approximately 550,000 new patients are diagnosed with HCC each year worldwide. However, regional differences in the incidence of HCC are significant. The highest prevalence is found in Southeast Asia and the sub-saharan Africa, mostly due to the high rates of chronic viral hepatitis, a high risk factor for HCC. Additional causes leading to HCC are alcohol, toxins such as aflatoxin, hemochromatosis, α1-antitrypsin deficiency and non-alcoholic fatty liver disease (NAFLD).1-5 Despite major efforts to improve diagnosis and treatment of HCC, therapeutic options remain limited. The main therapeutic strategies are surgical resection of the tumor or liver transplantation. However, most patients, especially in Asia and sub-saharan Africa, present at late stages of the disease or with underlying liver cirrhosis and consequently surgical options may no longer be indicated. Although palliative treatments are needed, they remain very limited. It was only 2007, that efforts to establish efficient systemic chemotherapy regimens have yet succeeded in a first multikinase inhibitor, sorafenib, resulting in increased overall survival.173 Besides, best supportive care is still considered standard of treatment. Thus, the need for novel therapeutic agents and strategies is obvious. Lately, genomic targets and networks have increasingly gained attention due to the efforts of the Human Genome Project. As a result, human and many other genomic sequences are publicly available. Due to this vast amount of newly available genomic data we are cumulating a profound knowledge of the genetic basis of HCC. The following section provides a summary on the current status of known genetic influences on HCC and on current hypotheses of genetic aspects to the development of liver cancer.

Chromosomal Aberrations

Chromosomal aberrations have been reported frequently in HCC. Meta-analysis of available data on chromosomal aberrations and genomic hybridisation analyses, demonstrated amplifications of the chromosomes 1q, 8q, 6p and 17q to be the most prominent ones. Among the chromosomes most frequently lost in HCC were 8p, 16q, 4q, 17p and 13q. Furthermore, in poorly differentiated HCCs, 13q and 4q were significantly under-represented.6 These chromosomal regions contain key players in hepatocarcinogenesis such as p53 (chromosome 17p) or Rb (chromosome 13q). However, data on correlation of these chromosomal aberrations with the clinical course of the disease are not available, mostly due to the limited overall number of the comparatively large chromosomal aberrations and to the especially low occurence of the same aberration within the same collective patients.

*Corresponding Author: Andreas Teufel—Department of Internal Medicine I, Johannes Gutenberg University, Building 606, Langenbeckstr. 1, 55101 Mainz, Germany. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Genetics of Hepatocellular Carcinoma

p53

21

p53 was originally identified in 1979 and initially believed to act as an oncogene. It took almost one decade until it was discovered that mistakenly only missense mutations of the p53 gene had been studied, instead of the wild-type gene and that wildtype p53 instead truly acts as a tumor suppressor gene. The allele-producing p53 mutants heterodimerize with wild-type p53, preventing binding to p53 regulated elements and blocking the tumor suppressor activity of wild-type p53.8 Subsequently, p53 has been discovered the most frequently mutated gene in human cancer with a mutation rate of over 50% in human cancer cases. This fundamental role of p53 in tumorigenesis has been furthermore validated by means of in vivo knock out models demonstarted to spontaneously develop tumors and also patients with the cancer prone Li-Fraumeni syndrome had germ-line p53 mutations.9,10 Our understanding of the role of p53 in tumorigenesis improved, after it was shown, that p53 can also act as a transcription factor involved in cell-cycle regulation and apoptosis. This was followed by the discovery of its multiple roles in development, differentiation, gene amplification, DNA recombination, chromosomal segregation and cellular senescence.11,12 In the late 1990s, p53’s role in DNA repair by facilitating nucleotide excision repair and base excision repair was demonstrated. Due to these key regulatory and prognostic functions, p53 has been adressed as “the guardian of the genome”, referring to its role in conserving genetic stability by preventing genome mutation. A variety of studies in recent years provided evidence that the p53 tumor suppressor gene plays a major role in hepatocarcinogenesis irrespective of the etiology.13 However, the frequency of p53 mutations and its mutation spectrum with 75% missense mutations are exceptionally diverse in their position and nature, affecting over 200 codons scattered mainly throughout the central portion of the gene.14 With respect to HCC it has been noted that these mutations vary in different geographic areas. In some areas, such as sub-Saharan Africa and China, Aflatoxin B1 (AFB1) exposure was suggested to account for a large proportion of the p53 mutations, in this case predominantely, 249ser mutation. In contrast, analysis of HCC in areas of hardly any AFB1 intake, e.g., USA and Western Europe, revealed a different mutational spectrum with no particular hotspot, further supporting a correlation between AFB1 intake and 249ser mutation. Besides, AFB1 p53 mutations have repeatedly been associated with the intake of vinyl chloride (VC) and typically associted mutations have been described at the codons 179, 249 and 255.19,20 Nevertheless, an association of VC with the development of HCC is less conclusive21,22 and some recent reports failes to demonstrate a clear correlation.23 However, p53 mutations associated with HCC are by no means explicitely dependend on chemical induction.16-18 A number of studies have demonstrated the effects of oxidative stress in liver carcinogenesis associated with typical p53 mutations. Among several oxyradical overload diseases are hemochromatosis and Wilson disease (WD). This results in the development of cirrhosis with a 200-fold risk for HCC in hemochromatosis and a lower incidence in WD.24 It has been shown for both diseases that transversions occur25 due to oxidative stress and subsequent generation of reactive sprecies, at least in part due to an inducible nitric oxide synthase (iNOS) induced oxidative stress resulting in p53 mutations.15 Besides chemical induction of p53 mutations, HBV and HCV infection may also contribute to p53 changes. HBV infection is associated with about 40% of all HCC cases worldwide.15 Multiple HBV-related genomic rearrangements have been described and as a result tumor suppressor genes such as p53 may get lost. Among the different HBV genes, the HBx gene seems to play a more causal role in HBV-related HCC because it is the most commonly integrated viral gene.15,26 Among the pathobiological effects of HBx are: transcriptional coactivation of cellular and viral genes, e.g., by transcriptional alteration through modulation of RNA polymerase II and III; action as cotranscription factor for the major histocompatibility complex (MHC), epidermal growth factor receptor and multiple oncogenes, decrease of nucleotide excision repair and interaction with the cellular DNA repair system, as well as deregulation of cell cycle checkpoint controls. However, there are also several more direct interactions between HBx and p53 functions. By decreasing p53’s

22

Recent Advances in Liver Surgery

binding to XBP, HBx indirectly reduces nucleotide excision repair27 and XBP functions as a basic transcription factor.28 Furthermore, HBx binds to p53 and suppresses a number of p53-dependend functions: p53 sequence-specific DNA-binding activity, p53-mediated transcriptional activation in vivo,27 and p53 transcription.29 HBx is capable of blocking p53-mediated apoptosis. Especially the latter function provides a selective cellular growth advantage for preneoplastic or neoplastic hepatocytes.30-32 Compared to HBV-related heptocarcinogenesis, none of the different parts of the HCV genome is integrated into the host genome. Still, several HCV-related protein interactions known, among them p53, possibly involved in hepatocarcinogenesis were described but depending on the cellular background contradictory data exist.33 This is also true for the known interaction between HCV and p53. To gain better insight into HCV-related hepatocarcinogenesis, the microarray technology has been used in several studies. Honda et al34 and Shackel et al35 analyzed HCV cirrhosis and showed an upregulation of pro-inflammatory, pro-apoptotic and pro-proliferative genes, which might reflect groups of genes being involved in HCV-related cirrhosis during progression to HCC. Dou et al analyzed gene expression profiles of the HCV genotypes 1b, 2a and 4d core proteins in HepG2 and Huh-7 cells and identified that each core protein has its own expression profile and that each of them seems to be implicated in HCV replication and oncogenesis.36,37 It was furthermore suggested that38 most transcriptionally changed genes, due to HCV core protein transfection, were involved in cell growth or oncogenic signalling. Reflecting the HCV core gene introduction into these three distinct HCV-related hepatocytic stages, the following cellular pathways have been identified: cell growth regulation, immune regulation, oxidative stress and apoptosis. Finally, to further focus on the role of p53 in HCC, a number of p53 mutant and p53 wild type HCC cases were analyzed by microarrays identifying 83 p53-related genes in p53 mutant HCCs when compared with wild type p53 HCCs.39 Among these genes, an overexpression (among others) was described for cell cycle-related genes (CCNG2, BZAP45) and cell proliferation-related genes (SSR1, ANXA2, S100A10 and PTMA). Based on their results the authors assume that mutant p53 tumors have higher malignant potentials than those with wild type p53. This concept is supported by previous reports demonstrating that p53 mutations constitute an unfavorable prognostic factor related to recurrence in HCC.37,38

Wnt Signalling Pathway

Originally identified in Drosophila melanogaster and subsequently described in several other organisms, members of the wingless gene family are secreted morphogenic ligands, essential to establishing body patterning and axis formation during embryonic development, cell/cell interaction and regulation of proliferation. Lately, the Wnt pathway has also been demonstrated to function as a key regulator in tumor development and differentiation. Members of the Wnt protein family initiate signalling through binding to cell-surface receptors of the Frizzled (Fz) family and their coreceptors, the LRP 5/6 proteins. Binding finally results in an increasing amount of β-catenin reaching the nucleus. Wnt/frizzled binding leads to activation of Dishevelled (Dsh), a component of a membrane-associated Wnt receptor complex, subsequently inhibiting a complex of proteins including Axin, GSK-3 and APC. This complex normally promotes the proteolytic degradation of the β-catenin intracellular signalling molecule. However, if inhibited by Dsh, cytoplasmatic degradation of β-catenin is decreased and an increasing amount of β-catenin is able to enter the nucleus and interact with TCF/LEF family transcription factors to promote specific gene expression.40 The Wnt signalling pathway has been studied extensively with respect to cancer development and differentiation.41-44 Several lines of evidence support an essential role of the Wnt/β-catenin singnaling pathway in HCC. These include an increased expression and nuclear accumulation of β-catenin as a feature of an activated Wnt signalling pathway.43,45,46 Up to 62% of all HCC were shown to display such a disregulation of β-catenin. In addition, a multivariate analysis has demonstrated poorer prognosis and higher rate of tumor recurrence in patients with nuclear accumulation of β-catenin.45,46

Genetics of Hepatocellular Carcinoma

23

Further attention was drawn to Wnt-/β-catenin-signalling when oncogenic β-catenin mutations were demonstrated to promote also the development of HCC. These mutations prevent β-catenin from being phosphorylated and thus prevent degradation, resulting in activation of Wnt-/β-catenin signalling. Prevalence of the mutations has been estimated from several reports to be within 26% and 41%47-50 and some reports describe a high association of the mutations with high exposure to aflatoxin B1 and HCV infection.51,52 In addition, multiple antagonists of the Wnt-/β-catenin signalling pathway have been demonstrated to be involved in regulation of the pathway critical to the development of HCC. Mutations of Axin1 have been reported to be highly prevalent in human HCC and transfection of wildtype Axin1 lead to reconstitution of Wnt signalling and apoptosis in cancer cells.53,54 At a lower frequency, Axin2 mutations may contribute to HCC development as well.54 Similarly, negative regulation of other inhibitors of the Wnt-/β-catenin signalling such as sFRP1 Prickle-1 or HDPR1 also resulted in promoting HCC development.54-56 But also positive regulating Wnt regulating genes were found to be involved in liver cancer development. Overexpression of Frizzled-7 (FDZ7) was predominant in most HCC and was regarded an early event in hepatocarcinogenesis.60,61 In contrast to other tumor entities, like colorectal carcinoma, no mutations of the Adenoma Polyposis Coli (APC) gene have been identified in HCC.58 However, a liver-specific disruption of the APC gene in mice resulted in an activation of the Wnt/β-catenin pathway and also in the development of HCC.59 Furthermore, the course of disease of patients with HCC harboring β-catenin mutations was demonstrated to be clinically distinct since, on average, they display a less aggressive and less invasive tumor progression and better prognosis compared to patients without β-catenin mutations.46,48-50 Together, an essential role of the Wnt signalling pathway in hepatocarcinogenesis has been established in several ways and targeting the pathway may be promising for therapeutic options. First attempts to target Wnt signalling showed promising results as in vitro RNA interference against β-catenin inhibited the proliferation of pediatric hepatic tumor cells suggesting β-catenin to be a possible target of further in vivo studies.62

TGFβ Pathway

The transforming growth factor (TGF) signalling pathway is essential to many cellular processes such as cell growth, cell differentiation and apoptosis. In the liver, a major function of TGF-β, which is normally produced by nonparenchymal stellate cells, is to limit regenerative growth of hepatocytes in response to injury by inhibiting DNA synthesis and inducing apoptosis.63,64 TGFβs have three mammalian isoforms, TGFβ1, TGFβ-2 and TGFβ-3 each with distinct functions in vivo. All three TGFβs use the same receptor signalling system.65 TGFβ has three receptors, typeI(RI), type II (RII) and type III (RIII). TGFβR3 is the most abundant of the TGFβ receptors yet, it has no known signalling domain. However, it may serve to enhance the binding of TGFβ ligands to TGFβ type II receptors by binding TGFβ and presenting it to TGFβR2. Type RIII (also called betaglycan) binds two TGFβ polypeptides, recruits TGFβ to RII and intensifies TGFβ signalling. Binding of a TGFβ ligand65-67 to a type II receptor results in the recruitment of and complex formation with a type I receptor and its phosphorylation. Together these proteins form a hetero-tetrameric complex with the ligand. After activation of the TGFβ type II/TGFβ type I (TGFβRII/TGFβRI) receptor complex, the signal is transmitted mostly through the Smad proteins. However, the activated receptor complex may also transduce the TGFβ signal through phosphatidylinositol 3-kinase (PI3K), protein phosphatase 2A/p70 S6 kinase (PP2A/ p70S6K) and various mitogen-activated protein kinase (MAPK) pathways. The later pathways are not dependent on Smad function. If bound by TGF/RII and phosphorylated, RI subsequently phosphorylates Smad2 and Smad3, subsequently forming a complex with Smad4. These Smad4 bound complexes translocate to the nucleus where they bind to specific DNA sequences and act to repress or activate transcription. TGFβ has repeatedly been demonstrated to be overexpressed in HCC. Elevated expression levels of TGFβ in HCC tissue have been found by means of Northern blot and

24

Recent Advances in Liver Surgery

immunohistochemistry.68-70 Expression of TGF-β1 in HCC tissue was correlated with poorer histological differentiation.69 In addition, serum and urin TGFβ levels have been shown to correlate with poorer prognosis and increased tumor angiogenesis.71-74 Furthermore, it has recently been described in several tumor entities that during tumor progression65-67,75 TGFβ activity continues to be increased due to autostimulation of the Tgfb1 gene and due to transcriptional activation by Ras and other effectors, as well as by the action of proteases that activate the latent TGFβ in the extracellular matrix.76,77 Also, attenuation of TGF-β signalling was observed as a result of downregulation of TGF-βRII.78,79 The stimulation of neoplastic growth of liver cancer despite an overexpression of TGFβ and a generally growth limiting function of TGFβ is not fully understood, but has lately been explained partly by evidence for resistance of the tumor to TGFβ function on the one hand site and a switch of TGFβ function towards a growth stimulating function during later stage tumor growth on the other hand site. Significant evidence that evasion from TGFβ may play a role during early HCC development comes from mice heterozygous for a target-inactivated TGFβ1 allele or TGFβ type II receptor. These animals show enhanced susceptibility to chemical carcinogens such as N-diethylnitrocosamine compared to their wild-type littermates, indicating a haploinsufficiency of tumor suppression.80-82 This hypothesis was further supported by in vitro and clinical data. Expression of TGFβR-II in liver tissues was significantly decreased in patients with HCC compared to patients with chronic hepatitis or liver cirrhosis. Conversely, transfection of TGFβR-II cDNA into the hepatoma cell line Huh7 induced cell arrest and apoptosis.83 In several tissues, an active involvement of TGFβ in tumor progression and metastasis has been suggested. For example, mice inoculated with prostate cancer cells overexpressing TGFβ-1 have tumors that are 50% larger than controls and are significantly more likely to develop metastases.84 As consequence of these findings a hypothesis of a switch of TGFβ action from a tumor suppressing effect to a tumor promoting function during cancerogenesis in several cancers has been proposed.85 However, such a tumor promoting effect has not yet been demonstrated in HCC. Besides disruption of the TGFβ pathway at the TGFβ/TGFβR level, the signalling pathway may be also disregulated further downstream at the level of Smad proteins. Smad7 expression was found highly elevated in HCC tissue, especially in patients with elevated TGFβ or normal TGFβRII levels suggesting that Smad7 may be one of the resistance mechanisms to TGFβ in late stage HCC.86 At present, only a few data are available on Smad mutations. In a small cohort of 35 patients, three were identified to have mutations of either Smad 2 or Smad 4.87 In contrast, levels of Smad 5 were rather found upregulated than downregulated and therefore Smad 5 was excluded to play a significant role in HCC development.88 Finally, in vitro experiments suggested that ability to repress the activity of Smad proteins of Ski and SnoN by interacting with Smad 2, Smad 3 and Smad 4 accounted for their transforming activity and resistance to TGFβ induced growth arrest.89

Ras Signalling

The three human ras genes (H-ras, N-ras and K-ras) encode for four proteins that function as small guanosine triphsophate (GTP) binding proteins, H-Ras, N-Ras, K-Ras4A and K-Ras4B.90-93 The two forms of K-Ras only differ in their C-terminal 25 amino acids due to alternate splicing. Ras proteins are positioned at the inner surface of the plasma membrane, where they serve as molecular switches to transduce extracellular signals into the cytoplasm to control signal transduction pathways that influence cell growth, differentiation and apoptosis.94 Ras proteins can be activated by a wide range of extracellular proteins. For example, Ras proteins become activated following triggering of receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR).95 Single amino acid substitutions at N-ras codon 12, H-ras codon 13 or K-ras codon 61, that unmask Ras transforming potential, create mutant proteins that are insensitive to GAP (Ras p120 GTPase activation protein) stimulation.96 Consequently, these oncogenic Ras mutant proteins are locked in the active, GTP-bound state, leading to constitutive, deregulated activation of Ras function.

Genetics of Hepatocellular Carcinoma

25

Activated Ras relays its signals downstream through a cascade of cytoplasmic proteins. Substantial biological, biochemical and genetic evidence has implicated the Raf-1 serine/threonine kinase as a critical effector of Ras function.97 A key observation was that only biologically active Ras forms a high affinity complex with Raf-1.98-102 The Ras-Raf association promotes a translocation of the cytoplasmic Raf protein to the plasma membrane, where subsequent events lead to the activation of its kinase function. These events are complex and remain to be fully understood.103 Upon activation, Raf then phosphorylates and activates the MAPK kinases (MKKs) MEK1 and MEK2. MEK1 and 2 are dual specificity kinases which catalyze the phosphorylation of Erk1 and 2 on both tyrosine and threonine residues after translocation to the nucleus. Erk1 and 2 in turn activate numerous downstream targets such as transcription factors (e.g., Elk-1 and c-Jun104,105), other kinases (e.g., p90rsk S6 kinase), upstream regulators (e.g., Sos Ras exchange factor) and other regulatory enzymes (e.g., phospholipase A2). These downstream targets then control cellular responses including growth, differentiation and apoptosis. Overexpression of Ras and members of the signalling pathway such as p21 have been demonstrated in HCC in multiple studies.106,107 Likewise, inhibitors of the Ras pathway were reported to be downregulated in HCC.108 Besides overexpression of Ras in HCC, mutations of the Ras proto-oncogenes, locking Ras in the active state, have been identified. The most commonly investigated mutations were the N-Ras codon 61,109-111 the H-Ras codon 12112 and the K-Ras codon 12 mutation.113-115 However, the absolute numbers of HCC investigated were rather low in these studies. Ras mutations were continuously observed in HCC induced by various chemical agents in rats. These chemicals inducing HCC were N-nitrosomorpholine (NNM116), a combination of bleomycin and 1-nitropyrene,115 methyl (acetoxymethyl) nitrosamine,117 acetylaminofluorene (AAF),118 3-methyl-(dimethylamino) azobenzene117 and nitroglycerine.119 In accordance with these data originating from murine HCC models, tumor tissue of workers exposed to vinyl chloride were demonstrated to contain a significant level of Ras mutations, supporting evidence for a role of Ras mutations in HCC.120,121 As a consequence of overexpression of the Ras pathway in HCC and in order to identify novel therapeutic targets for the treatment of HCC, various groups have lately studied regulation of the pathway by antisense RNA. Thereby, it has repeatedly been reported that antisense treatment for H-Ras significantly inhibited hepatocarcinogenesis and was able to reconstitute apoptosis in respective cells/tissues.116,122,123 In addition, novel treatment approaches with multikinase inhibitors such as sorafenib targeting the Raf kinase in patients with advanced HCC have displayed a moderate therapeutic efficacy as a single-agent and may now be evaluated for combination treatment with other anticancer agents.124,173

PDGF Signalling

Lately, the family of platelet derived growth factors (PDGF) has shifted to the centre of interests. At present, four members of the PDGF family have been identified PDGF-A, PDGF-B, PDGF-C and PDGF-D. PDGF also have important roles during embryonal development and their overexpression has been linked to different types of fibrotic disorders and malignancies. First implication of PDGF in cancer development was suggested as one of its peptide chains was found to be homologous to the viral sis oncogene (v-sis).125,126 Since, this family of growth factors has been extensively studied and PDGF and overactivity of PDGF family members has been implicated in several pathological conditions. In particular, overexpression has been demonstrated to be key pathogenic factor in multiple solid tumours. Biological relevance of this signalling pathway has lately been demonstrated by therapeutic strategies targeting PDGF signalling and thereby inhibiting tumour growth.127,128 The oncogenic function of PDGF family members is mediated by signalling of these factors as homo- or heterodimers through cell surface, tyrosine kinase receptors α and β (PDGFR).128 This stimulation subsequently leads to an activation of various cellular functions including growth, proliferation and differentiation. Accordingly, the biologic role of PDGF signalling may vary from autocrine stimulation of cancer cell growth to subtler paracrine interactions involving adjacent stroma and vasculature.128,129

26

Recent Advances in Liver Surgery

With respect to chronic liver disease and liver cancer, we and others have previously demonstrated an essential role of all PDGF family members in liver fibrosis, a prerequisite of HCC.130-132 PDGF-B transgenic mice were demonstrated to spontaneously develop liver fibrosis within a period of six months.130 As development of HCC is mostly observed as a sequence of liver fibrosis, liver cirrhosis and HCC, it was speculated that PDGF-B overexpression may ultimately also lead to an increased development of HCC. We have recently observed an essential role of PDGF-B in HCC development, investigated by means of transgenic PDGF-B overexpression in mice (unpublished data). For PDGF-C such an increase development of liver fibrosis and a spontaneous HCC development has recently been demonstrated as well.132 In addition we and others observed an increased liver fibrosis development in PDGF-A (unpublished data) and PDGF-D131 suggesting that these PDGF family members may also be involved in HCC development.

Rb

The tumor suppressor protein retinoblastoma protein (Rb), is critical for the development of several cancer types. Rb is the target for phosphorylation by several kinases as described below. In normal cell signalling, Rb prevents cell division and cell cycle progression. In particular, Rb prevents the cell from replicating damaged DNA, by preventing its progression through the cell cycle into S phase or progressing through G1.133 Bound to the transcription factor E2F, Rb acts as a growth suppressor and prevents progression through the cell cycle.148 Rb only inhibits cell cycle progression in a dephosphorylated state. Before entering S-phase, complexes of a cyclin-dependent kinases (CDK) and cyclins phosphorylate Rb.133-138 Dephosphorylated Rb binds to the transcription factor E2F.138 Subsequently, phosphorylation of Rb results in the dissociation of E2F-DP from Rb.133,138,139 Free E2F may then activate cell cycle activating factors like cyclins (e.g., Cyclin E and A), leading to progression of the cell cycle. Thus, cells with mutated Rb are subject to reduced control in cell cycle progression subsequently resulting in the development of cancer. In addition, the Rb-E2F/DP complex also binds a protein called histone deacetylase (HDAC) which when associated to chromatin, further suppresses DNA synthesis. HDAC inihibitors have recently attracted increasing attention as therapeutic agents. Furthermore, oncoproteins of several viruses can bind and inactivate Rb, possibly leading to cancer development.139-142 Although a vast amount of data has been accumulated on the role of Rb in cancer differentiation for several cancer entities, only limited insight is available on a role of Rb in HCC differentiation. Rb has been demonstrated to be inactivated in human HCC cell lines and in 28% of HCC.143,144 Simultaneously, additional members in the Rb network also have significantly aberrant expression in HCC. For example cyclin D1/Cdk4, phosphorylating and inactivating Rb, is overexpressed in 58% of HCC.145 Furthermore, the p16 protein, also a regulator of Rb activity through inhibition against Cdk4, is absent in 34% of HCC.146 Finally in vivo mutagenesis experiments dtrongly support the hypothesis that disruption of the Rb regulatory network is common in HCC carcinogenesis, as RB deletion in the mouse liver enhances DEN-induced tumorigenesis.147

Genome-Scale Analysis of Gene Expression in HCC

In recent years multiple data sets of microarray data from genome wide expression analysis of HCC have been published. Most of these have reported novel involvements of individual genes in differentation or development of HCC. In order to identify gene clusters, individual genes and pathways crucial to HCC development in general,148-150 solitary or multinodular development,151,152 metastasis153 and tumor recurrence after surgical resection154 multiple microarray experiments have been performed. These experiments revealed several gene cluster and multiple genes to perform essential roles in HCC differentiation. However, comparison between these different microarray experiments remains difficult as these experiments all defined diverse clusters of genes essential to tumor development, metastasis or recurrence. Thus, the challenge remains to identify a small subset of key regulatory genes, which may subsequently be chosen for evaluation as novel regulatory targets interfering with tumor development.

Genetics of Hepatocellular Carcinoma

27

The most valuable perception from genome-wide expression profiles of HCC was that HCC must not be regarded as a single tumor entity but rather represents several distinct subtypes of liver cancer defined by distinct gene expression profiles. Groups of HCC selected with respect to clinical outcome and distinct survival of patients varied significantly in their expression profile. However, these two tumor expression profiles were more closely related compared to normal tissue.155 These data were in accordance with expression studies performed in murine HCC. By means of molecular biology, Stahl et al confirmed that HCC contains at least two subtypes, which may be distinguished by expression of β-catenin156 Similarly, HCCs induced by chronic HBV or chronic HCV infection were demonstrated to display clearly distinct expression profiles and thus the conclusion was drawn that hepatocarcinogenesis due to HBV or HCV is driven by different pathophysiological mechanisms.157 Furthermore, the expression profile of HCCs was suggested to differ according to distinct histological tumor types.158 Besides the gene clusters identified to be essential to HCC development, differentiation of subtypes and clinical outcome, HCC expression profiles of multiple genes and genetic networks was demonstrated to be critical to response of HCC cell lines to treatment with several chemotherapeutic agents in vitro.159 The pharmacogenetic relevance has been evaluated in multiple studies revealing individual clusters of genes crucial to treatment response with 5FU and cisplatin,160 5FU plus interferon alpha,161 interferon alpha alone162 and histone deacetylase inhibitors.163,164 Although these data certainly contributed new insights to the pharmacogenetics of HCC treatment, the number of individual genes identified correlated with treatment response is still too large to be routinely tested for each individual patient before initiation of treatment. Thus, the future challenge remains to focus on a small subset of highly predictive genes which may be investigated more easily and rapidly and not at least cheaper in order to establish a personal prediction of chemotherapy response.

Altered DNA Methylation in HCC

In contrast to somatic mutations, changes in methylation, especially in promoter regions of individual genes, are capable of regulating gene expression without changes in DNA sequence. Methylation may occur on cytosine nucleotides, predominantly in CpG nucleotides and the methyl group can be added to the pyrimidine ring by either one of the three methyltransferases (DNMT 1, DNMT3a and DNMT3b). These methylations are passed through cell division. Methylation of promoters may interfere with the binding of transcription factors and other regulatory mechanisms. Subsequently, progressive methylation of promoter regions may result in decreased expression of the corresponding gene. In cancer, a “methylation imbalance” was frequently observed, where a genome-wide hypomethylation is accompanied by localized hypermethylation and an increase in expression of DNA methyltransferase. The investigation of altered methylation in pathogenesis of HCC remains limited to individual genes being investigated due to the lack of high throughput techniques for analysis of methylation. In a study on 133 genes investigated for changes in methylation in HCC, 32 were mostly hypermethylated, only a few hypomethylated. Wether these altered methylation profiles lead to significant changes in expression profiles and the function of genetic networks or whether these changes just indicate severe epigenetic disturbances remains to be investigated. However, as these genes were selected prior to analysis with respect to differential expression in HCC, altered methylation was suggested to contribute significantly to the differentiation of HCC. A second large investigation analyzed the global levels of DNA methylation as well as the methylation status of 105 putative tumor suppressor genes. It was demonstrated that methylation play a key role in HCC development as in all HCC at least one of the genes affected was associated with the major oncogenic pathways Ras, Jak/Stat, or Wnt/β-catenin. In particular hypermethylation of was identified in multiple inhibitors of the Ras pathway. In accordance with these data, Ras was significantly more active in HCC than in surrounding or normal livers.165

28

Recent Advances in Liver Surgery

Besides this comparatively large set of genes, only a few genes have repeatedly been investigated individually and reported to be hypermethylated in HCC. Thus, the SFRP1, RUNX3, RASSF1, OCT6, AR, p73, MYOD1, M-cadherin,166 TFPI-2,167 TMS1/ASC,168 PTEN169 and p16INK4a gene were reported hypermethylated in more than half of all HCC.170,171 Changes of methylation were not only observed in tumor tissue but also in peripheral blood.172 In addition, DNA methylation was demonstrated to be significantly decreased after surgery. These findings certainly represent initial, preliminary studies and need to be further confirmed. However, if confirmed, analyzing DNA methylation may develop into an additional aid in diagnosis and follow up of HCC.

Databases of Genetics of HCC

Lately, databases holding genetic associations for Hepatocellular Carcinoma have been established. Two of the widely used databases are the Library of Genetic Associations database and the Encyclopedia of Hepatocellular Carcinoma genes Online These databases may be accessed publicly at http://www.medicalgenomics.org/databases/LOGA or http://ehco.iis.sinica.edu.tw.

References

1. Motola-Kuba D, Zamora-Valdes D, Uribe M et al. Hepatocellular carcinoma. An overview. Ann Hepatol 2006; 5:16-24. 2. McGlynn KA, London WT. Epidemiology and natural history of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 2005; 19:3-23. 3. Srivatanakul P, Sriplung H, Deerasamee S. Epidemiology of liver cancer: an overview. Asian Pac J Cancer Prev 2004; 5:118-125. 4. Teo EK, Fock KM. Hepatocellular carcinoma: an Asian perspective. Dig Dis 2001; 19:263-268. 5. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 2006; 40:S5-S10. 6. Moinzadeh P, Breuhahn K, Stutzer H et al. Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade—results of an explorative CGH meta-analysis. Br J Cancer 2005; 92:935-941. 7. Hofseth LJ, Hussain SP, Harris CC. p53: 25 years after its discovery. Trends Pharmacol Sci 2004; 25:177-181. 8. Ratovitski EA, Patturajan M, Hibi K et al. p53 associates with and targets Delta Np63 into a protein degradation pathway. Proc Natl Acad Sci USA 2001; 98:1817-1822. 9. Malkin D, Li FP, Strong LC et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 1990; 250:1233-1238. 10. Srivastava S, Zou ZQ, Pirollo K et al. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 1990; 348:747-749. 11. Harris CC. p53 tumor suppressor gene: from the basic research laboratory to the clinic—an abridged historical perspective. Carcinogenesis 1996; 17:1187-1198. 12. Oren M, Rotter V. Introduction: p53—the first twenty years. Cell Mol Life Sci 1999; 55:9-11. 13. Edamoto Y, Hara A, Biernat W et al. Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis. Int J Cancer 2003; 106:334-341. 14. Hainaut P, Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 2000; 77:81-137. 15. Staib F, Hussain SP, Hofseth LJ et al. TP53 and liver carcinogenesis. Hum Mutat 2003; 21:201-216. 16. Hosono S, Chou MJ, Lee CS et al. Infrequent mutation of p53 gene in hepatitis B virus positive primary hepatocellular carcinomas. Oncogene 1993; 8:491-496. 17. Jaskiewicz K, Chasen MR. Differential expression of transforming growth factor alpha, adhesions molecules and integrins in primary, metastatic liver tumors and in liver cirrhosis. Anticancer Res 1995; 15:559-562. 18. Teramoto T, Satonaka K, Kitazawa S et al. p53 gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis. Cancer Res 1994; 54:231-235. 19. Hollstein M, Marion MJ, Lehman T et al. p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. Carcinogenesis 1994; 15:1-3. 20. Trivers GE, De Benedetti VM, Cawley HL et al. Anti-p53 antibodies in sera from patients with chronic obstructive pulmonary disease can predate a diagnosis of cancer. Clin Cancer Res 1996; 2:1767-1775.

Genetics of Hepatocellular Carcinoma

29

21. Evans DM, Williams WJ, Kung IT. Angiosarcoma and hepatocellular carcinoma in vinyl chloride workers. Histopathology 1983; 7:377-388. 22. Tamburro CH, Makk L, Popper H. Early hepatic histologic alterations among chemical (vinyl monomer) workers. Hepatology 1984; 4:413-418. 23. Weihrauch M, Lehnert G, Kockerling F et al. p53 mutation pattern in hepatocellular carcinoma in workers exposed to vinyl chloride. Cancer 2000; 88:1030-1036. 24. Hussain SP, Raja K, Amstad PA et al. Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci USA 2000; 97:12770-12775. 25. Britton RS. Metal-induced hepatotoxicity. Semin Liver Dis 1996; 16:3-12. 26. Hofseth LJ, Saito S, Hussain SP et al. Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc Natl Acad Sci USA 2003; 100:143-148. 27. Wang XW, Forrester K, Yeh H et al. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity and association with transcription factor ERCC3. Proc Natl Acad Sci USA 1994; 91:2230-2234. 28. Schaeffer L, Roy R, Humbert S et al. DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science 1993; 260:58-63. 29. Lee SG, Rho HM. Transcriptional repression of the human p53 gene by hepatitis B viral X protein. Oncogene 2000; 19:468-471. 30. Arbuthnot P, Capovilla A, Kew M. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. J Gastroenterol Hepatol 2000; 15:357-368. 31. Bergsland EK. Molecular mechanisms underlying the development of hepatocellular carcinoma. Semin Oncol 2001; 28:521-531. 32. Jia L, Wang XW, Harris CC. Hepatitis B virus X protein inhibits nucleotide excision repair. Int J Cancer 1999; 80:875-879. 33. Zhu N, Khoshnan A, Schneider R et al. Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J Virol 1998; 72:3691-3697. 34. Honda M, Kaneko S, Kawai H et al. Differential gene expression between chronic hepatitis B and C hepatic lesion. Gastroenterology 2001; 120:955-966. 35. Shackel NA, McGuinness PH, Abbott CA et al. Insights into the pathobiolog y of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression. Am J Pathol 2002; 160:641-654. 36. Dou J, Liu P, Wang J et al. Preliminary analysis of gene expression profiles in HepG2 cell line induced by different genotype core proteins of HCV. Cell Mol Immunol 2006; 3:227-233. 37. Dou J, Liu P, Zhang X. Cellular response to gene expression profiles of different hepatitis C virus core proteins in the Huh-7 cell line with microarray analysis. J Nanosci Nanotechnol 2005; 5:1230-1235. 38. Fukutomi T, Zhou Y, Kawai S et al. Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology 2005; 41:1096-1105. 39. Okada T, Iizuka N, Yamada-Okabe H et al. Gene expression profile linked to p53 status in hepatitis C virus-related hepatocellular carcinoma. FEBS Lett 2003; 555:583-590. 40. Luu HH, Zhang R, Haydon RC et al. Wnt/beta-catenin signaling pathway as a novel cancer drug target. Curr Cancer Drug Targets 2004; 4:653-671. 41. Johnson ML, Rajamannan N. Diseases of Wnt signaling. Rev Endocr Metab Disord 2006; 7:41-49. 42. Kelleher FC, Fennelly D, Rafferty M. Common critical pathways in embryogenesis and cancer. Acta Oncol 2006; 45:375-388. 43. Willert K, Jones KA. Wnt signaling: is the party in the nucleus? Genes Dev 2006; 20:1394-1404. 44. Janssens N, Janicot M, Perera T. The Wnt-dependent signaling pathways as target in oncology drug discovery. Invest New Drugs 2006; 24:263-280. 45. Inagawa S, Itabashi M, Adachi S et al. Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival. Clin Cancer Res 2002; 8:450-456. 46. Wong CM, Fan ST, Ng IO. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 2001; 92:136-145. 47. de La Coste A, Romagnolo B, Billuart P et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 1998; 95:8847-8851. 48. Hsu HC, Jeng YM, Mao TL et al. Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol 2000; 157:763-770.

30

Recent Advances in Liver Surgery

49. Mao TL, Chu JS, Jeng YM et al. Expression of mutant nuclear beta-catenin correlates with non-invasive hepatocellular carcinoma, absence of portal vein spread and good prognosis. J Pathol 2001; 193:95-101. 50. Terris B, Pineau P, Bregeaud L et al. Close correlation between beta-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. Oncogene 1999; 18:6583-6588. 51. Devereux TR, Stern MC, Flake GP et al. CTNNB1 mutations and beta-catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1. Mol Carcinog 2001; 31:68-73. 52. Huang H, Fujii H, Sankila A et al. Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol 1999; 155:1795-1801. 53. Satoh S, Daigo Y, Furukawa Y et al. AXIN1 mutations in hepatocellular carcinomas and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 2000; 24:245-250. 54. Taniguchi K, Roberts LR, Aderca IN et al. Mutational spectrum of beta-catenin, AXIN1 and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 2002; 21:4863-4871. 55. Shih YL, Shyu RY, Hsieh CB et al. Promoter methylation of the secreted frizzled-related protein 1 gene SFRP1 is frequent in hepatocellular carcinoma. Cancer 2006; 107:579-590. 56. Chan DW, Chan CY, Yam JW et al. Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer. Gastroenterology 2006; 131:1218-1227. 57. Yau TO, Chan CY, Chan KL et al. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene 2005; 24:1607-1614. 58. Ishizaki Y, Ikeda S, Fujimori M et al. Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. Int J Oncol 2004; 24:1077-1083. 59. Colnot S, Decaens T, Niwa-Kawakita M et al. Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci USA 2004; 101:17216-17221. 60. Merle P, de la Monte S, Kim M et al. Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology 2004; 127: 1110-1122. 61. Merle P, Kim M, Herrmann M et al. Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. J Hepatol 2005; 43:854-862. 62. Sangkhathat S, Kusafuka T, Miao J et al. In vitro RNA interference against beta-catenin inhibits the proliferation of pediatric hepatic tumors. Int J Oncol 2006; 28:715-722. 63. Oberhammer FA, Pavelka M, Sharma S et al. Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1. Proc Natl Acad Sci USA 1992; 89:5408-5412. 64. Romero-Gallo J, Sozmen EG, Chytil A et al. Inactivation of TGF-beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy. Oncogene 2005; 24:3028-3041. 65. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998; 67:753-791. 66. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001; 29:117-129. 67. Dumont N, Arteaga CL. Targeting the TGF beta signaling network in human neoplasia. Cancer Cell 2003; 3:531-536. 68. Abou-Shady M, Baer HU, Friess H et al. Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma. Am J Surg 1999; 177:209-215. 69. Idobe Y, Murawaki Y, Kitamura Y et al. Expression of transforming growth factor-beta 1 in hepatocellular carcinoma in comparison with the nontumor tissue. Hepatogastroenterology 2003; 50:54-59. 70. Matsuzaki K, Date M, Furukawa F et al. Autocrine stimulatory mechanism by transforming growth factor beta in human hepatocellular carcinoma. Cancer Res 2000; 60: 1394-1402. 71. Song BC, Chung YH, Kim JA et al. Transforming growth factor-beta1 as a useful serologic marker of small hepatocellular carcinoma. Cancer 2002; 94:175-180. 72. Tsai JF, Chuang LY, Jeng JE et al. Clinical relevance of transforming growth factor-beta 1 in the urine of patients with hepatocellular carcinoma. Medicine (Baltimore) 1997; 76:213-226. 73. Tsai JF, Jeng JE, Chuang LY et al. Elevated urinary transforming growth factor-beta1 level as a tumour marker and predictor of poor survival in cirrhotic hepatocellular carcinoma. Br J Cancer 1997; 76:244-250. 74. Ito N, Kawata S, Tamura S et al. Positive correlation of plasma transforming growth factor-beta 1 levels with tumor vascularity in hepatocellular carcinoma. Cancer Lett 1995; 89:45-48. 75. Yang YA, Dukhanina O, Tang B et al. Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest 2002; 109:1607-1615. 76. Akhurst RJ, Derynck R. TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol 2001; 11:S44-S51.

Genetics of Hepatocellular Carcinoma

31

77. Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 2002; 12:22-29. 78. Reisenbichler H, Chari RS, Boyer IJ et al. Transforming growth factor-beta receptors type I, II and III in phenobarbital-promoted rat liver tumors. Carcinogenesis 1994; 15:2763-2767. 79. Santoni-Rugiu E, Jensen MR, Factor VM et al. Acceleration of c-myc-induced hepatocarcinogenesis by Co-expression of transforming growth factor (TGF)-alpha in transgenic mice is associated with TGF-beta1 signaling disruption. Am J Pathol 1999; 154:1693-1700. 80. Kanzler S, Meyer E, Lohse AW et al. Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis. Oncogene 2001; 20:5015-5024. 81. Tang B, Bottinger EP, Jakowlew SB et al. Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med 1998; 4:802-807. 82. Im YH, Kim HT, Kim IY et al. Heterozygous mice for the transforming growth factor-beta type II receptor gene have increased susceptibility to hepatocellular carcinogenesis. Cancer Res 2001; 61:6665-6668. 83. Ueno T, Hashimoto O, Kimura R et al. Relation of type II transforming growth factor-beta receptor to hepatic fibrosis and hepatocellular carcinoma. Int J Oncol 2001; 18:49-55. 84. Steiner MS, Barrack ER. Transforming growth factor-beta 1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol Endocrinol 1992; 6:15-25. 85. Iyer S, Wang ZG, Akhtari M et al. Targeting TGFbeta signaling for cancer therapy. Cancer Biol Ther 2005; 4:261-266. 86. Park YN, Chae KJ, Oh BK et al. Expression of Smad7 in hepatocellular carcinoma and dysplastic nodules: resistance mechanism to transforming growth factor-beta. Hepatogastroenterology 2004; 51:396-400. 87. Yakicier MC, Irmak MB, Romano A et al. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 1999; 18:4879-4883. 88. Zimonjic DB, Durkin ME, Keck-Waggoner CL et al. SMAD5 gene expression, rearrangements, copy number and amplification at fragile site FRA5C in human hepatocellular carcinoma. Neoplasia 2003; 5:390-396. 89. He J, Tegen SB, Krawitz AR et al. The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. J Biol Chem 2003; 278:30540-30547. 90. Barbacid M. Ras genes. Annu Rev Biochem 1987; 56:779-827. 91. Bourne HR, Wrischnik L, Kenyon C. Ras proteins. Some signal developments. Nature 1990; 348: 678-679. 92. Boguski MS, McCormick F. Proteins regulating Ras and its relatives. Nature 1993; 366:643-654. 93. Q uilliam LA, Khosravi-Far R, Huff SY et al. Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. Bioessays 1995; 17:395-404. 94. Satoh T, Kaziro Y. Ras in signal transduction. Semin Cancer Biol 1992; 3:169-177. 95. Reuther GW, Der CJ. The Ras branch of small GTPases: Ras family members don’t fall far from the tree. Curr Opin Cell Biol 2000; 12:157-165. 96. Clark GJ, Q uilliam LA, Hisaka MM et al. Differential antagonism of Ras biological activity by catalytic and Src homology domains of Ras GTPase activation protein. Proc Natl Acad Sci USA 1993; 90:4887-4891. 97. Moodie SA, Wolfman A. The 3Rs of life: Ras, Raf and growth regulation. Trends Genet 1994; 10:44-48. 98. Van Aelst L, Barr M, Marcus S et al. Complex formation between RAS and RAF and other protein kinases. Proc Natl Acad Sci USA 1993; 90:6213-6217. 99. Moodie SA, Willumsen BM, Weber MJ et al. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 1993; 260:1658-1661. 100. Zhang XF, Settleman J, Kyriakis JM et al. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 1993; 364:308-313. 101. Warne PH, Viciana PR, Downward J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 1993; 364:352-355. 102. Vojtek AB, Hollenberg SM, Cooper JA. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 1993; 74:205-214. 103. Morrison DK, Cutler RE. The complexity of Raf-1 regulation. Curr Opin Cell Biol 1997; 9:174-179. 104. Marais R, Wynne J, Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 1993; 73:381-393. 105. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol 2002; 4:E131-E136. 106. Jagirdar J, Nonomura A, Patil J et al. ras oncogene p21 expression in hepatocellular carcinoma. J Exp Pathol 1989; 4:37-46. 107. Nonomura A, Ohta G, Hayashi M et al. Immunohistochemical detection of ras oncogene p21 product in liver cirrhosis and hepatocellular carcinoma. Am J Gastroenterol 1987; 82:512-518.

32

Recent Advances in Liver Surgery

108. Schuierer MM, Bataille F, Weiss TS et al. Raf kinase inhibitor protein is downregulated in hepatocellular carcinoma. Oncol Rep 2006; 16:451-456. 109. Tsuda H, Hirohashi S, Shimosato Y et al. Low incidence of point mutation of c-Ki-ras and N-ras oncogenes in human hepatocellular carcinoma. Jpn J Cancer Res 1989; 80:196-199. 110. Takada S, Koike K. Activated N-ras gene was found in human hepatoma tissue but only in a small fraction of the tumor cells. Oncogene 1989; 4:189-193. 111. Challen C, Guo K, Collier JD et al. Infrequent point mutations in codons 12 and 61 of ras oncogenes in human hepatocellular carcinomas. J Hepatol 1992; 14:342-346. 112. Cerutti P, Hussain P, Pourzand C et al. Mutagenesis of the H-ras protooncogene and the p53 tumor suppressor gene. Cancer Res 1994; 54:1934s-1938s. 113. Boix-Ferrero J, Pellin A, Blesa JR et al. K-ras Gene Mutations in Liver Carcinomas from a Mediterranean Area of Spain. Int J Surg Pathol 2000; 8:267-270. 114. Soman NR, Wogan GN. Activation of the c-Ki-ras oncogene in aflatoxin B1-induced hepatocellular carcinoma and adenoma in the rat: detection by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 1993; 90:2045-2049. 115. Bai F, Nakanishi Y, Takayama K et al. Codon 64 of K-ras gene mutation pattern in hepatocellular carcinomas induced by bleomycin and 1-nitropyrene in A/J mice. Teratog Carcinog Mutagen 2003; (Suppl 1):161-170. 116. Baba M, Yamamoto R, Iishi H et al. Ha-ras mutations in N-nitrosomorpholine-induced lesions and inhibition of hepatocarcinogenesis by antisense sequences in rat liver. Int J Cancer 1997; 72:815-820. 117. Watatani M, Perantoni AO, Reed CD et al. Infrequent activation of K-ras, H-ras and other oncogenes in hepatocellular neoplasms initiated by methyl (acetoxymethyl) nitrosamine, a methylating agent and promoted by phenobarbital in F344 rats. Cancer Res 1989; 49:1103-1109. 118. Li H, Lee GH, Liu J et al. Low frequency of ras activation in 2-acetylaminofluorene- and 3ʹ-methyl-4-(dimethylamino) azobenzene-induced rat hepatocellular carcinomas. Cancer Lett 1991; 56:17-24. 119. Yamamoto S, Mitsumori K, Kodama Y et al. Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control nontransgenic mice. Carcinogenesis 1996; 17:2455-2461. 120. Weihrauch M, Benick M, Lehner G et al. High prevalence of K-ras-2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride. Int Arch Occup Environ Health 2001; 74:405-410. 121. Weihrauch M, Benicke M, Lehnert G et al. Frequent k-ras-2 mutations and p16 (INK4A) methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer 2001; 84:982-989. 122. Liao Y, Tang ZY, Ye SL et al. Modulation of apoptosis, tumorigenesity and metastatic potential with antisense H-ras oligodeoxynucleotides in a high metastatic tumor model of hepatoma: LCI-D20. Hepatogastroenterology 2000; 47:365-370. 123. Liao Y, Tang ZY, Liu KD et al. Apoptosis of human BEL-7402 hepatocellular carcinoma cells released by antisense H-ras DNA—in vitro and in vivo studies. J Cancer Res Clin Oncol 1997; 123:25-33. 124. Abou-Alfa GK, Schwartz L, Ricci S et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24:4293-4300. 125. Borkham-Kamphorst E, van Roeyen CR, Ostendorf T et al. Pro-fibrogenic potential of PDGF-D in liver fibrosis. J Hepatol 2007; 46:1064-1074. 126. Waterfield MD, Scrace GT, Whittle N et al. Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature 1983; 304:35-39. 127. Doolittle RF, Hunkapiller MW, Hood LE et al. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 1983; 221:275-277. 128. Ding J, Feng Y, Wang HY. From cell signaling to cancer therapy. Acta Pharmacol Sin 2007; 28:1494-1498. 129. Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 1999; 79:1283-1316. 130. Alvarez RH, Kantarjian HM, Cortes JE. Biology of platelet-derived growth factor and its involvement in disease. Mayo Clin Proc 2006; 81:1241-1257. 131. Czochra P, Klopcic B, Meyer E et al. Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. J Hepatol 2006; 45:419-428. 132. Campbell JS, Hughes SD, Gilbertson DG et al. Platelet-derived growth factor C induces liver fibrosis, steatosis and hepatocellular carcinoma. Proc Natl Acad Sci USA 2005; 102:3389-3394. 133. Das SK, Hashimoto T, Shimizu K et al. Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1. Biochim Biophys Acta 2005; 1726:328-335. 134. Munger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res 2002; 89:213-228.

Genetics of Hepatocellular Carcinoma

33

135. Bartkova J, Lukas C, Sorensen CS et al. Deregulation of the RB pathway in human testicular germ cell tumours. J Pathol 2003; 200:149-156. 136. Bartkova J, Rajpert-De Meyts E, Skakkebaek NE et al. Deregulation of the G1/S-phase control in human testicular germ cell tumours. APMIS 2003; 111:252-265; discussion 265-266. 137. Korenjak M, Brehm A. E2F-Rb complexes regulating transcription of genes important for differentiation and development. Curr Opin Genet Dev 2005; 15:520-527. 138. De Veylder L, Joubes J, Inze D. Plant cell cycle transitions. Curr Opin Plant Biol 2003; 6:536-543. 139. Dannenberg JH, te Riele HP. The retinoblastoma gene family in cell cycle regulation and suppression of tumorigenesis. Results Probl Cell Differ 2006; 42:183-225. 140. Barbosa MS, Edmonds C, Fisher C et al. The region of the HPV E7 oncoprotein homologous to adenovirus E1a and Sv40 large T antigen contains separate domains for Rb binding and casein kinase phosphorylation. EMBO J 1990; 9:153-160. 141. Hagemeier C, Caswell R, Hayhurst G et al. Functional interaction between the HCMV IE2 transactivator and the retinoblastoma protein. EMBO J 1994; 13:2897-2903. 142. DeCaprio JA, Ludlow JW, Figge J et al. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 1988; 54:275-283. 143. Suh SI, Pyun HY, Cho JW et al. 5-Aza-2ʹ-deoxycytidine leads to down-regulation of aberrant p16INK4A RNA transcripts and restores the functional retinoblastoma protein pathway in hepatocellular carcinoma cell lines. Cancer Lett 2000; 160:81-88. 144. Azechi H, Nishida N, Fukuda Y et al. Disruption of the p16/cyclin D1/retinoblastoma protein pathway in the majority of human hepatocellular carcinomas. Oncology 2001; 60:346-354. 145. Joo M, Kang YK, Kim MR et al. Cyclin D1 overexpression in hepatocellular carcinoma. Liver 2001; 21:89-95. 146. Hui AM, Sakamoto M, Kanai Y et al. Inactivation of p16INK4 in hepatocellular carcinoma. Hepatology 1996; 24:575-579. 147. Mayhew CN, Carter SL, Fox SR et al. RB loss abrogates cell cycle control and genome integrity to promote liver tumorigenesis. Gastroenterology 2007; 133:976-84. 148. Nam SW, Lee JH, Noh JH et al. Comparative analysis of expression profiling of early-stage carcinogenesis using nodule-in-nodule-type hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2006; 18:239-247. 149. Shao RX, Hoshida Y, Otsuka M et al. Hepatic gene expression profiles associated with fibrosis progression and hepatocarcinogenesis in hepatitis C patients. World J Gastroenterol 2005; 11:1995-1999. 150. Kim JW, Ye Q, Forgues M et al. Cancer-associated molecular signature in the tissue samples of patients with cirrhosis. Hepatology 2004; 39:518-527. 151. Okamoto M, Utsunomiya T, Wakiyama S et al. Specific gene-expression profiles of noncancerous liver tissue predict the risk for multicentric occurrence of hepatocellular carcinoma in hepatitis C virus-positive patients. Ann Surg Oncol 2006; 13:947-954. 152. Yang LY, Wang W, Peng JX et al. Differentially expressed genes between solitary large hepatocellular carcinoma and nodular hepatocellular carcinoma. World J Gastroenterol 2004; 10:3569-3573. 153. Budhu AS, Zipser B, Forgues M et al. The molecular signature of metastases of human hepatocellular carcinoma. Oncology 2005; 69 Suppl 1:23-27. 154. Iizuka N, Oka M, Yamada-Okabe H et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet 2003; 361:923-929. 155. Lee JS, Thorgeirsson SS. Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction and identification of therapeutic targets. Gastroenterology 2004; 127: S51-S55. 156. Stahl S, Ittrich C, Marx-Stoelting P et al. Genotype-phenotype relationships in hepatocellular tumors from mice and man. Hepatology 2005; 42:353-361. 157. Iizuka N, Oka M, Yamada-Okabe H et al. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res 2002; 62:3939-3944. 158. Chung EJ, Sung YK, Farooq M et al. Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray. Mol Cells 2002; 14:382-387. 159. Moriyama M, Hoshida Y, Otsuka M et al. Relevance network between chemosensitivity and transcriptome in human hepatoma cells. Mol Cancer Ther 2003; 2:199-205. 160. Hoshida Y, Moriyama M, Otsuka M et al. Identification of genes associated with sensitivity to 5-fluorouracil and cisplatin in hepatoma cells. J Gastroenterol 2002; 37 Suppl 14:92-95. 161. Moriyama M, Hoshida Y, Kato N et al. Genes associated with human hepatocellular carcinoma cell chemosensitivity to 5-fluorouracil plus interferon-alpha combination chemotherapy. Int J Oncol 2004; 25:1279-1287.

34

Recent Advances in Liver Surgery

162. Wong N, Chan KY, Macgregor PF et al. Transcriptional profiling identifies gene expression changes associated with IFN-alpha tolerance in hepatitis C-related hepatocellular carcinoma cells. Clin Cancer Res 2005; 11:1319-1326. 163. Gray SG, Qian CN, Furge K et al. Microarray profiling of the effects of histone deacetylase inhibitors on gene expression in cancer cell lines. Int J Oncol 2004; 24:773-795. 164. Chiba T, Yokosuka O, Fukai K et al. Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin A, on human hepatoma cells. Oncology 2004; 66:481-491. 165. Calvisi DF, Ladu S, Gorden A et al. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest 2007; 117:2713-22. 166. Yamada S, Nomoto S, Fujii T et al. Frequent promoter methylation of M-cadherin in hepatocellular carcinoma is associated with poor prognosis. Anticancer Res 2007; 27(4B):2269-74. 167. Wong CM, Ng YL, Lee JM et al. Tissue factor pathway inhibitor-2 as a frequently silenced tumor suppressor gene in hepatocellular carcinoma. Hepatology 2007; 45:1129-38. 168. Zhang C, Li H, Zhou G et al. Transcriptional silencing of the TMS1/ASC tumour suppressor gene by an epigenetic mechanism in hepatocellular carcinoma cells. J Pathol 2007; 212(2):134-42. 169. Wang L, Wang WL, Zhang Y et al. Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma. Hepatol Res 2007; 37:389-396. 170. Yeo W, Wong N, Wong WL et al. High frequency of promoter hypermethylation of RASSF1A in tumor and plasma of patients with hepatocellular carcinoma. Liver Int 2005; 25:266-272. 171. Yu J, Zhang HY, Ma ZZ et al. Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis. Cell Res 2003; 13:319-333. 172. Wong IH, Johnson PJ, Lai PB et al. Tumor-derived epigenetic changes in the plasma and serum of liver cancer patients. Implications for cancer detection and monitoring. Ann N Y Acad Sci 2000; 906:102-105. 173. Llovet J et al. Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial). Proc ASCO 2007; Abstract LBA1.

Chapter 3

Staging Algorithms for Patients with HCC and Prognostic Indicators Christos S. Georgiades*

Abstract

A

ssigning a specific prediction of survival to any patient with HCC is difficult under the best of circumstances. The nature of the disease, the underlying liver function, the performance status of the patients as well as the misleading conclusions with which the relevant literature is replete, all impart their own uncertainty to any survival calculation. The choice of an appropriate staging algorithm can minimize this prognostic inaccuracy and should include a suitable staging system, relevant independent prognostic variables, patient’s performance status, comorbid conditions and planned treatment. Furthermore, these factors are interdependent as the choice of a staging system for example depends partly on the planned treatment and/or extent of underlying liver disease. For a physician to be able to provide a patient with a meaningful prognosis, he must be familiar with the literature regarding the most popular staging systems, be able to critically evaluate each paper and know the limitations of each system. He must also be able to incorporate independent prognostic factors in his calculations as well as the expected outcomes of the proposed treatment. There is no such thing as “the best HCC staging system”. A system valid for one patient may be invalid for another thus the staging algorithm must be tailored to each specific patient, disease and treatment combination.

Introduction

There are more than a dozen staging systems for patients with cirrhosis, hepatocellular carcinoma or both and all are used to varying extend by different groups around the globe. The large number of liver staging systems is misleading with regards to their true value. It is instead indicative of the lack of one parsimonious and accurate staging system for patients with liver disease and liver cancer. All other epidemiologically important cancers (i.e., primary lung, prostate or breast cancer) are staged by well established, nearly universally accepted and prognostically accurate staging systems compared to those for HCC. In addition, staging systems for nonliver cancer are conducive to treatment planning and correlate well with outcomes, a far cry from the accuracy—or lack thereof—of the multitude of liver cancer staging systems. There are many reasons why liver cancer/disease is difficult to stage. First, primary hepatocellular carcinoma (HCC) is itself a cancer that has a variable prognosis which depends on many underlying factors. Such factors include of course the size, number and location of tumors but also histological and biochemical factors such as vessel invasion and P53 overexpression among many others. In addition, the extent of underlying liver disease is a critical determining factor in disease staging, unlike many other cancers. For example the prognosis of a patient with prostate, breast, bone and many other cancers does not usually depend on the condition of the organ involved. Liver cirrhosis itself has a quite variable course depending on its cause (Hepatitis B, C, alcoholic, autoimmune, cryptogenic etc) and extent. Even patients *Christos S. Georgiades—Vascular and Interventional Radiology, Johns Hopkins Hospital, 600 N. Wolfe Street-Blalock 544, Baltimore, MD 21287, USA. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

36

Recent Advances in Liver Surgery

with the same cause of liver cirrhosis (i.e., Hepatitis C) have a vastly variable prognosis with some progressing faster than others or some developing HCC while others do not. Another source of prognostic uncertainty is the fact that liver cirrhosis is usually relentlessly progressive—albeit to varying degrees. This is contrary to—for example—lung cancer where the underlying extent of COPD is usually arrested at the time of smoking cessation. Two final factors that add to the difficulty in choosing the appropriate liver staging system have to do with the staging systems themselves: First, the choice of staging system depends on the planned treatment. For example, MELD may be useful for patients awaiting a liver transplantation but poor for those treated with TACE for unresectable HCC. Second, not all systems have been compared or even validated for all possible treatment options for HCC (resection, transplantation, transarterial chemoembolization (TACE), percutaneous ablation, chemotherapy etc). Each of the issues above imparts a significant degree of uncertainty to any liver staging system. The cumulative uncertainty of all these factors (that must be included in a parsimonious liver staging system) is therefore considerable. One final note is that there are independent prognostic variables that correlate strongly with outcome not incorporated into any of the current liver staging system (Trabecular vs adenoid histology or P53 overexpression for example) which means even under ideal circumstances these suffer from a quantum uncertainty that cannot be overcome. The above are not to say that liver staging systems are not useful. Many have indeed been validated and their appropriate use results in tangible benefits. One example is the reduction in waiting list mortality for patients requiring liver transplantation with the use of the MELD system. It is crucial however, when choosing a staging system for liver cirrhosis/HCC to select the one appropriate for the disease, population and treatment plan. The objective of this Chapter is to display the challenges of the current liver staging systems and guide the readers to select the appropriate one for their patient(s).

Staging Systems

The prognosis of a patient with HCC is determined to the greatest extent by three factors, tumor morphology, residual liver function and clinical performance. Whether or not a staging system includes all three factors, prior to deciding the course of treatment or prognosis all three have to be considered even in a qualitative manner. The twelve liver staging systems considered in this Chapter are detailed in Appendix A. Some incorporate only tumor morphology, some only residual liver function and some both. Very few incorporate any measure of clinical performance which can be a very important prognostic variable. Table 1 shows which of the above three factors—tumor morphology, residual liver function and clinical performance—are included in each of these staging systems. Staging systems based solely on tumor morphology describe the anatomic characteristics and extent of the tumor itself and attempt to correlate these with survival. They incorporate tumor size, lesion number, location, lymph node involvement, metastases and the presence of vascular invasion. Each of these aspects imparts its own prognostic weight. For example, portal vein invasion is a far stronger predictor of negative outcome than tumor size. Though important, the usefulness of incorporating tumor morphology in prognosis depends nearly entirely on whether the patient is resectable or not. Put another way, prognosis is impacted more so by tumor size being less than 5 cm rather than the tumor being any size below or any size above 5 cm. The 5 cm limitation is set by the Milan criteria for patients considered for liver transplantation for HCC. Indeed there is a very significant drop off in survival between patients who are surgical candidates (resection or transplantation) and patients who are not. If the tumor is deemed unresectable, tumor morphology in general has limited value in prognosis. For example the prognosis of a patient with HCC will not change much if the tumor size is 7 cm vs 9 cm. In unresectable disease, regional lymph involvement and even distal metastases (usually lung) have limited bearing on survival because most patients will die from liver failure, either as a result of liver tumor progression or progression of cirrhosis to end stage liver disease (ESLD). There are however a few notable exceptions to this. One is the presence of portal vein thrombosis. The 1-, 2- and 3-year survival of patients with HCC

37

Staging Algorithms for Patients with HCC and Prognostic Indicators

Table 1. The twelve most commonly HCC/liver staging systems used worldwide are shown

AJCC/UICC TNM 6th Ed BCLC CP CLIP CUPI GRETCH JIS LCSGJ MELD OKUDA TNM TOKYO

Tumor Morphology

Liver Function

Clinical Performance

X X X X X (PVT only) X X X X X

X X X X X X X X X

X X (Symptoms only) X -

Each system’s score is calculated based on combination of tumor morphology characteristics (column 1), liver function tests (column 2) and patient’s clinical performance (column 3). The score of some systems such as the AJCC/UICC TNM, LCSGJ and classic TNM depends exclusively on tumor morphology characteristics. Such systems are in general useful for patients with early or no cirrhosis and good performance status. In other words, patients who are expected to die from tumor progression. The score of some other systems depends on liver function tests (i.e., CP and MELD) and not on tumor morphology. Such systems are useful for patients with HCC who have moderate to advanced cirrhosis and who are expected to die from ESLD, not tumor progression. Most systems (BCLC, CLIP, CUPI, GRETCH, JIS, Okuda, Tokyo) include both tumor morphology characteristics and liver function tests in the calculation of their score. These systems are not necessarily more accurate than the rest. They are more useful in situation where it is unclear whether the patient will die from tumor progression or ESLD. Table 2 shows the settings in which each of these systems has been validated.

and PVT is 17%, 8% and 0% compared to 65%, 35% and 17% respectively, for those without PVT, yielding an adjusted risk factor of 2.7 (Llado et al1). Another obvious but neglected prognostic variable is the location of the metastatic disease. For example, the prognosis of a patient with an unresectable HCC and a 1 cm pulmonary metastasis is vastly different from the same patient with a brain metastasis (albeit rare), yet no staging system takes this into account. Residual liver function is a measure of the liver ability to perform its function(s). Pre- and postresection liver volume calculations have shown noncirrhotic liver has a capacity four to five times the minimum required to sustain life. Therefore, surgical resection of an HCC can be safely performed if the residual liver volume is at or more than 25% of baseline by volume. On the other hand, in patients with moderate to advanced liver cirrhosis, a residual volume of at least 40-45% is desired, after resection for HCC. It is notoriously difficult to gauge the actual liver function or reserve and we rely on mostly surrogate markers such as bilirubin, albumin, INR and others to quantify it. However, by the time such markers are affected by liver disease, there has been significant loss of liver function. The value of incorporating a measure of liver function in determining the prognosis of a patient with HCC depends on tumor stage and liver reserve. If the patient is resectable and has minimal or no cirrhosis, using a staging system that includes measures of liver function will have no advantage to one which depends purely on tumor morphology. If on the other hand, a patient has moderate to advanced liver cirrhosis any system that lacks a measure of liver function will yield inaccurate prognosis. There has been an emergence of a variety of treatment options for unresectable HCC (TACE, cryoablation, RFA, ethanol ablation) as well as an increase in the use of combination treatments (TACE followed by resection, resection and RFA). Each of

38

Table 2. List of the HCC/liver disease staging systems that have been validated according to the current literature (Column 1) System Validated

System not Validated

Validated for Prognosis in

Citation

Limitations/Notes

AJCC/UICC TNM, Modified 6th Edition

Japanese TNM, BCLC, CLIP, JIS

Disease free survival after transplant

Vauthev et al2 Kee et al3 -

Okuda, CLIP, BCLC

-

All patients varied treatments

Kung et al4

BCLC

-

Varied treatments

Cillo et al5

All patients varied treatments Varied treatments 6

JIS

BCLC

Varied treatments Early detection

Toyoda et al

Varied treatments

Tokyo

BCLC

Cirrhosis percutaneous treatments

Tadeishi et al7

-

8

BCLC

-

Resectable

Cillo et al

CP

Okuda, LCSGJ, BCLC

TACE unresectable

Georgiades et al9

10

TNM

Okuda, CLIP, JIS

XRT unresectable

Seong et al

TNM

CLIP,Okuda

Resectable

Huang et al11

Hep B -

Cirrhosis

Gianni et al

CLIP L large JIS small

Resection

Chen et al13

CUPI

Cirrhosis

Leung et al14

Varied treatments Hep B

GRETCH

Early cirrhosis

Giannini et al15

Hep C

CLIP,Okuda

-

All treatments

continued on next page

Recent Advances in Liver Surgery

12

-

System Validated

System not Validated

Validated for Prognosis in

Citation

Limitations/Notes

JIS

TNM CLIP CP

Resection

Nanashima et al16 17

LCSGJ TNM

-

Resection

Ikai et al

MELD

-

Transplantation waiting list mortality

De la Mata et al18

Hep B -

11

-

TNM

-

Resection early/no cirrhosis

Huang et al

-

Tokyo score

-

Percutaneous ablation

Tateishi et al19

-

Column 2 shows the staging systems that were found not to be valid by the cited report (column 4). Column 3 shows the setting in which each system has been validated and column 5 lists the shortcomings of the cited report. Toyoda et al6 in row 5 for example, compared the prognostic accuracy of JIS and BCLC systems for patients with early detection (small, liver limited) HCC treated with a variety of methods (surgical and locoregional). The authors concluded that the JIS system’s successive stages correlated significantly with worst prognosis while those of BCLC were not. However, though the conclusions of the authors are indeed valid they have limited practical use because they may not valid in a specific disease/patient/treatment combination.

Staging Algorithms for Patients with HCC and Prognostic Indicators

Table 2. Continued

39

40

Recent Advances in Liver Surgery

these treatments affects liver function in a different way. For example, TACE causes significant but transient liver injury whereas RFA usually results in incremental but permanent loss of liver function. For the more than 85% of patients with HCC who have some degree of liver cirrhosis, accurate prognosis requires a staging system that includes a measure of residual liver function for treatment planning purposes. Clinical performance is an absolutely crucial factor in determining both prognosis and the success of any treatment for HCC under consideration. The only systems that incorporate clinical performance in calculating prognosis are the French GRETCH and the BCLC system. The CUPI system includes the presence of symptoms at presentation which can also be considered a measure of clinical performance, albeit deficient. These are not necessarily more prognostically accurate than the others as they have their own limitations. Irrespective of the staging system used, planned treatment and disease stage, the patient’s clinical performance must be quantified and included in the decision making process. The two accepted methods of assigning a measurable value to clinical performance for a patient with HCC is the Eastern Cooperative Oncology Group (ECOG) Performance Status and the Karnofsky Index (Appendix B). In general, a nontransient ECOG status of more than 2 or a Karnofsky Index of less than 70% portends a poor outcome irrespective of tumor morphology, liver function reserve or treatment. A cursory review of the literature will reveal a large number of publications comparing, validating or rejecting one or another liver staging system. One has to assess these papers critically in order to weed out the flawed or useless majority. Even considering those with proper methodology and valid conclusions most have no practical application. The most common mistake made in designing a comparison of liver staging systems is that the question posed is not specific enough. Many authors compare the prognostic accuracy of different systems but include resectable and unresectable patients, patients with all causes and stages of cirrhosis as well as patients receiving variable treatments. Though the conclusions may be valid they have no practical application because the system that proves to be the most prognostically accurate overall for this general population is not necessarily the most accurate for a specific patient, i.e., one who has unresectable HCC treated with TACE. A second shortcoming is that most authors compare only 2-3 systems which still leaves the questions which is the most accurate system unanswered. Certain conclusion however can be obtained from the published literature especially related to the validity of a system. To say that an HCC staging system has been validated means that its successive stages correlate significantly with worse prognosis in the selected population, undergoing the reported treatment. Table 2 shows the HCC staging systems and under which circumstances each has been validated according to the current literature.

Prognostic Variables

Certain markers—some related to tumor morphology, some to liver function and some to neither—independently impart their own influence on the survival of patients with HCC. These independent prognostic variables are tabulated in Table 3 according to their relative risk. The four more important independent prognostic variables for patients with HCC are the presence of portal vein invasion, abnormal AFP, poor performance status and histologic type all imparting an odds ratio for shorter survival of between 3 and 5. Despite the prognostic significance of these independent variables they are mostly ignored by the available staging systems. For example the presence of portal vein invasion will cut the median survival of patients with HCC from 25 months down to 5 months (all patients included, resectable and unresectable); yet only half the staging systems include portal vein invasion (a tumor morphology characteristic easily discernible on contrast enhanced cross sectional imaging) in their calculations. Similarly, the histological type of HCC cuts survival by three fold if adenoid (vs trabecular) yet none of the systems include this variable. Certainly all patients with HCC would have had an MRI and/or CT thus the status of the portal vein should be available for all patients. Similarly AFP is almost universally available in HCC patients. Though it is difficult to calculate its quantitative influence on survival, a normal AFP is predictive of longer survival. It behooves the physician then, whatever liver staging system

41

Staging Algorithms for Patients with HCC and Prognostic Indicators

Table 3. List of independent prognostic factors for patients with HCC and/or liver disease (Column 1). The factors are listed according to decreasing odds ratio (Column 3) as indicated by the reduction in survival in patients with the risk factor vs those without (Column 2). Column 5 lists the number of the twelve HCC/liver staging systems that incorporate the specific factor in their score calculation. For example, Gianni et al12 (row 5) reports a reduction in median survival from 43 to 15 months if the HCC histological type is adenoid vs trabecular. This yields an odds ratio of 2.8. Despite its potential contribution to calculating survival, histology is not included in any of the staging systems. Such important independent variables should ideally be considered prior to providing the patient with a prognosis Relative Median Survival (Months) Odds Ratio

# Staging Systems Included

Citation

Portal Vein Invasion (N vs Y)

25 vs 5

5

Marrero et al20 6/12

AFP (<44 vs >44)

30 vs 10

3.0

Marrero et al20 3/12

Performance Status 0/1/2

30/16/6

1/2.7/5

Marrero et al20 2/12

Histology (Trabecular vs adenoid)

43 vs 15

2.8

Gianni et al12

T.Bilirubin (<1.5 vs >1.5 mg/dl)

57 vs 21

2.7

Huo et al

p53 Overexpression (N vs Y)

43 vs 16

2.7

Gianni et al12

21

21

0/12 9/12 0/12

Encephalopathy (N vs Y)

37 vs 13

2.6

Huo et al

4/12

Ascites (N vs Y)

46 vs 19

2.4

Huo et al21

7/12

21

5/12 7/12

INR (<1.5 vs >1.5)

41 vs 22

1.9

Huo et al

Albumin (>3.5 vs <3.5 g/dl)

47 vs 27

1.7

Huo et al21 22

Platelet Count (<100 k)

-

1.5

Ryder et al

0/12

AGE (>65)

-

1.34

Ryder et al22

0/12

he chooses to somehow incorporate, even in a qualitative manner, such important independent variables as are available in the patients’ prognosis and treatment planning.

Staging Algorithms

A staging algorithm is more than just a liver staging system. The use of an algorithm implies the consideration of all prognostically relevant factors in appropriate succession and according to their relevant weight to provide the most accurate prediction of survival. Before one chooses a staging system the objective must be stated. Is the system going to be used to provide a prognosis for a specific patient or is it going to be used to stage a population of patients with HCC for comparative purposes (i.e., compare effectiveness of one type of treatment, as in a research study)? If the latter is the case one ought to ideally choose a staging system that has been validated for the specific treatment and population in the proposed study. The fact that a staging system has not be validated yet does not mean it is not valid for a specific population and treatment plan, however the authors must ensure an appropriate choice. For example, using a liver staging system that relies exclusively on liver function markers for a population who is planned to undergo resection is inappropriate because by virtue of being resectable patients must not suffer from significant liver dysfunction. If the objective is to calculate the prognosis of a specific patient, then choosing an appropriate staging system is necessary but not adequate. The proposed algorithm is shown in Figure 1. The first task is to decide on resectability. Resectability depends on disease and patient alike, therefore the

42

Recent Advances in Liver Surgery

tumor morphology and patient/liver status must both be considered without however settling on a system yet. If a patient is resectable, he is expected to die from progression of their HCC and not their liver cirrhosis (otherwise surgery would be of no benefit to begin with), therefore a staging system based on tumor morphology would be more appropriate. For the vast majority of patients with HCC who are unresectable one has to then ascribe the most likely future lethal event to the patient. That is, is the patient going to die from tumor progression, progression of liver cirrhosis to end stage liver disease or his comorbid condition? Once this is determined, one chooses the appropriate staging system, i.e., tumor morphology based for those expected to die from tumor progression, liver function based for those expected to die from end stage liver disease or hybrid based if it is unclear. After the choice of the most appropriate staging system is made one has to consider other significant independent prognostic variables. Table 3 tabulates the most important ones described up to date. If the selected staging system does not include these or at least some of the most important ones, then the physician should consider each prior to providing the patient with a specific prognosis.

Discussion

A review of Table 2 shows correlation between a certain staging system and treatment type for which the system has been validated. LCSGJ, JIS, TNM and AJCC/UICC have been validated for patients who undergo resection. By default these patients have disease confined to the liver, relatively small in size, that lacks vascular invasion and importantly, the extent of their cirrhosis is limited enough to allow for extensive surgery. In addition they have good enough performance status to make hepatic resection worthwhile. It is obvious then that in general these patients will likely die from tumor progression and not liver disease if left untreated. On the other hand, Okuda, CLIP, BCLC and Tokyo systems have been validated mostly for unresectable patients who are thus because of advanced liver disease, poor performance status or advanced tumor morphology. Many of these patients (advanced liver disease and poor performance status) will likely die from progression of their already advanced cirrhosis or comorbidities rather than tumor progression. Therefore tumor morphology staging systems have less value than systems that incorporate liver function markers. Specific validations make the most useful validations. For example, the use of the MELD system (which was originally designed to stage patients with portal hypertension requiring a transjugular portosystemic shunt for palliation) to assign priority to liver transplant candidates has resulted in a significant reduction in waiting list mortality. Similarly, the Child-Pugh system has been validated as the most accurate prognostic system in patients with unresectable HCC treated with TACE. Considering the above one can see a major difference between liver and nonliver staging systems: the choice of liver staging system for HCC depends on disease, patient and treatment plan, instead of the other way around (i.e., the treatment plan depends on tumor staging). Even under ideal circumstances the statistical variation in predicting survival may be prohibitively large therefore a specific expected survival cannot be given to a patient. There are two HCC patient subgroups that can be told with acceptable certainty of their prognosis: First, those whose disease is too advanced (i.e., large infiltrative HCC with vascular invasion, borderline liver function and poor performance status) and second, those who are resectable, have early or no cirrhosis and good performance status. Unfortunately the latter group comprises less than 15% of all patients with HCC. In the final analysis when one asks, which the best HCC staging system is, the only appropriate answer is that there is no such thing. The only valid question is: Which among the available HCC staging systems is the least inaccurate in predicting survival for a specific patient, with specified liver disease, quantified performance status and planned to undergo a specific treatment.

Staging Algorithms for Patients with HCC and Prognostic Indicators

References

43

1. Llado L, Virgili J, Figueras J et al. A prognostic index of the survival of patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization. Cancer 2000; 88(1):50-57. 2. Vauthey JN, Ribero D, Abdalla EK et al. Outcomes of liver transplantation in 490 patients with hepatocellular carcinoma: validation of a uniform staging after surgical treatment. J Am Coll Surg 2007; 204(5):1016-1027; discussion 1027-1028. 3. Kee KM, Wang JH, Lee CM et al. Validation of clinical AJCC/UICC TNM staging system for hepatocellular carcinoma: analysis of 5,613 cases from a medical center in southern Taiwan. Int J Cancer 2007; 120(12):2650-2655. 4. Kung JW, MacDougall M, Madhavan KK et al. Predicting survival in patients with hepatocellular carcinoma: a UK perspective. Eur J Surg Oncol 2007; 33(2):188-194. Epub 2006. 5. Cillo U, Vitale A, Grigoletto F et al. Prospective validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol 2006; 44(4):723-731. 6. Toyoda H, Kumada T, Kiriyama S et al. Comparison of the usefulness of three staging systems for hepatocellular carcinoma (CLIP, BCLC and JIS) in Japan. Am J Gastroenterol 2005; 100(8):1764-1771. 7. Tateishi R, Yoshida H, Shiina S et al. Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients. Gut 2005; 54(3):419-425. 8. Cillo U, Bassanello M, Vitale A et al. The critical issue of hepatocellular carcinoma prognostic classification: which is the best tool available? J Hepatol 2004; 40(1):124-131. 9. Georgiades CS, Liapi E, Frangakis C et al. Prognostic accuracy of 12 liver staging systems in patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization. J Vasc Interv Radiol 2006; 17(10):1619-1624. 10. Seong J, Shim SJ, Lee IJ et al. Evaluation of the prognostic value of Okuda, Cancer of the Liver Italian Program and Japan Integrated Staging systems for hepatocellular carcinoma patients undergoing radiotherapy. Int J Radiat Oncol Biol Phys 2007; 67(4):1037-1042. Epub 2007; 11. Huang YH, Chen CH, Chang TT et al. Evaluation of predictive value of CLIP, Okuda, TNM and JIS staging systems for hepatocellular carcinoma patients undergoing surgery. J Gastroenterol Hepatol 2005; 20(5):765-771. 12. Gianni S, Cecchetto A, Altavilla G et al. Tumour staging, morphology and p53 overexpression concur in predicting survival in hepatocellular carcinoma. J Intern Med 2005; 257(4):367-373. 13. Chen TW, Chu CM, Yu JC et al. Comparison of clinical staging systems in predicting survival of hepatocellular carcinoma patients receiving major or minor hepatectomy. Eur J Surg Oncol 2007; 33(4):480-487. Epub 2006. 14. Leung TW, Tang AM, Zee B et al. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer 2002; 94(6):1760-1769. 15. Giannini E, Risso D, Botta F et al. Prognosis of hepatocellular carcinoma in anti-HCV positive cirrhotic patients: a single-centre comparison amongst four different staging systems. J Intern Med 2004; 255(3):399-408. 16. Nanashima A, Sumida Y, Abo T et al. Modified Japan Integrated Staging is currently the best available staging system for hepatocellular carcinoma patients who have undergone hepatectomy. J Gastroenterol 2006; 41(3):250-256. 17. Ikai I, Takayasu K, Omata M, Liver Cancer Study Group of Japan et al. A modified Japan Integrated Stage score for prognostic assessment in patients with hepatocellular carcinoma. J Gastroenterol 2006; 41(9):884-892. 18. De la Mata M, Cuende N, Huet J et al. Model for end-stage liver disease score-based allocation of donors for liver transplantation: a spanish multicenter experience. Transplantation 2006; 82(11):1429-1435. 19. Tateishi R, Yoshida H, Shiina S et al. Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients. Gut 2005; 54(3):419-425. 20. Marrero JA, Fontana RJ, Barrat A et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005; 41(4):707-716. 21. Huo TI, Lee SD. Role of the model for end-stage liver disease and serum alpha-fetoprotein as prognostic predictors for hepatocellular carcinoma. Liver Int 2006; 26(10):1300-1301. 22. Ryder S. Predicting survival in early hepatocellular carcinoma. Gut 2005; 54(3):328-329.

44

Recent Advances in Liver Surgery

Appendix A—The HCC/liver disease staging systems considered in this Chapter Stage Tumor Node Metastasis I

T1

N0

M0

T1 < 2 cm, solitary, no vascular invasion

II

T2

N0

M0

T2 > 2 cm, < 5 cm, solitary or multiple, no vascular invasion

IIIa

T3

N0

M0

T3 ≤ 5 cm, solitary, involving segmental branch of portal or hepatic veins

IIIb

T4

N0

M0

T4 > 5 cm, multiple, or tumors involving major branch of portal or hepatic veins, or tumors with direct invasion of adjacent organs other than the gallbladder, or perforation of visceral peritoneum

Any

N1

M0

N1, regional lymph nodes

Any

Any

M1

M1, distal metastasis

IV

American Joint Committee on Cancer/Union Internationale contre le Cancer [AJCC/UICC] TNM Modified 6th edition. Barcelona Clinic Liver Cancer Stage (BCLC)

Stage

PST Morphology

Okuda

Portal Total Hypertension Bilirubin Child-Pugh

A1

0

Uninodular

I

No

Normal

A2

0

Uninodular

I

Yes

Normal

A3

0

Uninodular

I

Yes

Elevated

A4

0

< 3 lesions, Each <3 cm I-II

A-B

B

0

> 5 cm, Multinodular

I-II

A-B

C

1-2

Vascular Invasion and/ or Metastases

I-II

A-B

D

3-4

Any

III

C

(PST = Performance Status Test) Class A (5-6), Class B (7-11) and Class C (12-15); Child-Pugh Class (Categorical and Nominal) Score

Ascites Encephalopathy Albumin (g/dl) Bilirubin (mg/dl) PT Prolongation (s)

1

2

3

None None ≥ 3.5 ≤ 2.0 < 4.0

Mild-Moderate Mild-Moderate 3.0-3.5 2.0-3.0 4.0-6.0

Severe Severe <3.0 >3.0 >6.0

Staging Algorithms for Patients with HCC and Prognostic Indicators

Cancer of the Liver Italian Program (CLIP) Score Variable

Score

Child-Pugh Class A

0

B

1

C

2

Tumor Morphology Uninodular, <50% of Liver

0

Multinodular, <50% of Liver

1

>50% of Liver

2

α-Fetoprotein (AFP) <400 ng/ml

0

>400 ng/ml

1

Portal Vein Thrombosis Yes

0

No

1

Chinese University Prognostic Index (CUPI) Variable

Weight

TNM Stage I-II

−3

IIIa-IIIb

−1

IVa-IVb

0

Asymptomatic on Presentation

−4

Ascites

3

α-Fetoprotein >500 ng/mL

2

Bilirubin (μmol/L) <34

0

34-51

3

>52

4

Alkaline Phosphatase >200 IU/L

3

45

46

Recent Advances in Liver Surgery

Group d’Etude de Traitement du Carcinoma Hepatocellulaire (GRETCH) Weight 0

1

2

3

>80%

Karnofsky Index Bilirubin (mg/dl)

<3.0

Alkaline Phosphatase

<2.0 ULN

α-Fetoprotein (μg/L)

<35

Portal Vein Obstruction

No

<80% >3.0 >2.0 ULN >35 Yes

ULN = Upper Limit of Normal Japan Integrated Staging (JIS) Score Score 0

1

2

3

Child-Pugh Score

A

B

C

-

TNM by LCSGJ

I

II

III

IV

Liver Cancer Study Group of Japan (LCSGJ) Score Stage

Single

<2 cm

No Vascular Invasion

I

Yes

Yes

Yes

II

Two of above

III

One of above

IV

None

Model End-Stage Liver Disease (MELD) Score MELD = 10 {0.957 Ln(Scr) + 0.378 Ln(Tbil) + 1.12 Ln(INR) + 0.643}

• • •

Where, Ln is natural logarithm Scr is serum creatinine (mg/dl) TBil is total bilirubin (mg/dl) INR is International Normalized Ratio 1 is the minimum acceptable value for any of the three variables The maximum acceptable value for serum creatinine is 4 The maximum value for the MELD score is 40

47

Staging Algorithms for Patients with HCC and Prognostic Indicators Stage I, 0 points; Stage II, 1 or 2 points; Stage III, 3 or 4 points; Okuda Stage Points 0

1

Tumor Size

<50% of liver

>50% of liver

Ascites

No

Yes

Albumin (g/dl)

>3.0

<3.0

Bilirubin (mg/dl)

<3.0

>3.0

Stage I Stage II Stage IIIA Stage IIIB Stage IVA Stage IVB

T1+N0+M0 T2+N0+M0 T3+N0+M0 T1-3+N1+M0 T4+N0+M0 Tany+Nany+M1

T

Number

Size (cm)

Vascular Invasion

1

1

<2

No

2

1

<2

Yes

2

Many/one lobe

<2

No

2

1

>2

No

3

1

>2

Yes

3

Many/one lobe

4

Many/both lobes

Any

Any

4

Any

Any

Portal Vein

Yes

N0 = No nodes; N1 = Regional nodes only; M0 = No metastases; M1 = Extrahepatic Metastases; TNM (Tumor, Nodes, Metastases) Stage. Tokyo Score Score 0

1

2

Albumin (g/dl)

>3.5

2.8-3.5

<2.8

Bilirubin (mg/dl)

<1

1-2

>2

Tumor Size (cm)

<2

2-5

Tumor Number

<3

>5 >3

48

Recent Advances in Liver Surgery

Appendix B—Clinical patient performance tests ECOG Performance Status Grade ECOG 0

Fully active, able to carry on all predisease performance without restriction

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

2

Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

3

Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4

Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair

5

Dead

Karnofsky Index 100% Perfectly well 90% Minor symptoms—can live a normal life 80% Normal activity with some effort 70% Unable to carry on normal activity but able to care for oneself 60% Requires occasional help with personal needs 50% Disabled 40% The patient needs nursing assistance and medical care, but is not hospitalized 30% Severely disabled, in hospital 20% Very sick, active support needed 10% Moribund 0% Death

Chapter 4

Staging Systems to Predict Survival in Hepatocellular Carcinoma Sonia Pascual* and Miguel Pérez-Mateo

Abstract

T

here has been considerable controversy regarding which is the best prognostic staging system to predict survival in patients with cirrhosis and hepatocellular carcinoma (HCC). Several prognostic models have been developed in recent years but none has been widely accepted. The staging systems developed by European groups are the French model (GRETCH, Groupe d´Etude de Traitement du Carcinoma Hepatocellulaire), the Barcelona Clinic Liver Cancer classification (BCLC), the Cancer Liver Italian Program classification (CLIP) and the Vienna Survival Model for HCC (VISUM-HCC). The Asiatic staging systems are: Okuda score, JIS score ( Japan Integrated Staging), CUPI (Chinese University Prognosis Index) and Tokyo score. The lack of consensus is in part related to the heterogeneity of models because have been developed in different parts of the world, with different population characteristics and using different variables. Factors that may affect the prognosis of the patients with HCC include tumour stage at diagnosis, physical status of the patient, residual liver function and the therapeutic modality. In order to best assessing the prognosis of patients with HCC it is recommended that the staging systems take into account all of these variables. Most of the prognostic staging systems for HCC use a combination of factors related to liver function, such as presence of ascites, levels of albumin, bilirubin, Child-Pugh score and others related to the tumour characteristics including portal vein thrombosis, alfa-fetoprotein (AFP), size, number of lesions and distribution, morphology and TNM (Tumour, Nodule, Metastasis) stage. All available staging systems have been useful in predicting survival, but only a few have been externally validated. CLIP, BCLC and JIS staging systems are the most extended and validated. Moreover, BCLC and CLIP have been supported by relevant scientific societies. The BCLC model includes treatment, which is a relevant aspect to consider in these patients and is not included in the other prognostic systems. Until we have more information and considering all of these aspects, probably BCLC should be the preferred staging system.

Introduction

Diagnosis of cancer has obvious prognostic implications that are mostly related to tumour stage in a given patient. Multiple efforts have been made to establish an adequate prognostic staging system in each particular type of tumour since both prognosis and therapeutic decisions are intimately related to tumour stage. In fact, prognosis is the first question that the patients make when the diagnosis of cancer arises and in the particular case of hepatocellular carcinoma (HCC), estimating survival becomes an even more complex procedure. Indeed, not only characteristics of tumour influences prognosis, but almost all these patients share cirrhosis as the underlying disease, which implies a new factor to determine all future decisions that have to be taken. *Corresponding Author: Sonia Pascual—Unidad Hepática. Hospital General Universitario de Alicante, C/Pintor Baeza s/n, Alicante 03010. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

50

Recent Advances in Liver Surgery

As with other solid tumours, prognosis is related to stage at presentation, the patient’s physical status and in the particular case of HCC, to the severity of the underlying liver dysfunction. Therefore, both circumstances, tumour stage and liver function, must be considered in a given patient before taking a treatment decision since most of available therapies may be contraindicated in patients with advanced cirrhosis and the size and extension of the tumour determine the therapeutic modality: surgery, liver transplantation, percutaneous ablation or arterial chemoembolization. As with other tumours, prognosis depends on whether the tumour is suitable or not for intention-to cure treatment.1-5 Therefore, the ideal staging systems to predict survival in HCC should have to combine all of these aspects, including tumour stage, liver function, physical status of the patient and eventually, the therapy applied and this is the recommendation of the last practice guidelines of the American Association for the Study of Liver Disease (AASLD) about management of HCC.6 Until recently, Okuda’s was the most commonly used staging system to predict survival in patients with HCC,7 but more sensitive and specific new prognostic models have been developed and published. These new scores have been designed using the prognostic factors that showed a better prediction value for survival in large series of patients with HCC from Europe and Asia. Some of the models have been already externally validated but others do not. Most of the prognostic staging systems for HCC use a combination of factors related to liver function: presence of ascites, levels of albumin, bilirubin, Child-Pugh score, MELD and others related to the tumour characteristics: portal vein thrombosis, alfa-fetoprotein (AFP), size, number of lesions and distribution, morphology, TNM (Tumour, Nodule, Metastasis) stage. Only few staging systems include information regarding the overall clinical situation of the patient which is a crucial prognosis data in oncology (Karnofsky index, performance status or presence of symptoms). The evaluation of residual liver function is an important issue to consider in staging systems for HCC. Child-Pugh has been the most widely used score to determine liver function in patients with cirrhosis and it is still considered the cornerstone in the prognostic evaluation of these patients, although it was formulated more than 30 years ago.8 Recently, the Model for End-Stage Liver Disease (MELD)9,10 has been introduced and prospectively validated as a tool to predict risk of mortality and assess disease severity in patients with cirrhosis. This score had been included in modifications of previous known prognostic staging systems for HCC, replacing Child-Pugh score, but its usefulness in the prediction of survival of patients with HCC has still not been completely established. Tumour stage is another crucial variable that should be included in all staging systems, but the modality of classification varies among different scores. In Okuda’s, Tokyo score, VISUM-HCC, CLIP and BCLC model, the variable is described as tumour morphology, considering size and/or number of nodules or percentage of the liver affected. Other models include serum laboratory values that indirectly reflect the size of the tumour such as serum AFP. The probability of extra-hepatic extension is considered in some models with PVT, TNM or presence of enlarged lymph nodes. The consequence is that there is no homogeneous consensus on how to use this important data and the way it must be expressed. Table 1 shows the staging systems developed by European groups: the French model (GRETCH, Groupe d´Etude de Traitement du Carcinoma Hepatocellulaire),11 the Barcelona Clinic Liver Cancer classification (BCLC),12 the Cancer Liver Italian Program classification (CLIP)13 and the Vienna Survival Model for HCC (VISUM-HCC).14 Table 2 shows the Asiatic staging systems: Okuda score,7 JIS score ( Japan Integrated Staging),15 CUPI (Chinese University Prognosis Index)16 and Tokyo score.17 There is no international consensus on which staging system is best in predicting survival of patients with HCC. This is relevant, since reaching a consensus on the use of a unique and worldwide prognostic staging system for HCC would allow performing prospective trials using the same system, similarly to what has represented the Child-Pugh score in assessment of liver function. In this chapter we will review the published prognostic staging systems, their characteristics and usefulness, its external validation when available and the studies where the different systems

51

Staging Systems to Predict Survival in Hepatocellular Carcinoma

Table 1. European staging systems Cancer Liver Italian Program (CLIP) Scoring System Score 0

1

2

Child-Pugh stage

A

B

C

Tumour morphology

Uninodular and extension ≤50% <400 No

Multinodular and extension ≤50% ≥400 Yes

Massive or extension >50%

AFP (ng/ml) Portal vein thrombosis

AFP: alfa-fetoprotein; Early stage (0 points); intermediate stage (1-3 points); advanced stage (4-6 points). French Classification Points 0 Karnofsky index (%)1 Serum bilirrubin (μmol/l) Serum alkaline phosphatase (ULN)2 Serum alpha-fetoprotein (μg/l) Portal vein obstruction (ultrasonography)

1

≥80 <50 <2 <35 No

2

3 <80 ≥50

≥2 ≥35 Yes

1 Karnofsky score ≥80%: complete autonomy of the patient; 2ULN: upper limit of normal range; Group A: low risk of death, score = 0; group B: intermediate risk of death, score from 1 to 5; group C: high risk of death, score ≥6.

Vienna Survival Model for HCC Points

PT (%)1 Bilirubin (mg/dll) AFP(kU/l)2 Tumour >50% PVT3 Enlarged lymph nodes

0

1

>70 ≤2 ≤125 ≤50% No No

≤70 >2 >125 >50% Yes Yes

1 PT: Prothrombin time; 2AFP: Alpha-fetoprotein; 3PVT: Portal vein thrombosis; Stage 1: 0-2 points; stage 2: 3 points; stage 3: 4-6 points.

have been compared. Finally, we will try to establish which staging system is the best according to the published information.

Staging System in Hepatocellular Carcinoma

Prognostic staging systems have been developed in order to predict survival of patients with a certain type of tumour and theoretically they should be able to help deciding the best therapeutic

52

Recent Advances in Liver Surgery

option in a given case. To achieve this objective, patients are classified into subgroups with known different outcomes and the treatment option eventually depends on this classification.

TNM

TNM is the classical prognostic staging system in oncology and it has been applied historically to patients with HCC.18 The American Joint Committee on Cancer (AJCC) version of the TNM system has been internally validated and subsequently recommended for patients undergoing resection or liver transplantation.5 Subsequent trials compared the Japanese TNM and AJCC/ International Union against Cancer (UICC)19 and validated the fifth and sixth editions of the AJCC/UICC TNM staging system for HCC in cirrhotic undergoing liver resection.20,21 However in an external and prospective validation in patients undergoing liver transplantation, TNM did not have the adequate prognostic accuracy.22 The most likely limitation of TNM model in patients with cirrhosis and HCC relies on the fact that it does not consider the degree of liver dysfunction secondary to cirrhosis. The TNM Stage by the Liver Cancer Study Group is considered in detail elsewhere in this book.

Okuda

It has been suggested that besides tumour stage, liver function should be included in any prognostic system utilized in patients with cirrhosis and HCC. In this regard, Vogel published in the 70’s a well documented staging scheme for HCC that was subsequently modified by Primack23,24 and included ascites, weight loss, portal hypertension and serum bilirubin. Subsequently Okuda and cols. from Japan published in 1985 a modification of this model and described a new score combining two different patterns of variables: indicators of liver function (ascites, jaundice and serum albumin) and data regarding tumour extension. During almost two decades this score has been worldwide accepted (Table 2).7 Patients were stratified in three stages according to the different probability of survival. The study included a population of 850 patients with HCC coming from three institutions and the treatments applied were either surgical (18%) or nonsurgical (82%), including intra-arterial chemotherapy, systemic chemotherapy, trans-catheter arterial chemoembolization (TACE) and 229 received supportive therapy. A known drawback of Okuda score is that the initial study did not include patients undergoing liver transplant or percutaneous treatment, which are actually considered as therapies applied with intention-to-cure. This may be the reason explaining why the Okuda score is better classifying patients with the worst prognosis.

CLIP

In 1993 a group of investigators in liver cancer coming from several Italian hospitals established the CLIP with the aim of performing prospective multicenter trials. In 1998 they presented the results of a retrospective study of 435 patients with HCC.13 In this study they proposed a new staging system, the CLIP score, that comprised variables of both liver function (Child-Pugh stage) and tumour characteristics (levels of AFP, portal vein thrombosis and tumour morphology) (Table 1). Accordingly, patients are classified in five subgroups with different probabilities of survival. In this case treatments applied were: surgery (3%), percutaneous ethanol injection (PEI) (32%), trans-arterial chemoembolization (17%), combined therapy (5%) and supportive therapy (42%). When compared with Okuda’s CLIP score has a higher number of categories and a greater discriminative ability. The same group published two years later a prospective validation study including a series of 196 patients with HCC and they compared CLIP and Okuda score.25 Authors concluded that CLIP model gave more accurate prognostic information, it was statistically more efficient and it had a greater survival predictive power than Okuda’s staging system. CLIP score has been externally validated too. Several authors obtained the same conclusions in three different cohorts of patients with HCC in Italy,26 Japan27 and Canada28 when comparing CLIP with Okuda and TNM. They included patients in all stages of the disease and the patients received all of available treatments. With this support, the American Hepatico-Pancreatico-Biliary Association (AHPBA/AJCC) consensus conference recommended the use of CLIP and AJCC

53

Staging Systems to Predict Survival in Hepatocellular Carcinoma

Table 2. Asiatic staging systems Okuda Staging System Points

Tumour size Ascites Albumin (g/dl) Bilirubin (mg/dl)

0

1

<50% of liver No ≥3 <3

>50% of liver Yes <3 ≥3

Okuda stage I: 0 points, Okuda stage II: 1 or 2 points, Okuda stage III: 3 or 4 points. Japan Integrated Staging Score (JIS) Points

Child-Pugh TNM stage score

0

1

2

3

A I

B II

C III

IV

JIS score is obtained via the summation of TNM stage score and Child-Pugh score. Chinese University Prognostic Index (CUPI) Points –4 TNM stage Asymptomatic disease at presentation AFP ≥500 (ng/mL)1 TB (μmol/L)2 ALP ≥200 (IU/L)3 Ascites

–3

–1

0

2

I and II

IIIa and IIIb

IVa and IVb

3

4

34-51 Yes Yes

≥52

Yes Yes

<34

1

AFP: alphafetoprotein, 2TB: total bilirubin,3ALP: alkaline phosphatase CUPI score ≤1 (low-risk group), CUPI score 2-7 (intermediate risk group), CUPI score ≥8 (high-risk group). Tokyo Score Score

Albumin (g/dl) Bilirubin (mg/dl) Tumour size (cm) Tumour number

Tokyo score 0, 1, 2, 3, 4-6.

0

1

2

≥3.5 <1 <2 ≤3

2.8-3.5 1-2 2-5

<2.8 >2 >5 >3

54

Recent Advances in Liver Surgery

version of the modified TNM system for stratification of patients with HCC into prognostic groups.5 They concluded that CLIP should be the clinical staging system of choice because it is generally applicable to most patients (except patients with chronic hepatitis B infection) and it includes easily collected variables. A modified CLIP staging system based on the MELD has been proposed.29 In this study Child-Pugh score in the CLIP model was replaced with MELD score at cut-offs of <10, 10-14, >14 and it was compared with the original CLIP. Authors concluded that MELD-based modifi ed CLIP system may have better predictive ability than the original model for cancer staging. The same authors published another investigation comparing CLIP, JIS and BCLC original model and MELD modified models.30 Both CLIP and JIS modified models showed better results than the original. However, BCLC did not improve its predictive ability with the MELD modification. Another modification of CLIP has been conducted for evaluating prognosis after hepatectomy for HCC.31-33 In this modified CLIP, AFP has been substituted by a new marker named PIVKA-II (protein induced by vitamin K absence or antagonist II) with a cut-off level of 400 mAU/mL.

BCLC

When developing the BCLC model authors intended to create a new staging system to stratify patients with HCC in subgroups according to the life expectancy and to link this fact with the different treatment modalities. The system was developed on the basis of their published experience in the natural history of HCC and the results of the studies with different modalities of treatment according to the stage of the disease. The variables included were presence of cancer related symptoms and associated diseases, the physical status of the patient (Performance Status), the assessment of liver function (Child-Pugh, portal pressure, bilirubin) and the evaluation of tumour stage (size, number of nodules, portal invasion) (Fig. 1). Accordingly patients were subdivided into four groups. The early stage includes a subgroup, named the Very Early Stage., which refers to patients with a single and small HCC, without both high portal pressure and microvascular invasion and normal bilirubin that may benefit from tumour resection. The rest of patients classified in the early stage are those with early HCC who may benefit from other curative therapies (percutaneous ablation and liver transplant). Intermediate stage includes patients with multinodular tumours but preserved liver function and good general status who may be treated with palliative TACE. However, this same subset of patients but with portal invasion or worst general status may be susceptible of treatment with new agents such as sorafenib. Finally, patients with very poor life expectancy who may only benefit from symptomatic treatment are classified in the terminal stage. In successive years after the publication of BCLC model several authors have compared other prognostic systems with BCLC in Europe (Italy and Spain) and USA.34-38 One of these investigations included only patients with early-intermediate HCC undergoing nonsurgical therapy37and other two included patients mainly treated with potentially radical therapies.35-36 The other authors included all patients with HCC irrespective of tumour stage and therapeutic availability.34,38 The main conclusion of these studies was that BCLC provided the best prognostic interpretation allowing an adequate stratification of therapy. Indeed, the last consensus conference of AASLD for management of HCC recommended that the ideal staging system to predict survival of HCC patients should consider tumour stage, liver function, physical status and the impact of treatment if it is applicable. Finally AASLD considered that BCLC system is the only staging system that accomplished all of these aims.6

JIS

Recently, a system based on a combination of the Child-Pugh system and the TNM stage by the Liver Cancer Study Group of Japan (LCSGJ) has been proposed by Kudo et al (Table 1).15 TNM classification by LCSGJ is concordant with that by the International Hepato-Pancreato-Biliary Association and the UICC.5 A study for validation was subsequently performed in a large patient population comparing CLIP and JIS models (4,525 patients diagnosed at five institutions). The patients underwent all modalities of therapy with the exception of liver transplant (26% surgery,

Staging Systems to Predict Survival in Hepatocellular Carcinoma

55

Figure 1. BCLC model.

19% percutaneous ablation therapy, 39% TACE and 16% others). Authors concluded that both the stratification ability and prognostic predictive power of the JIS score were much better than that of CLIP score, being the variables simple to obtain and remember.39 Several subsequent studies all of them conducted in Asia have confirmed this assumption.33,40-43 In these trials the JIS system has been compared with other known prognostic systems including CLIP, BCLC, Tokyo, CUPI and GRETCH classification. The main conclusion of these studies is that JIS score provides the best prognostic stratification in HCC patients, mostly in patients undergoing radical therapies. Accordingly, the JIS system seems to be the most appropriate in the actual era of early detection and potentially curative treatment of HCC almost in these geographic areas. Later modifications of JIS model have been developed with the aim of improving its accuracy. In one of the studies the Child-Pugh score was replaced with MELD cut off scores of <10, 10 to 14 and >14 points44 and this modified JIS system was therefore compared with the original JIS in patients with HCC undergoing locoregional therapy (TACE or percutaneous injection) and the results suggested that it might be better than the original system. A second modification of JIS score was calculated from the TNM stage and the grade of liver damage as defined by the LCSGJ.45 This modified liver damage classification results from the summation of the scores of five variables: serum bilirubin, albumin levels, prothrombin activity, indocyanine green retention rate at 15 minutes and presence of ascites and classified patients into grades A-C in a similar manner as in the Child-Pugh classification.45-47 With this change JIS score also showed a better prediction of prognosis than other staging systems in HCC patients who have undergone hepatic resection.47

56

Recent Advances in Liver Surgery

Other Prognostic Staging Systems

The new generation of prognostic models promises better stratifying ability in patients with HCC than the Okuda score. The actual requirements for new prognostic models are to improve the accuracy of the previous models. CLIP, BCLC and JIS staging systems are the most extended and validated systems but other groups have developed prognostic scores in Europe and Asia: the GRETCH model in France,11 the VISUM-HCC model in Austria,14 the CUPI model in China16 and the Tokyo score.17 With few exceptions most authors have found that all of these new staging systems are better than Okuda,48,49 but have not received yet international support and they do not show clear advantages when are compared with CLIP, BCLC or JIS. The French classification has been compared with other staging systems in some studies34-36,38,42 and these trials have shown that although GRETCH model is able to divide patients into strata with different prognosis it does not improve other models’ accuracy (Table 1). In summary this scheme is mostly helpful in identifying the patients with the worst prognosis. Only few trials have included the VISUM-HCC model in external and prospective validation studies (Table 1). One trial from central Europe found that VISUM-HCC together with others (BCLC, GRETCH and CLIP) was similar to the Okuda score in the receiver operating characteristics (ROC) analysis and there was no advantage of using the newer scores instead of Okuda score.48 In a trial from Germany the authors assessed the usefulness of this score to stratify patients but no clear advantages were obtained.49 A Hong-Kong’s single-centre based study including 962 patients with HCC (being mostly associated with hepatitis B virus) was developed to build the CUPI model (Table 2).16 Two studies comparing several staging systems and CUPI did not show advantages however.51 The last recently described staging system is the Tokyo score (Table 2). The aim of the authors was to create a simple and easy-to-calculate score, suitable for estimating prognosis during radical treatment of early HCC.17 Two subsequent studies were conducted in Japan comparing several staging system in patients who undergo radical therapies including Tokyo score.41,42 In both trials JIS score was the best staging system. A recent review of current staging system for HCC recommend that further validation studies of staging systems for HCC should focus on the revised Barcelona Clinic Liver Cancer (BCLC) staging classification, Japan Integrated Staging ( JIS) score and Tokyo score.52

Staging in Hepatocellular Carcinoma: Conclusions

All the available prognostic staging systems for HCC have limitations and still there is no worldwide consensus on the election of the best prognosis model. Table 3 shows the main characteristics of all of the available prognostic systems. CLIP, JIS and BCLC are probably the most extended models and some them have been supported by relevant scientific societies such as AASLD or AJCC. Several external studies have validated the usefulness of these three systems in different parts of the world. JIS score has been employed mostly in Asia and especially in Japan and there are few data about its usefulness in other areas. Further validation studies are needed in other geographic areas where the aetiology of cirrhosis is quite different. CLIP seems a good staging system and its usefulness has been widely demonstrated. The AHPBA/AJCC consensus conference recommended the use of CLIP for stratification of patients with HCC with only two exceptions, patients with chronic hepatitis B infection and patients undergoing resection or liver transplant. More recently AASLD has recommended the use of BCLC system to assess the prognosis of HCC patients. The BCLC model has been validated in many studies, it is easy to apply and it includes treatment, which is a relevant aspect to consider in these patients and it is not included in other prognostic systems. Information derived from new genomic and proteomic studies in HCC that will give a molecular profile of the HCC is expected soon. This new approach to patients with HCC will likely increase our knowledge regarding certain HCC characteristics such as capacity of progression and invasiveness and this will help us deciding the best treatment decision. Until this information is available it is likely that BCLC should be the staging system to choose.

Score

External Validation Treatment Assessment Physical Status Liver Function

Tumour Evaluation

Okuda

Yes

No

No

Ascites, albumin and bilirrubin

% of the liver

CLIP

Yes

No

No

Child-Pugh

Nodular and % of the liver

AHPBA/AJCC

BCLC

Yes

Yes

Performance status

Child-Pugh

Number and size of nodules

AASLD/EASL

JIS

Yes

No

No

Child-Pugh

TNM

GRETCH

Yes

No

Karnofsky index

Bilirrubin

PVT and ALP

CUPI

No

No

Presence of symptoms

Bilirrubin, ascites

TNM, AFP, ALP

Tokyo

No

No

No

Albumin, bilirrubin

Number and size of nodules

VISUM-HCC No

No

No

Bilirrubin, prothrombin % of the liver, AFP, PVT, nodules time

TNM

No

No

No

Yes

Tumour, nodules, metastasis

Endorsement

Staging Systems to Predict Survival in Hepatocellular Carcinoma

Table 3. Main characteristics of the prognostic staging systems: variables included in each one, existence of external validation and endorsement

AHPBA/AJCC LCSGJ

CLIP: Cancer Liver Italian Program; BCLC: Barcelona Clinic Liver Cancer; JIS: Japan Integrated Staging; GRETCH: Groupe d´Etude de Traitement du Carcinoma Hepatocellulaire; CUPI: Chinese University Prognostic Index; VISUM_HCC: Vienna Survival Model for Hepatocellular Carcinoma; TNM: Tumour; Nodules, Metastasis; ALP: Alkaline Phosphatase; PVT: Portal Vein Thrombosis; AFP: alfafetoprotein; AHPBA: American Hepato-Biliary-P ancreatic Association; AJCC: American Joint Committee on Cancer; AASLD: American Association for the Study of Liver Disease; EASL: European Association for the Study of Liver; LCSGJ: Liver Cancer Study Group of Japan. 57

58

References

Recent Advances in Liver Surgery

1. Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 2002; 122:1609-1919. 2. Bruix L, Llovet JM. Prognostic Prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002; 35:519-524. 3. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362:1907-1917. 4. Bruix J, Sherman M, Llovet JM et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference. J Hepatol 2001; 35:421-430. 5. Henderson JM, Sherman M, Tavill A et al. AHPBA/AJCC consensus conference on staging of hepatocellular carcinoma: consensus statement. HPB Surg 2003; 5:243-250. 6. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42:1208-1236. 7. Okuda K, Ohtsuki T, Obata H et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Cancer 1985; 56:918-928. 8. Pugh RN, Murray-Lyon IM, Dawson JL et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646-649. 9. Kamath PS, Wiesner RH, Malinchoc M et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001; 33:464-470. 10. Botta F, Gianninni E, Romagnoli P et al. MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: a European study. Gut 2003; 52:34-139. 11. Chevret S, Trinchet JC, Mathieu D et al. A new classification for predicting survival in patients with hepatocellular carcinoma. J Hepatol 1999; 31:133-141. 12. Llovet JM, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19:329-338. 13. Manghisi G, Elba S, Mossa A et al. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients. Hepatology 1998; 28:751-755. 14. Schoniger-Hekele M, Muller C, Kutilek M et al. Hepatocellular carcinoma in Central Europe: prognostic features and survival. Gut 2001; 48:103-109. 15. Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP): its value and limitations and a proposal for a new staging system, the Japan Integrated Staging Score. J Gastroenterology 2003; 38:207-215. 16. Leung TW, Tang AM, Zee B et al. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system and the Cancer of the Liver Italian Program staging system. Cancer 2002; 94:1760-1769. 17. Tateishi R, Yoshida H, Shiina S et al. Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients. Gut 2005; 54:419-425. 18. Fleming ID. AJCC/TNM cancer staging, present and future. J Surg Oncol 2001; 77:233-236. 19. Minagawa M, Ikai I, Matsuyama Y et al. Staging of hepatocellular carcinoma: assessment of the Japanase TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg; 245:909-922. 20. Varotti G, Ramacciato G, Ercolani G et al. Comparison between the fifth and the sixth editions of the AJCC/UICC TNM staging system for hepatocellular carcinoma: multicenter study on 393 cirrhotic resected patients. Eur J Surg Oncol 2005; 31:760-767. 21. Ramacciato G, Mercantini P, Cautero N et al. Prognostic evaluation of the new American Joint Committee on Cancer/International Union Against Cancer staging system for hepatocellular carcinoma: analysis of 112 cirrhotic patients resected for hepatocellular carcinoma. Ann Surg Oncol 2005; 12:289-297. 22. Llovet JM, Bruix J, Fuster J et al. Liver transplantation for small hepatocellular carcinoma: the tumor-node-metastasis classification does not have prognostic power. Hepatolog y 1998; 27:1527-1577. 23. Vogel CL, Linsell CA. International symposium on hepatocellular carcinoma, Kampala, Uganda 1971. J Nat Cancer Inst 1972; 48:567-571. 24. Primack A, Vogel CL, Kyalwazi SK et al. A staging system for hepatocellular carcinoma: prognostic factors in Uganda patients. Cancer 1975; 35:1357-1364. 25. Perrone F, Daniele B, Battiste G et al. Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and the hepatocelular carcinoma. Hepatology 2000; 31:840-845. 26. Farinati F, Rinaldi M, Gianni S et al. How should patients with hepatocellular carcinoma be staged? Validation of new prognostic system. Cancer 2000; 89:2266-2273. 27. Ueno S, Tanabe G, Sako K et al. Discrimination value of the new Western prognostic system (CLIP Score) for hepatocellular carcinoma in 662 japanese patients. Hepatology 2001; 34:529-534.

Staging Systems to Predict Survival in Hepatocellular Carcinoma

59

28. Levy I, Sherman M, the Liver Cancer Study Group of the University of Toronto. Staging of hepatocelullar carcinoma: assessment of the CLIP, Okuda and Child-Pugh staging systems in a cohort of 257 patients in Toronto. Gut 2002; 50:881-885. 29. Huo TI, Huang YH, Lin HC et al. Proposal of a modified Cancer of the Liver Italian Program staging system based on the model for end-stage liver disease for patients with hepatocellular carcinoma undergoing locoregional therapy. Am J Gastroenterol 2006; 101:975-982. 30. Huo TI, Lin HC, Hsia CY et al. The model for end-stage liver disease based cancer staging systems are better prognostic models for hepatocellular carcinoma: a prospective sequential survey. Am J Gastroenterol 2007; 102:1920-1930. 31. Nanashima A, Morino S, Yamaguchi H et al. Modified CLIP using PIVKA-II for evaluating prognosis after hepatectomy for hepatocellular carcinoma. Eur J Surg Oncol 2003; 29:735-742. 32. Nanashima A, Omagari K, Tobinaga S et al. Comparative study of survival of patients with hepatocellular carcinoma predicted by different staging systems using multivariate analysis. Eur J Surg Oncol 2005; 31:882-889. 33. Nanashima A, Sumida Y, Abo T et al. Modified Japan Integrated Staging is currently the best available staging system for hepatocellular carcinoma patients who undergo hepatectomy. J Gastroenterol 2006; 41:250-256. 34. Pascual S, Zapater P, García-Herola A et al. Comparison of staging system to predict survival in hepatocellular carcinoma. Liver International 2006; 26:673-679. 35. Cillo U, Basanello M, Vitale A et al. The critical issue of hepatocellular carcinoma prognostic classification: which is the best tool available? J Hepatol 2004; 40:124-131. 36. Cillo U, Vitale A, Grigoletto F et al. Prospective validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol 2006; 44:723-731. 37. Grieco A, Pompili M, Caminiti G et al. Prognostic factors for survival in patients with early-intermediate hepatocellular carcinoma undergoing nonsurgical therapy: Okuda, CLIP and BCLC staging systems in a single Italian centre. Gut 2005; 54:411-418. 38. Marrero JA, Fontana RJ, Barrat A et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005; 41:707-716. 39. Kudo M, Chung H, Haji S et al. Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score. Hepatology 2004; 40:1396-1405. 40. Toyoda H, Kumada T, Kiriyama S et al. Comparison of the usefulness of three stages system for hepatocellular carcinoma (CLIP, BCLC and JIS) in Japan. Am J Gastroenterol 2005; 100:1764-1771. 41. Chung H, Kudo M, Takahashi S et al. Comparison of three staging system for hepatocellular carcinoma: Japan integrated staging score, new Barcelona Clinic Liver Cancer staging classification and Tokyo score. J Gastroenterol Hepatol 2008; 23: 445-452. 42. Kondo K, Chijiiwa K, Nagano M et al. Comparison of seven prognostic staging systems in patients who undergo hepatectomy for hepatocellular carcinoma. Hepatogastroenterology 2007; 54: 1534-1538. 43. Lee SW, Han SY, Kim KT et al. Evaluation of Okuda, TNM, CLIP, JIS staging systems for hepatocellular carcinoma patients. Korean J Hepatol 2007; 13:196-207. 44. Huo TI, Lin HC, Huang YH et al. The model for end stage liver disease based Japan Integrated Scoring system may have better predictive ability for patients with hepatocellular carcinoma undergoing locoregional therapy. Cancer 2006; 107:141-148. 45. Chung H, Kudo M, Haji S et al. A proposal of the modified liver damage classification for hepatocellular carcinoma. Hepatol Res 2006; 34:124-129. 46. Omagari K, Ohba K, Kadokawa Y et al. Comparison of the grade evaluated by “Liver damage” of Liver Cancer Study Group of Japan and Child.-Pugh classification in patients with hepatocellular carcinoma. Hepatol Res 2006; 34:266-272. 47. Ikai I, Takayasu K, Omata M et al. A modified Japan Integrated Stage store for prognostic assessment in patients with hepatocellular carcinoma. J Gastroenterol 2006; 41:884-892. 48. Giannini E, Risso D, Botta F et al. Prognosis of hepatocellular carcinoma in anti-HCV positive cirrhotic patients: a single centre comparison amongst four different staging systems. J Intern Med 2004; 255:399-408. 49. Rabe C, Lenz M, Schmitz V et al. An independent evaluation of modern prognostic scores in a central European cohort of 120 patients with hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2003; 15:1305-1315. 50. Helmberger T, Dogan S, Straub G et al. Liver resection or combined chemoembolization and radiofrequenty ablation improve survival in patients with hepatocellular carcinoma. Digestion 2007; 75:104-112. 51. Chen TW, Chu CM, Yu JC et al. Comparison of clinical staging systems in predicting survival of hepatocellular carcinoma patients receiving major or minor hepatectomy. Eur J Surg Oncol 2007; 33:480-487. 52. Chung H, Kudo M, Takahashi S et al. Review of current staging systems for hepatocellular carcinoma. Hepatol Res 2007; 37 (Suppl 2):S10-S15.

Chapter 5

Virtual Liver Surgery:

Computer-Assisted Operation Planning in 3D Liver Model Hauke Lang,* Milo Hindennach, Arnold Radtke and Heinz Otto Peitgen

Abstract

O

ngoing development in CT imaging-based computer assistance has enabled an optimal visualization of the intrahepatic vascular branching in a virtual 3D liver model providing an individual territorial liver mapping as well as volume calculation of the corresponding vascular territories. Thus, liver resections can be planned with regard to the individual intrahepatic vascular anatomy. The advantages of computer-assisted resection planning refer to a better assessment of functional resectability as areas at risk for either devascularization or impaired venous drainage can be identified and precisely calculated already preoperatively. In selected cases, this information may have considerable influence on surgical strategy, especially with regard to the extent of resection or the need for vascular reconstruction. This appears to be of particular importance for planning of extended left hepatectomies—because of the great variability of the branching patterns within the right liver lobe—or in repeated hepatectomies, when the intrahepatic vascular anatomy may be altered after previous vascular dissection. Current research efforts are directed towards the development of navigation techniques to ensure an accurate application of the preoperatively planned resection line into the situs during surgery. These navigation systems are under intense investigation but not available yet.

Introduction

Liver resection represents the only curative treatment option for many malignant liver tumors. Despite large progress in operative technique and perioperative management over the last two decades complex liver resections are still associated with a considerable operative risk. Postoperative mortality is dependent on the extension of the resection ranging between 0-8%. In extended resections with possible vascular or biliary reconstructions it even may exceed 10%. Liver failure is by far the most common cause for postoperative mortality. The minimal amount of liver tissue to be preserved at resection in order to maintain sufficient postoperative liver function depends on many factors and is difficult to be predicted in the individual case. For healthy liver parenchyma about 20-25% of the functional liver volume can be regarded as reference value for the minimum quantity of liver mass to be retained at resection, provided that this tissue has an intact portal and arterial blood supply as well as a sufficient venous and biliary drainage.3-5,15-16,19,27,29 Thus, a comprehensive knowledge of the liver anatomy is a fundamental prerequisite for liver surgery. According to Couinaud the liver is divided into eight functionally independent segments each of them having a separate portal venous supply.7 However, the segmental liver model proposed by Couinaud presupposes a regular distribution of the intrahepatic vascular tree. Anatomical as well *Corresponding Author: Hauke Lang—Department of General and Visceral, Surgery, University Hospital Mainz, Langenbeckstr. 1, D-55131 Mainz, Germany. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Virtual Liver Surgery: Computer-Assisted Operation Planning in 3D Liver Model

61

as radiological investigations have already shown that this regularity is not the rule but an idealized schematic mapping, pointing to the fact that in reality many anatomical variations exist regarding both the size and the number of liver segments.21 Consequently, based on the visualization of intrahepatic vascular branches alone, neither a precise topographic localization of the individual segments nor an determination of their real extent can be postulated exactly.8 When planning liver resections for malignant tumors both oncologic criteria as well as functional aspects must be considered. In order to predict the postresectional functional liver capacity, calculation of the remaining liver volume is routinely performed by radiological methods. Currently, 2D-CT or 2D-MRI imaging has become the “gold standard” for remnant volume estimations.1,4-5 Although these standard methods provide a sufficient visualization of the intrahepatic vascular tree by reaching even the level of the subsegmental branches, they do not allow a precise assessment of the depending territory of each vascular branch. In consequence, an accurate volumetric calculation for the single vascular territory is not possible. Thus, the volume of the residual liver can be reliably predicted, however a precise anticipation whether the remnant liver parenchyma is fully vascularized, is not possible with these methods. Especially in centrally localized tumors the problem of potentially devascularized liver tissue is evident. In these tumors, the achievement of an appropriate safety margin sometimes requires the dissection of large intrahepatic vessels which increases the risk for insufficiently perfused or congested areas of liver parenchyma6,15,23 In the clinical situation this may be of paramount relevance, as poorly, vascularised liver parenchyma may be functionally compromised and also be a potential source for septic complications.

Technology

On the basis of multiphasic (thin section) computer tomography images, recently developed software systems now allow the segmentation of all intrahepatic systems (bile ducts, arteries, portal and hepatic veins) and its three-dimensional reconstruction (MeVis LiverAnalyzer and LiverExplorer).6,23,26,28 Furthermore, for each vascular or biliary branch the dependent territory can be calculated (Figs. 1,2). By use of this, liver resections can be planned virtually with consideration of both the individual liver anatomy and the topographic relationship of the liver tumor to the intrahepatic vascular and biliary structures. Here, two different approaches for resection planning are possible, a fully automatically resection proposal with variable and freely selectable safety margins by the computer and a manually “free-hand” resection where the surgeon can determine the resection line within the 3-dimensionally reconstructed liver. These options allow to simulate the influence of different cutting planes on the postresectional volume of the liver parenchyma and to accurately compute and visualize the vascular supply and/or venous drainage of the remnant. Thus, areas at risk for either devascularization or venous congestion can be identified and calculated preoperatively (computer-assisted vascular risk analysis)6,11,15-16,23,26,28 (Fig. 3).

Clinical Experience

In an initial study we tried to investigate the potential use of 3-D-reconstruction and computer-assisted risk analysis in comparison to standard resection planning. Therefore, we prospectively analyzed 25 complex liver resections by employing the MeVis software for the computer-assisted operation planning with the aim to identify and quantify the extent of potential perfusion/ drainage deficits in the liver parenchyma remaining according to resection planning by use of the current “gold standard.”15 For this purpose, liver resections were initially planned on the basis of 2-D-multi-slice-CT images and the residual postresectional liver volumes were calculated based on 2-D-CT-scans but without knowledge of the 3-D-reconstruction. Thereafter, the resection plane drawn on the conventional 2D CT images was transferred into the individual 3D vascular liver model. Here, the percentage of only that residual postresectional liver parenchyma having both a preserved portal-venous perfusion and an intact hepatic-venous drainage was calculated again by means of computer-aided risk analysis (see Table 1). The results of this study revealed that by realizing the standard 2D CT- based resection proposals only in about 50% of complex resections the remaining liver parenchyma contained a nearly completely intact vascularity (defined as more

62

Recent Advances in Liver Surgery

A

B

C

D

Figure 1. Segmental and three-dimensional demonstration of the individual vascular territories, based on the analysis of multi phasic (thin section) computer tomography images. A-D. Analysis of portal tree (A), of the hepatic venous system (B), of the hepatic arterial system (C) and of the biliary duct system (D). Note the tremendous variations of the extent of the respective portal (A), arterial (C) and biliary (D) territories, as indicated for segment 3.

than 90% of the residual liver volume to be without vascular impairment), whereas in about one third of resections larger areas at risk for poorly vascularised liver tissue were identified, affecting 20-50% of the calculated residual liver volume. This means, that in rare cases nearly half of the remaining liver parenchyma (as calculated after surgery planning in 2D-CT) would be at risk for poor vascularization (see Table 1). The main reason for the affected vascularity in the areas at risk was the impairment of the hepatic venous drainage. This is obvious as the intrahepatic venous system is subjected to a substantially higher variability in comparison to the portal venous system.20,24 Owing to the additional information derived from the computer-aided risk analysis in the 3D-reconstructed liver, in our series in about 25% of all extended resections the operation proposal and surgical strategy as “derived” on standard 2D CT-imaging was changed. This included either the extension of the originally planned resections in order to remove potentially poorly vascularized areas of liver parenchyma or the reconstruction of intrahepatic venous branches

Virtual Liver Surgery: Computer-Assisted Operation Planning in 3D Liver Model

63

Figure 2. A-D Shows the corresponding vascular territories to Figure 1, supplied by the portal vein (A), the hepatic veins (B), the hepatic artery (C) and the bile duct system (D).

to preserve the venous drainage of the liver remnant. In particular the necessity of venous reconstruction to avoid congestion of liver tissue was derived by computer-assisted risk analysis only and had initially not been anticipated by the information given by 2D CT images. This experience is interesting, since in the past the decision for the reconstruction of intrahepatic vessels was based exclusively on the radiologic two-dimensional visualization of the hepatic vessels and the surgeons experience but not on a precise computation of the respective drainage territories.10 Even more, the newer computed visualization techniques for the first time enabled to predict the potential need for reconstruction of a single vessel by virtue of the exact assessment of the dependent territory. This is in so far of a practical relevance as devascularised or venously congested liver areas need not always be recognized immediately during operation. In contrast, in some situations the demarcation may occur in the later postoperative course after a latent period of some hours or even days. This underlines the practical value to be aware of these potential areas at risk already at operation.

64

Recent Advances in Liver Surgery

A

B

C

A’

B’

C’

Figure 3. Vascular risk analysis for the resection of colorectal metastases with a safety margin of 1 cm. The intrahepatic vessels within the virtual specimen are marked red. A-C) Shows the risk analysis for the portal vein (A), for the hepatic veins (B) as well as for both vascular systems (C). The intrahepatic vessels within the virtual specimen are marked red. A’-C’) Shows the vascular territories supplied by the vessels marked under A-C. A’) Shows the portal-venous, B’) the hepatic-venous and, C’) the combination of both vascular systems of the vascular territory in concern. A color version of this figure is available at www.landesbioscience.com/curie.

Our experience with more than 50 complex liver resections planned by computer-assistance confirmed that the risk for tissue devascularisation certainly is dependent on the type of resection. In this regard, it is of particular clinical importance that even standard operations such as left or right hepatectomies often do not represent strictly anatomical liver resections, as in particular situations these resection are associated with a potentially devascularised portion of more than 20% of retained liver parenchyma (Table 1). In extended left hepatectomies (left trisectionectomies) or central liver resections (mesohepatectomies) even larger areas at risk for impaired vascularity are to be expected because of the extreme anatomical variability encountered in the right liver lobe. In particular the right and the middle hepatic vein exhibit multiple variations, deviating substantially from the regularity as described by Couinaud.20,24 During surgery one additional problem arises because there are no real landmarks to identify segmental borders on the surface of the right liver lobe, which makes anatomical orientation during parenchymal transsection particularly difficult. On the contrary, in the left liver lobe the falciform ligament and the umbilical fissura represent an anatomical boundary line which assures a reliable anatomical orientation and a safe identification of the main portal and hepatic-venous branches. These different anatomical conditions encountered in the right and left liver lobes correlate with the clinical experience that clearly shows a much higher complication rate for extended left resections—despite much larger residual liver volume—compared with the extended right resections.15-17,19,22 Further to extended left and central hepatectomies the information obtained by the computer-assisted surgery planning may also be of value in repeated resections because the intrahepatic vascular system may substantially be altered after previous vascular dissection. First reports show that in these cases three-dimensional reconstruction together with a computer-aided risk analysis offers a much more detailed analysis of the vascular system in comparison to conventional two-dimensional CT scan, thus allowing a better estimation of functional resectability.14

65

Virtual Liver Surgery: Computer-Assisted Operation Planning in 3D Liver Model

Table 1. Portion of the potentially devascularized liver parenchyma in the future liver remnant (as calculated by 3-D-vascular risk analysis) after planning of resections in the 2-D-CT Portion of the Potentially Poorly-Perfused Liver Parenchyma after Surgical Planning in the 2-D-CT 0-10%

10-20%

20-30%

30-40%

40-50%

Planned Resection Extended right hemihepatectomy

8

Right hemihepatectomy

3

Left hemihepatectomy

1 1

Extended left hemihepatectomy Central resection

1 2

1

2 2

Table modified according to reference 15.

Outlook

So far, those few clinical evaluations regarding virtual liver resection were directed only towards the analysis of the hepatic veins and the portal venous system. On one side this was mainly due to technical reasons—in the beginning of computer-assisted liver surgery these two vascular systems were the only for which 3-D-reconstruction was reliably possible—and on the other side of course due to anatomical aspects as the portal vein is regarded as guiding structure for the hepatic arteries and the bile ducts within the Glisson triad.9,13,15-16,25 However, similar to the portal vein the arterial and biliary systems are characterized by a high anatomical variability sometimes differing very much from the portal tree, as it is for instance the case in the presence of an accessory or replaced left artery. Regarding this anatomical complexity it is to be assumed that the areas at risk for devascularization or impaired drainage in the remnant liver may be fairly larger than revealed by analysis of the portal/hepatic venous system only. In the future it is to be expected that the inclusion of the hepatic arteries and bile ducts into the virtual simulations (which is technically already feasible) will allow an even more precise calculation of the true functional postresectional parenchyma, even though the analysis becomes substantially more complex. However, despite ongoing progress in virtual resection at operation it is still difficult to accurately transform the planning data into the real situation. This is mainly due to the fact that there are no reliable reference points on the liver surface that might be regarded as landmarks for segmental boundaries. Thus, it is difficult to have an exact anatomical orientation, particularly within the right liver lobe. Currently, intraoperative application of the planning data of the virtual resection line is mainly adjusted to the course of the intrahepatic vessels based on its visualization by intraoperative ultrasonography as well as on the anatomical knowledge of the surgeon and its ability to convey the preoperative planning data to the surgical field. The latter is substantially difficult due to deformations of the mobilized and exposed liver. In particular the mobilization of the right liver lobe, which must be often completely detached from the diaphragm and dislocated under the costal arch, can lead to substantial deformations of the entire right lobe and consequently may explain some substantial discrepancies between preoperative 3-D-reconstructed planning data and intraoperative liver anatomy. In these situations tactile orientation at the intrahepatically located tumor sometimes represents the most important guide for the surgeon. Navigation systems for the reliable conversion of the preoperative planning data on the mobilized and altered liver shape are the subject of intensive research efforts, however they are still not available for the clinical use.2,12,18

66

Recent Advances in Liver Surgery

Practical Guide and Summary

With the assistance of new generation software systems all intrahepatic structures (bile ducts, arteries, portal and hepatic veins) can be sliced and reconstructed three-dimensionally. Additionally, the dependent vascular territory can be computed for each vascular branch. Thus, it is possible to simulate liver partitions in a 3D liver model with the consideration of the individual liver anatomy. This offers a precise calculation of the residual liver volume as well as of the areas of potentially devascularized liver parenchyma. The information gathered by computer-assisted operation planning enhances the surgeon’s anatomical and physiological knowledge of the individual vascular liver anatomy which may contribute to patient’s safety during the operation. Such a comprehensive knowledge allows resection planning adopted to the individual liver anatomy. This may be particularly important in extended left or central liver resections—because of the great anatomical variability seen in the right liver lobe—as well as for repeated liver resections because of probable changes in the intrahepatic vascular system caused by previous vascular dissection. The information given by vascular risk analysis also allows to determine the necessity for intrahepatic vessel reconstructions or the need for the extension of the resection, based on a proper volume calculation of potential areas at risk for either devascularization or congestion. However, for the validation of this initial clinical experience further prospective controlled studies are required. Continuous advances in virtual surgery planning may be expected in the future primarily by the inclusion of all intrahepatic vascular and biliary systems into the computer-aided risk analysis. Furthermore, the development of navigation systems to reliably apply the preoperative planning data into the operative situs are subject of research projects.

References

1. Abdalla EK, Denys A, Chevalier P et al. Total and segmental liver volume variations: Implications for liver surgery. Surgery 2004; 135:404-410. 2. Beller S, Hünerbein M, Lange T et al. Image-guided surgery of liver metastases by three-dimensional ultrasound-based optoelectronic navigation. Br J Surg 2007; 94:866-875. 3. Bismuth H. Surgical anatomy and anatomical surgery of the liver. World J Surg 1982; 6:3-9. 4. Blumgart LH, Belghiti J. Liver resection for benign disease and for liver and biliary tumors. In: Blumgart LH, Belghiti J, Büchler M et al, eds. Surgery of the Liver, Biliary Tract and Pancreas. 4th Edition. London: WB. Saunders Company Ltd., 2006:1341-1416. 5. Blumgart LH, Hann LE. Surgical and radiological anatomy of the liver and biliary tract. In: Blumgart LH, Fong Y, eds. Surgery of the Liver and Biliary Tract. 3rd Edition. London: WB Saunders, 2000:3-34. 6. Bourquain H, Schenk A, Link F et al. HepaVision 2: A software assistant for preoperative planning in living-related liver transplantation and oncologic liver surgery. Proc CARS Springer 2002:341-346. 7. Couinaud C. Le Foie: Etudes anatomicales et chirurgicales. Paris: Masson 1957:187-208. 8. Fasel JHD, Selle D, Evertsz CJG et al. Segmental anatomy of the liver: Poor correlation with CT. Radiology 1998; 206:151-156. 9. Fuchs J, Warmann SW, Szavay P et al. Threedimensional visualization and virtual simulation of resection in pediatric solid tumors. J Pediatr Surg 2005; 40:364-370. 10. Hemming AW, Reed AI, Langham MR et al. Hepatic vein reconstruction for resection of hepatic tumors. Ann Surg 2002; 235:850-858. 11. Jarnagin WR, Gonen M, Fong Y et al. Improvement in perioperative outcome after hepatic resection: analysis of 1803 consecutive cases over the past decade. Ann Surg 2002; 236:398-406. 12. Kleemann M, Hildebrand P, Mirow L et al. Navigation in der Viszeralchirurgie. Chir Gastroenterol 2005; 21:14-21. 13. Lamadé W, Glombitza G, Fischer L et al. The impact of 3-Dimensional Reconstruction on operation planning in liver surgery. Arch Surg 2002; 135:1256-1261. 14. Lang H, Radtke A, Liu C et al. Improved assessment of functional resectability in repeated hepatectomy by computer-assisted risk analysis operation planning. Hepato-Gastroenterology 2005; 52:1645-1646. 15. Lang H, Radtke A, Hindennach M et al. Impact of Virtual tumor resection and computer-assisted risk analysis on operation planning and intraoperative strategy in major hepatic resection. Arch Surg 2005; 140:629-638. 16. Lang H, Peitgen HO, Broelsch CE. Virtual liver surgery. In: Blumgart LH, Belghiti J, Büchler M, eds. Surgery of the Liver, Biliary Tract and Pancreas. 4th Edition. London: W.B. Saunders Company Ltd., 2006:1405-1416.

Virtual Liver Surgery: Computer-Assisted Operation Planning in 3D Liver Model

67

17. Lang H, Sotiropoulos GC, Brokalaki EI et al. Left trisectionectomy for hepatobiliary malignancies. J Am Coll Surg 2006; 203:311-321. 18. Marescaux J, Clément JM, Tasseti V et al. Virtual reality applied to hepatic surgery simulation: The next revolution. Ann Surg 1998; 228:627-634. 19. Melendez J, Ferri E, Zwillman M et al: Extended hepatic resection: A 6-year retrospective study of risk factors for perioperative mortality. J Am Coll Surg 2001; 192:47-53. 20. Neumann JO, Thorn M, Fischer L et al. Branching patterns and drainage territories of the middle hepatic vein in computer-simulated living-donor hepatectomies. Am J Transplant 2006; 6:1407-1415. 21. Platzer W, Maurer H. Zur Segmenteinteilung der Leber. Acta anatomica 1966; 63:8-31. 22. Povoski S, Fong Y, Blumgart LH. Extended left hepatectomy. World J Surg 1999; 23:1289-1293. 23. Preim B, Bourquain H, Selle D et al. Resection proposals for oncologic liver surgery based on vascular territories. Proc CARS Springer 2002:353-358. 24. Radtke A, Nadalin S, Sotiropoulos GC et al. Computer-assisted operative planning in adult living donor liver transplantation: A new way to resolve the dilemma of the middle hepatic vein. World J Surg 2007; 31:175-185. 25. Saito S, Yamanaka J, Miura K et al. A novel 3D hepatectomy simulation based on liver circulation: application to liver resection and transplantation. Hepatology 2005; 41:1297-1304. 26. Schenk A, Prause G, Peitgen HO. Efficient semiautomatic segmentation of 3D objects in medical images. IN: MICCAI—Medical Image Computing and Computer-Assisted Intervention. New York: Springer, LNCS 2000; 1935:186-195. 27. Shoup M, Gonen M, DÁngelica M et al: Volumetric analysis predicts hepatic dysfunction in patients undergoing major liver resection. J Gastrointest Surg 2003; 7:325-330. 28. Van Ooijen PMA, Wolf R, Schenk A et al. Recent developments in organ-selective reconstruction and analysis of multiphase liver CT. Imaging Decisions 2003; 7:37-43. 29. Vauthey JN, Chaoui A, Do KA et al. Standardized measurement of the future liver remnant prior to extended liver resection: Methodology and clinical associations. Surgery 2000; 127:512-19.

Chapter 6

Transection Techniques in Liver Surgery

Luigi Boni,* Gianlorenzo Dionigi, Mario Diurni and Renzo Dionigi

Abstract

T

he main problem which is experienced during liver resection still remains the bleeding control in course of parenchymal division. Over the past decades several techniques such as crush-clamp, ultrasonic dissection, radiofrequency or stapler assisted liver dissection have been proposed in order to reduce operative time and blood losses but, to date no conclusive study has been able to identify which one of those approaches is the most efficient. Aim of this chapter is to review the basic principles of different transection techniques and survey the results published in the literature.

Introduction

Since the first elective liver resection performed by Wendell in 1911,1 intraoperative bleeding continued to be the major technical problem. To date even in dedicated centers, major hepatectomies result in a median blood loss of 700-1200 ml,2 which is directly correlated with the incidence of intra- and post-operative morbidity and mortality.3 This is why the history of liver surgery is very much the history of controlling bleeding. In order to reduce intraoperative hemorrhage different techniques have been used for several years: inflow occlusion by the Pringle manoeuver,4 total or selective vascular occlusion,5 low central venous pressure anesthesia.6 Nevertheless all these techniques do not ensure complete bloodless resection and, anyway, cause an evident, even if transient, amount of cellular damage due to ischemia and reperfusion effect. Liver parenchyma is extremely soft and the rich network of thin-walled portal and hepatic venous branches as well as biliary ducts need to be secured during the procedure. Traditional gross transfixing sutures or ligatures, placed throughout hepatic tissue, have been shown to be ineffective due to the intrinsic characteristic of the liver and the tenderness of its parenchyma, whereas meticulous isolation of the intra-hepatic vascular and biliary structures is considered mandatory to perform a safe and a possible bloodless liver resection. In the last twenty-five years several techniques and many new surgical devices have been proposed for liver transection. A short description of the major technical principles and the newest and most widely used instruments and techniques are thoroughly reviewed.

Circumferential Hepatic Compression

This technique, which has been proposed in the 1950s by Nakayama,7 has been almost totally abandoned. It is basically represented by the application of preventive sutures, ligature or clamp (Nakayama’s clamp) or tourniquets before the liver resection.8,9 *Corresponding Author: Luigi Boni—Azienda Ospedaliera-Polo Universitario, Via Guicciardini, 21100—Varese, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Transection Techniques in Liver Surgery

69

Results of this technique have been discouraging, because liver clamps and tourniquets may slip; they may crush and injure the liver at the clamp/tourniquets site and the traction on them during liver resection may lacerate small hepatic veins from the inferior vena cava.

“Finger-Fraction” and “Crush-Clamp” Technique

The finger fracture of the hepatic parenchyma makes possible a gentle resection and, if anatomy is respected, a good control of bleeding in the plane of section can be achieved. The finger fracture technique was first described by Keen, who stripped the liver capsule with his thumb.10 Since then several surgeons reported to have divided the parenchyma using finger fracture, having shared the experience that the surgeon’s fingers can crush the liver parenchyma and isolate the vessels and the biliary ducts which are more resistant than the surrounding tissue. The technique has been systemized in 1960 by Thien-Yu-Lin who reported “fracturing and crushing the tissue between fingers” and indicated that when resistant duct or vessels were encountered, they were tied or divided.11 After the incision of the Glisson’s capsule along the line of ischemia demarcation the liver parenchyma is crushed by the surgeon using a gentle compression between his first fingers. Biliary ducts and vessels, due to the higher collagen content, feel like a resistant “thread”. When completely isolated they are legated with absorbable suture and divided. This technique, which is usually associated with the Pringle manoeuver, can be safely used in any kind of minor and major resections. The technique described by Lin11 was modified in 1963 by Ton That Tung who occluded the portal pedicle and then transected the liver by finger fracture.12 Lin in 197413 modified his technique and proposed the so-called “crush method”. A special clamp is applied just aside the resection line in order to create a sort of vascular control. After incision of the Glisson’s capsule the crush-clamp or a more common Kelly’s clamp is applied a few times in sequence in order to fracture the parenchyma and disclose the vascular and biliary structures (Fig. 1). The “crush-clamp technique” has been shown to be fast and effective causing significant less bleeding than finger fraction.

Water-Jet Parenchymal Transection

First used during liver resection by Papachristou et al14 in 1982, water-jet technique is based on the use of a high-pressure pump that generate potential energy to a fluid (usually hypertonic saline), which is delivered to a nozzle that generate a sort of high-pressure “jet”. This technology is well known and widely used in the machine tool industry. It is mainly used to cut different substances since, if the pressure rises to 4000 bar, the water speed can reach twice the speed of sound, allowing precise division even of hard materials. Water-jet transection has been modified and adjusted by the medical industry and then applied to liver surgery to fracture liver parenchyma, avoiding vessels and bile ducts. The instrument

Figure 1. The crush clamping technique.

70

Recent Advances in Liver Surgery

potential and its cutting effect, can be regulated by adjusting several of its components and features: the distance of the hand-piece from the tissue, the size of the nozzle, the initial pressure, the liquid viscosity and its temperature. The most recent instruments have been provided with an integrated suction device which allows to clear the surgical field from the destroyed hepatocytes. The water-jet technique requires appropriate training and concern for a few important details: 1. The hand piece should be applied on the liver parenchyma only after the liver capsule has been incised; 2. The tip of the instrument must be rapidly moved along the dissecting line; 3. Running for a prolonged period of time on a single spot could damage the structures that have to be preserved, sutured and divided. If used correctly, water-jet instruments are supposed to save vessels and ducts greater than 0.2 mm, to fracture the surrounding parenchyma and leave a uniform surface with minimal necrotic debris.15 A major concern using the water-jet dissection technique in liver surgery, is the splash due to the action of the high pressure water-jet against the most resistant tissue.16 The potential risk of operating room contamination and the likelihood of disseminating cancer cells are factors which cannot be ignored. Wearing surgical glasses and careful handling and dissection of the tumor are highly recommended. Due to its relatively easy technology, specifically designed water-jet hand-pieces are also used in laparoscopic surgery, although in these cases, the splashing effect can create a remarkable visual impairment.

Ultrasonic Energy

Ultrasonic energy dissectors are based on the high frequency vibration generated by a transducer which is able to transform the electric signal into mechanical motion produced at the instrument tip. This effect can create either dissection or coagulation or both, depending upon the used frequency, which is between 20 and 60 kHz. The components of an ultrasonic dissector are: • Electrical generator • Piezoelectric transducer • Dissection instrument The hand piece, incorporating the transducer and dissection instrument, is connected to the generator by an electrical cable. The ferroelectric ceramic crystals of the transducer vibrate and produce ultrasound waves. Frequency (Hz) of the vibration depends upon the extent of polarization of the crystals. The vibrations generated by the piezoelectric transducer are conducted by a metal rod to the tip of the hand-piece. An efficient system transmits most of the vibration energy to the probe-tip with no generation of thermal energy, avoiding the need of a cooling device. Depending on the frequency of the tip vibration, ultrasonic instrument can be divided into two classes: • Ultrasonic Dissector Systems (low frequency) • Ultrasonic Dissection-Coagulation Systems (high frequency)

Ultrasonic Dissector Systems

Ultrasonic devices, which use low frequency (between 23 and 36 kHz) waves, cannot divide fibrous organized structures (arteries, veins, etc) and they cause minimal collateral damage. This process, which is called “cavitation”, does not coagulate or cut, but “cleave” cells with a high water content by a process of ultrasonic cleaning. The low frequency waves cause an implosion of the cell, due to a vaporization of intracellular water by forming vacuoles which then resonate with the vibrating tip of the instrument.

Transection Techniques in Liver Surgery

71

Figure 2. Ultrasonic energy for hepatic transsection/division.

Connective tissue contains less water than fat and parenchymatous cells, thus the cavitational effects keep intact vessels and nerves (structures which contain a significant amount of collagen) and cause the fragmentation of fat and parenchymatous cells. For example, during liver surgery, the Glisson’s capsule, rich in collagen and low in water, has to be incised by the electrosurgical knife before the ultrasonic division of the hepatic parenchyma. The ultrasonic dissectors used in hepatic resections, have an integrated irrigating and aspiration system, which allows to remove cells debris created during the dissection. The optimal vibration and power setting greatly depend on parenchymal characteristics, since in some cases, if the energy setting is too high or too low, the transection might result in accidental vessels destruction (leading to excessive bleeding) or in increased transection time (Fig. 2). In general, there is agreement to accept that in older patients ultrasonic dissector system should be set at lower vibration and that cirrhotic livers usually require higher vibrating frequency.17

Ultrasonic Coagulating-Dissection Systems

More recently, ultrasonic systems have been used at a higher vibrating range, which leads to cutting and coagulating effect at the tissue-instrument interface. They are called harmonic scalpels or dissectors. Cutting effect of the ultrasonic harmonic scalpel is due to two different principles: the first effect is a change in the state of water molecules of tissues, which shift from the liquid phase to the gaseous one, due to a drop in pressure caused by longitudinal vibrations. These rapid modification of the state of water produces an equally rapid change in volume of cells and the resultant destruction of the cell wall (cavitational fragmentation). The second effect is the mechanical friction of the blade against the tissue, which eventually creates a dividing-cutting effect.

72

Recent Advances in Liver Surgery

Kinetic energy, produced by piezoelectric oscillations, induces a vibration frequency through an aluminium rod at the functional tip of 55000 Hz over a 50-100μm arc (amplitude: movements of the tips); vibrations have an exclusively longitudinal direction. There is also an acoustical system located into the generator, which gives information to the surgeon about the frequency of the oscillation. The same device can apprise when the instrument, via a feedback system, reacts to any change in frequency, tissue resistance or high temperature. Ultrasonic dissection systems allow surgeons to perform both transection of parenchymatous structures and skeletonization of solid organ (colon, stomach etc) with an appreciable safety, a reduced resection time and a minimized blood loss.18 High power ultrasonic dissectors are widely used for both laparoscopic and open surgical procedures. The haemostatic effect of the high power ultrasonic dissection system is due to the denaturation of proteins and the subsequent sealing of blood vessels as it occurs when laser or high frequency current (mono or bipolar) are used. Friction of the blade against tissues, produced by the high frequency longitudinal vibrations, develops a high local temperature (80˚C) on the tip of the instrument but the denaturation of proteins is due to fragmentation of hydrogen compounds in the cells. One important advantage of this instrument is that heat dissipation is only one sixth of that observed during traditional thermocoagulation with high frequency current. For this reason it is generally assumed that ultrasonic dissection systems disperse less energy to surrounding tissue during use and thus have reduced tendency for collateral or proximity heating damage. In theory there are no contraindication to the use of ultrasonic dissection system in liver resection, where they can be efficiently used during parenchymal division (including the liver capsule) only for vessels and duct up to 5 mm in diameter (Fig. 2).

Radiofrequency Assisted Hepatic Resection

Radiofrequency (RF) has been widely used as a thermo ablative technique in the treatment of different type of solid tumors of the liver, breast, kidney, pancreas, lung etc.19-21 RF induces temperature changes by utilizing high-frequency alternating current applied by electrode(s) placed within the tissue to generate ionic agitation. This creates localized frictional heat and, as a direct effect, high temperature: tissue surrounding the electrode generates localized areas of coagulative necrosis and tissue desiccation. The radiofrequency energy radiates from the individual electrodes into the adjacent tissue and, as a consequence, the energy level and the heating effect dissipates rapidly at an increasing distance from the electrodes. Thanks to its highly effective coagulating effects, Weber et al22 proposed the use of a linear RF probe, connected to a commonly used RF generator, in order to induce a preventive hemostasis by coagulated surface on the liver parenchyma along the resection margin, followed by a sharp transection performed with the scalpel. According to these authors, this technique, if accurately applied, will allow to perform an almost bloodless liver resection even without the need for vascular occlusion. Radiofrequency assisted hepatic resection is divided in four steps (Fig. 3): at the beginning an inner line is marked on the liver around the tumor using argon diathermy (Fig. 3A), then a second line, 2 cm away from the first is marked (Fig. 3B) in order to define the RF probe position; at this point high energy RF is applied following the second line (Fig. 3C) and finally the liver parenchyma is divided using the scalpel (Fig. 3D). The encouraging results obtained by RF assisted liver resection (see ahead) lead Haghighi et al23 to develop specifically designated in line-RF probes. These probes allow to create a linear coagulative plane, into the parenchyma.

Heat Conducting Technique

This technique for liver resection has been described by Sakamoto et al24 in 2004 and is based on a combined use of two different electrical devices: • A computer assisted bipolar instrument (LigaSure™, Tyco Healthcare USA)

Transection Techniques in Liver Surgery

73

Figure 3. Radiofrequency assisted hepatic parenchymal transsection.

• A radiofrequency monopolar device (Monopolar Floating Ball™, TissueLink Medical, USA) Among the vessel sealing devices, one of the most important, effective and innovative instruments is represented by the LigaSure™ system. This is an electro-thermal computer assisted bipolar vessel sealer, developed as an alternative to suture ligatures, hemoclips, staplers and ultrasonic coagulators, for vessels closure and tissue bundles. LigaSure™ is able to seals vessels up to 7 mm in diameter by denaturing collagen and elastin within the vessels wall and surrounding connective tissue. The sealing mechanism uses the body’s collagen to change the nature of the vessel walls to obliterate its lumen. This instrument is easy to use even with a limited learning curve because it is equipped with a feedback-controlled generator that allows the precise amount of energy delivery while the vessel wall and tissue bundle is held in apposition. In comparison with standard electrocautery or ultrasonic coagulating-dissector devices, LigaSure™ generates only few smoke and/or tissue spray. Furthermore the risk of thermal lateral spread of energy is absent since the current is applied between the two jaws and the posterior one is coated and insulated. The thermal effect generated by the ionic agitation caused by a radiofrequency generator system, can be also used as coagulating technique. The Monopolar Floating Ball™ employs radiofrequency (almost 480 KHz) energy that is focused near the tip of the instrument and conducted to the tissue by a low-volume saline solution that increases ionic concentration around the tissue and, as direct effect, generates higher coagulating temperature by molecular changes in collagen, causing it to shrink and seal blood vessels and tissue. The combined use of these two instruments has been proposed to perform liver resection without the need of inflow occlusion, by setting the RF device at 95 watts and moving the tip of the instruments in a “painting” fashion all along the line of resection. This generates a sort of precoagulating effect on the liver parenchyma that can be subsequently divided with clamp or forceps. The exposed portal and hepatic vein up to 5 mm in diameter are then sealed with LigaSure™. Saiura et al25 used the LigaSure™ system by itself during hepatectomy performed with intermittent Pringle manoeuvre and parenchymal crushing with forceps followed by vessels suture and section when using the computer assisted bipolar devices.

74

Recent Advances in Liver Surgery

Among the heat guided hepatic resection technique, Yamamoto et al26 proposed the use of saline dripping to prevent adhesion of debris to the jaws of an ordinary bipolar forceps used to coagulate vessels exposed by ultrasonic aspirator system.

Surgical Staplers

Surgical staplers are mechanical devices that have been widely used for many years to facilitate the speed and safety of gastrointestinal, pancreatic, gynecologic, thoracic and other different types of surgery. Staplers principal characteristic is the ability to close and simultaneously transect part of an organ, as well as to create anastomosis between tissues. Since staplers efficacy are mainly related to the characteristics of the cartridges, to date different models can be found according to the required use. Vascular staplers have been developed for laparoscopic surgery, where traditional suture-closure of large vessels is extremely difficult. They are based on the same principle of all staplers with a specifically designated cartridge that is able to release more lines of smaller staples than traditional gastro-intestinal devices: this characteristic guarantees a high haemostatic effects even for large vessels. Laparoscopic staplers are also articulated allowing to reach difficult areas such as the pelvis or left and right upper quadrants. All these specific characteristics of laparoscopic vascular staplers have been found to be ideal for their use during both open and laparoscopic hepatic resections.27-29 Different techniques for hepatic resection have been proposed along the years. Vascular Endo-GIA are often used to divide the selected sovra-hepatic vein during right of left hepatectomy; in this specific case the use of an articulated stapler is particularly useful (Fig. 4). Fong et al28 proposed their use also fro the parechymal division during hemiepatectomy: after the hepatic and portal vein are isolated, ligated and divided, the capsula is incised by diathermy and the liver parenchyma is crushed with a vascular clamp and, finally, divided by multiple applications of vascular staplers. If necessary the division can be performed under intra-operative ultrasound guidance and without the need for in-flow vascular occlusion. Hepatic resection with vascular staplers is a definite, suggestive and fascinating technique, but it carries some concerns about costs and safety especially in cases of accidental malfunction of the device during major vessels section. Furthermore, the design of the staplers currently available on the market is still quite bulky and often cumbersome, mainly when surrounding of fragile structures is required. To avoid accidental damages when surrounding major vessels with the staplers, Wang et al30 proposed the use of a clamp-guided stapler. In detail, a right angle smooth clamp or forceps is safely placed around the vessel and it is used to grab the thinner jaw of the stapler that can be guided during the insertion.

Figure 4. The use of surgical staplers during liver resection.

Transection Techniques in Liver Surgery

Results of Different Types of Transection Techniques

75

Parenchymal transection is a very challenging and delicate phase during liver resection: accidental damages of major blood vessels and biliary structures can occur, leading to a significant increase of morbidity and mortality rate. It is appropriate to remark that the ideal method to transect the liver it has not been found yet. We have described the most important techniques which have been proposed along the years, but we would like to mention that they have been received and applied according to personal judgment, surgeon’s attitude and experience, availability, cost and volume of surgical procedures. Evidence based on randomized control trials, even if in this specific case is quite possible and recommendable, is deficient. Anyway, in a recent prospective randomized study over 100 consecutive patients, Lesurtel et al31 compared four of the most used different transection techniques: • Crush-claping by means of 3 mm Kelly clamp during Pringle maneuver. • Low frequency ultrasonic dissector by means of cavitron ultrasonic surgical aspirator (CUSA) with a 23 kHz standard tip, cauter 70 Watt, flush at 4 mL/min, with Pringle maneuver used only in selective cases. • Hydrojet dissection using 30-40 bar of water pressure with Pringle maneuvers used in selective cases. • Radiofrequency monopolar device (Tissue-link technology) with Pringle maneuvers used in selective cases. The crush-clamping technique, used in noncirrhotic liver, recorded a significant decrease of blood losses and shorter resection time in comparison with all the other techniques (Graph 1). The degree of ischemia-reperfusion injury assessed by serial serum level of transaminases, bilirubin and prothrombine times as well as the incidence of postoperative complications,31 were fully comparable in the four groups, although all patients undergone crush-clamp technique also received Pringle manoeuver which was applied in 20%, 28% and 36% of the patients in the CUSA, hydrojet and radiofrequency monopolar device group respectively. A significant advantage in favor of the crush-clamping technique was also obtained in term of cost-effectiveness, regardless the amount of liver parenchyma resected. More recently a randomized clinical trial was performed by Saiura et al,25 who compared the use of traditional crush clamping technique, followed by standard vessels suture and sections versus LigaSure™ assisted resection. They reported a significant reduction in intraoperative blood losses in the LigaSure™ group during minor hepatectomies whereas, in case of major resections, blood loss was decreased but not significantly. The postoperative complications, in particular bile leaks, were comparable in both groups, showing that LigaSure™ is able to effectively seal also bile ducts. Better results seem to be achieved if LigaSure™ is combined with a radiofrequency monopolar device as proposed by Sakamoto et al24 but the results have to be considered preliminary in term of blood loss and resection time (compared with crush-clamping and Pringle manoeuver), since they deal with a nonrandomized and short trial on 16 patients. Clinical trials comparing the two most used techniques: “crash-clamp versus ultrasonic dissection” are more common. Takayama et al2 performed a randomized clinical trial on 120 patients using crush clamp by means of Pean’s forceps versus low energy ultrasonic aspirator system, having as primary end-point blood loss and quality of the operation (measured by a specifically designated grading system); as a secondary end-point they studied transection time, surgical margins, technical errors and postoperative morbidity and mortality. They found no difference in term of median blood loss and transection time, but a higher incidence of technical error during the transection has been recorded (e.i. accidental injury of structures, exposure of tumor margins etc.) in the ultrasonic aspirator group, leading to a lower grade in the quality of hepatectomy. No difference in term of post-operative complications and mortality was found.

76

Recent Advances in Liver Surgery

Graph 1.

As previously described ultrasonic coagulating-dissection systems such as Ultracision ( Johnson and Johnson Medical, Cincinnati—USA), have been used by several hepato-biliary surgeons during liver trasection. Schweiger et al32 compared the use of harmonic scalpel associated with ultrasonic surgical aspirator system (CUSA) versus CUSA associated with standard sutured ligation during elective liver resection. They found a shorter resection time and lower incidence of complications in the Ultracision group. Similar results have been also reported by Kim et al33 who compared harmonic scalpel and crush clamping technique, since they found a significant reduction in operative time (357 vs 404 min), a reduction in blood losses, but they observed a significant increase in postoperative biliary fistula rate (24% vs 7%). Higher biliary fistula rate (9%) was also found by Sugo et al34 and this might be related to the incomplete biliary duct sealing during dissection due to the different anatomical structure of the duct itself. Beside to the reduction in blood loss and operative time, one of the main advantages in the use of harmonic scalpel during liver surgery, seems the quality of thetransection, during wedge or non anatomical resections, where the use of crush clamping technique could lead to accidental intra-operative tumour exposure. Aldrighetti et al35 demonstrated significant better results when using a combination of harmonic scalpel and CUSA technology versus crush clamp, in terms of operative time, blood losses and incidence of tumor exposure. The advent of staplers in abdominal and thoracic surgery has been one of the most important technological advances, leading to a reduction in operative time and post-operative complications. Their use during liver resections have gained significant success during the last decades. McEntee et al27 as well as many other authors28-30 described their efficacy and safeness especially for division of the sovra-hepatic vein during major hepatectomies. Most of the surgeon agree that, although in most of the cases over-sewing of the stump controlled by a vascular clamp can be performed, in some situation, such as cases of very short vein, this manoeuvre can be cumbersome and in case of accident, severe bleeding can occur. Staplers can be used not only for vascular control but also for parenchymal transection. Schemmer et al36 reported their results of this technique in more than 300 hepatectomies, where the vascular endo-GIA was used to transect the liver both in open and laparoscopic surgery concluding that their use was safe and effective, although no randomized control clinical trial is, to date, been performed.

Transection Techniques in Liver Surgery

77

Graph 2.

Since these instruments are still quite bulky, rigid and not easy to handle especially in certain areas, extreme care has to be taken in order to avoid accidental vessel tearing as well as damage of vital structure such as the biliary ducts. Furthermore it should be remembered that each year over the past five there have been 8,000 to 9,000 adverse event reports related to surgical staplers. Ninety-percent were malfunctions, 9% injuries and less than 1% deaths. The most frequently reported device problems were: staples did not form, staplers misfired or failed to fire. Between November 14, 1994 and July 1, 2001 FDA received 112 surgical stapler adverse event death reports. The death reports involved staplers that did not fire or staples that did not form properly. Physicians and other health care professionals should be aware of problems with surgical staplers and report deaths, serious injuries, or malfunctions to the manufacturer or distributor.37 One of the most recent new technique for liver transection is the in-line RF assisted hepatic resection, proposed by Weber et al22 and then developed by other authors.23 One of the major advantages of this technique is to obtain a significant reduction of intra-operative blood losses even without the need for in-flow occlusion (Graph 2).38 Nevertheless, in another randomized clinical trial Lupo et al39 compared crush-clamping with radiofrequency assisted liver resection. Results of these study demonstrated non significant difference in term of blood losses and operative time, but a significant higher incidence of post-operative complications in the radiofrequency assisted group.

Conclusions

Different transection techniques for hepatic resection with or without inflow occlusion have been proposed. Most of these technologies claim to be able to reduce intraoperative blood losses, operative time and overall surgical quality. Nevertheless data available on the literature are missing and only few randomized control trial compared all the available options and most of the studies are between two different techniques. In our opinion, the choice of the “gold standard” technique is mainly related to the surgeons’ personal experience as well as the kind of resection that has to be performed. According to the current data, crush clamping technique, ultrasonic dissections, vascular stapler, bipolar electrocoutery and radiofrequency can be equally considered safe and effective for transection of the liver parenchyma, therefore all these techniques should be available in a dedicated center for liver surgery and used according to specific circumstances and conditions.

78

References

Recent Advances in Liver Surgery

1. Wendell W. Beitrag zur Chirurgie del leber. Arch Klin Chir 1911; 95:887. 2. Takayama T, Makuuchi M, Kubota K et al. Randomized comparison of ultrasonic vs clam transection of the liver. Arch Surg 2001; 136:922-928. 3. Arnoletti JP, Brodky J. Reduction of transfusion requirements during major hepatic resection for the metastatic disease. Surgery 1999; 125:166-171. 4. Pringle J. Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg 1908; 48:541-549. 5. Capussotti L, Muratore A, Ferrero A et al. Randomised clinical trial of liver resection with or without hepatic pedicle clamping. Br J Surg. 2006; 93:685-689. 6. Jones RM, Moulton CE, Hardy KJ. Central venous pressure and its effect on blood loss during liver resection. Br J Surg. 1998; 85(8):1058-1060. 7. Nakayama K. Simplified hepatectomy. Br J Surg 1958; 45:645-649. 8. Ma X. Experience in use of nylon velcro tourniquet for hepatic surgery. Zhonghua Wai Ke Za Zhi 1981; 19:768-769. 9. Li AK C, Mok SD. Simplified hepatectomy: the tourniquet method. Aust NZ J Surg 1989; 59:161-163. 10. Keen WW. Report of a case of resection of the liver for the removal of a neoplasm with a table of seventy-six cases of resection of the liver for hepatic tumor. Am Surg 1899; 30:267-283. 11. Lin TY, Chen KM, Liu TK. Total right hepatic lobectomy for primary hepatoma. Surgery 1960; 48:1048-1060. 12. Tung TT. A new technique for operation on the liver. Lancet 1963; i:192-193. 13. Lin TY. A simplified technique for hepatic resection: the crush method. Ann Surg 1974; 180 (3):285-290. 14. Papachristou DN, Berters R. Resection of the liver with a water jet. Br J Surg 1982; 69:93-94. 15. Une Y, Uchino J, Horie T et al. Liver resection using water jet. Cancer Chemother Pharmacol 1989; 23(suppl):s74-s76. 16. Meyers WC, Shekherdimian S, Owen SM et al. Sorting through methods of dividing the liver. Eur Surg 2004; 36/5:289-295. 17. Putnam CW. Techniques of ultrasoning dissection in resection of the liver. Surg Gynecol Obstet 1983; 157:474-478. 18. Schweiger W, El-Shabrawi A, Werkgartner G et al. Impact of parenchymal transection by Ultracision® harmonic scalpel in elective liver surgery. Eur Surg 2004; 36/5:285-288. 19. McGahan JP, Schneider P, Brock BS et al. Treatment of liver tumours by percutaneous radiofrequency electrocautery. Sem Intervent Radiol 1993; 10:143-149. 20. Rossi S, Di Stasi M, Buscarini E et al. Percutaneous radiofrequency interstitial thermal ablation in the treatment of small hepatocellular carcinoma. Cancer J Sci Am 1995; 1:73-81. 21. Cuschieri A, Bracken J, Boni L. Initial experience with laparoscopic ultrasound-guided radiofrequency thermal ablation of hepatic tumours. Endoscopy 1999; 31:318-21. 22. Weber JC, Navarra G, Jiao LR et al. New technique for liver resection using heat coagulative necrosis. Ann Surg 2002; 236:560-563. 23. Haghigi KS, Wang F, King J et al. In-line radiofrequency ablation to minimize blood loss in hepatic parenchymal transection. Am J Surg 2005; 190:43-47. 24. Sakamoto Y, Yamamoto J, Kokudo N et al. Bloodless liver resection using the monopolar floating ball plus ligasure diathermy: preliminary results of 16 liver resections. World J Surg 2004; 28:166-172. 25. Saiura A, Yamamoto J, Koga R et al. Usefulness of ligasure for liver resection: analysis by randomized clinical trial. Am J Surg 2006; 192:41-45 26. Yamamoto Y, Ikay I, Kume M et al. New simple technique for hepatic parenchymal resection using cavitron ultrasonic surgical aspirator and bipolar cautery equipped with a channel for water dripping resection. World J Surg 1999; 23:1032-1037. 27. Mc Entee GP, Nagorney DM. Use of vascular staplers in major hepatic resections. Br J Surg 1991; 78:40-41. 28. Fong Y, Blumgart LH. Useful stapling techniques in liver surgery. J Am Coll Surg 1997; 185:93-100. 29. Lefor AT, Flowers JL. Laparoscopic wedge biopsy of the liver. J Am Coll Surg 1994; 178:307-308. 30. Wang WX, Fan ST. Used of the endo-GIA vascular stapler for hepatic resection. Asian J Surg 2003; 26:193-196. 31. Lesurtel M, Selzner M, Petrowsky H et al. How should transection of the liver be performed? A prospective randomized study in 100 consecutive patients: comparing four different transection strategies. Ann Surg 2005; 242:814-823. 32. Schweiger W, El-Shabrawi A, Werkgartner G et al. Impact of parenchymal trasection by ultracision harmonic scalpel in elective liver surgery. Eur Surg 2004; 36:285-288.

Transection Techniques in Liver Surgery

79

33. Kim J, Ahmad SA, Lowy AM et al. Increased biliary fistulas after liver resection with the harmonic scalpel. Am Surg 2003; 69:815-819. 34. Sugo H, Mikami Y, Matsumoto F et al. Hepatic resection using the harmonic scalpel. Surg Today 2000; 30:959-962. 35. Aldrighetti L, Pulitanò C, Arru M et al. Technological approach versus clamp crushing technique for hepatic parenchymal transection: a comparative study. J Gastrointest Surg 2006; 10:974-999. 36. Schemmer P, Friess H, Hinz U et al. Stapler hepatectomy is a safe dissection technique: analysis of 300 patients. World J Surg 2006; 30:419-430. 37. Brown SL, Woo EK. Surgical stapler-associated fatalities and adverse events reported to the food and drug administration. J Am Coll Surg 2004; 199(3):374-81. 38. Ayav A, Bachellier P, Habib NA et al. Impact of radiofrequency assisted hepatectomy for reduction of transfusion requirements. Am J Surg 2007; 193(2):143-148. 39. Lupo L, Gallerani A, Panzera F et al. Radomized clinical trial of radiofrequency-assisted versus clap-crushing. Br J Surg 2007; 94:287-291.

Chapter 7

Vascular Isolation Techniques in Liver Resection

Jacques Belghiti,* Safi Dokmak and Catherine Paugam-Burtz

Abstract

D

uring liver resection, various techniques of hepatic vascular control have been proposed to minimize the intraoperative blood losses. They include the isolated occlusion of the hepatic inflow (pedicular clamping) or the combination of occlusion of the hepatic inflow and outflow (total vascular exclusion). Hepatic vascular exclusion which has been shown to consistently reduce the rate of intraoperative bleeding, has major drawbacks including longer continuous liver parenchymal ischemia, splanchnic venous congestion and more pronounced hemodynamic instability. Ischemic preconditioning, intermittent clamping and hepatic vascular exclusion with caval flow preservation minimize hemodynamic instability. Currently, intermittent pedicular clamping has been shown to be the easiest procedure to reduce bleeding associated with the lower intra and postoperative morbidity. Anesthetic management during liver resection is crucial during hepatic vascular exclusion for prevention and adjustment of hemodynamic disturbance. In patients resected with pedicular clamping, low central venous pressure during liver transection is consistently associated with reduced blood loss. Compared with intermittent pedicular clamping, total hepatic vascular exclusion does not offer a greater reduction of blood loss and is associated with increased morbidity. This leads to limit its indications to tumors involving the major hepatic veins. Under these circumstances, the intraoperative management requires an appropriate tool for monitoring and anticipation of expected hemodynamic variations.

Introduction

Bleeding and subsequent blood transfusions which remains a main cause of mortality and morbidity of hepatectomies, may be associated with an increased risk of recurrence of malignancy through impairment of the patient’s immune response.1-3 Vascular clamping, irrespective of its modality, minimizes the risk of bleeding during liver resection. Liver injury induced by ischemia and reperfusion is the major drawback of clamping. Long duration of clamping carries a risk of postoperative liver failure especially in patients with abnormal liver parenchyma.4 With technical improvements in liver surgery, more and more patients with various underlying liver conditions (cirrhosis, fibrosis, cholestasis, steatosis or chemotherapy-induced injury), are undergoing complex and extensive liver resections.5,6 Hepatic vascular control can be achieved with the only occlusion of the liver inflow or by both liver inflow and outflow occlusion. In this regard, pedicular intermittent clamping which alternates short periods of clamping with intervals of restoration of blood flow has shown to be the best tolerated clamping modality, especially in patients with diseased liver parenchyma.7,8 Similarly, ischemic preconditioning, which initiates a short period of clamping and restoration of blood flow followed by continuous clamping seems to be an attractive concept.9 On the other hand, better understanding of vascular anatomy (particularly venous tributaries), better *Corresponding Author: Jacques Belghiti—Department of HPB Surgery, University of Paris, 7 Denis Diderot, Hospital Beaujon, 92118 CLICHY Cédex, France. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Vascular Isolation Techniques in Liver Resection

81

anesthetic management with intraoperative low central venous pressure (CVP) combined with the development of modern tools of transection-coagulation (ultrasonic dissector and bipolar coagulation) has made possible liver resection, even major, without vascular clamping. Therefore, vascular clamping needs to be applied balancing its efficacy to control bleeding with the potential side-effects of ischemic liver injury. The aim of this chapter is to describe techniques, benefits, drawbacks and hemodynamic monitoring of vascular control so as to use the most appropriate technique to each patient’s requirements.

Anatomic Basis for Vascular Control

The liver receives a dual vascular inflow providing approximately one quarter of the total cardiac output, or a blood flow of 1500 mL/minute. The portal vein provides 75% of the total hepatic blood flow and the hepatic artery the remaining 25%. The portal vein originates behind the neck of the pancreas at the confluence of the superior mesenteric and splenic veins and courses posterior to the bile duct and hepatic artery in the free edge of the lesser omentum. At the hilum of the liver, the vein divides in to a shorter, more vertically oriented right and longer, horizontally oriented left branch. The right portal branch may be absent when the right anterior and posterior sectorial veins originate directly from the trunk of the portal vein. Thus the right portal branch can be more difficult to dissect and control than the left portal branch. The hepatic artery is highly variable, but most commonly arises as a branch of the celiac axis and enters the hepatoduodenal ligament after providing the right gastric and gastroduodenal arteries; the right and left branches usually lie on a plane posterior to the bile ducts at the hilum of the liver. In fact, this classical branching pattern is found in only 50% of patients. The accessory or replaced arteries pertinent to vascular clamping include a left artery, which can arise from the left gastric artery (25-30%) and a right artery which can arise from the superior mesenteric artery (17-20%). The three large hepatic veins which lie postero-superior to the liver just below the diaphragm form the major drainage of the liver (Fig. 1). The right hepatic vein is formed by a short wide trunk by the convergence of an anterior trunk situated in the right portal fissure which drains mainly the segment V and VI and a posterior trunk which drains mainly the segment VII. The right hepatic vein also drains part of the segment VIII. The middle hepatic vein is situated in the plane of principal portal fissure. It drains the entire central sector. It receives the veins from segments V and VIII at its right border and the veins of segment IV at its left border. Thus, it forms the major drainage vein of segment IV and part of segments V and VIII. The left hepatic vein arises from the confluence of segment II and III veins. It often receives drainage from the posterior part of segment IV and it terminates as a short common trunk with middle hepatic vein in the majority of cases. In 10-20% of cases a significant right inferior hepatic vein may be found (>5 mm diameter) which mainly drains segment VI. In addition to these, there are two groups of accessory hepatic veins, the right and the left. The right accessory veins drain the posterior part of the dorsal sector. On the left, they are formed by the veins of the caudate lobe. In half of the cases a large solitary vein terminates in the inferior vena cava (IVC) and in the other half, 2 or 3 veins are present and end in a staged fashion in the left border of IVC. These anatomical variations are important in the context of vascular clamping as the presence of large drainage veins can result in inability to achieve complete vascular control during the clamping procedure.

Surgical Aspects of Vascular Clamping

The easiest procedure to reduce bleeding during liver resection is inflow control. Vascular inflow control involving pedicular clamping combined with low CVP is the most efficient way to reduce peroperative bleeding. A recent meta-analysis confirmed that vascular occlusion decreases the intraoperative blood loss.10 The mean decrease of blood loss is around by 790 mL (356-1224) (mean (range) whilst reduction in the rate of blood transfusion does not reach statistical significance. On the other hand, continuous clamping increases ischemic injury of the liver parenchyma and induces splanchnic congestion. Intermittent clamping has supplanted the use of continuous

82

Recent Advances in Liver Surgery

Figure 1. A schematic view of hepatic vein drainage through the three main hepatic veins (a, b and c) and two accessory veins including right inferior hepatic vein (d) and caudate vein (e).

pedicular clamping to overcome these two drawbacks. Patients with large tumors involving caval hepatic confluence may require additional outflow vascular control.

Inflow Vascular Occlusion

The hepatic pedicle clamping (Pringle’s maneuver) which interrupts arterial and portal venous inflow to the liver is a standard in hepatic surgery.

Surgical Techniques for Total Inflow Control

Inflow control implies encirclage of the hepatic pedicle (Fig. 2). Adhesions to the gallbladder are freed and the lesser omentum is opened at the level of the pars flacida, taking care to avoid injury to the right gastric pedicle. A finger or a blunt dissector may thereafter be easily passed through Winslow’s foramen and the hepatoduodenal ligament is encircled with a tape. Clamping is easily achieved by a vascular clamp or Tourniquet that should be closed until the pulse in the hepatic artery distal to the clamp is stopped. Excessive closure should be avoided as it may otherwise result in arterial or biliary injury. A search for a left hepatic artery originating from the left gastric artery is mandatory to prevent persistent bleeding during parenchymal transection. When a left hepatic artery exists, simultaneous occlusion of this latter should be performed to complete the vascular inflow control. In patients who have undergone previous abdominal surgery, there may be dense adhesions between the right lateral and posterior aspects of the hepatoduodenal ligament (in particular the portal vein) and the anterior surface of the inferior vena cava and segment I. Adhesions may form between duodenum, greater omentum and the anterior aspect of the hepatoduodenal ligament. All these adhesions should be lysed prior to pedicular clamping to avoid accidental injury to vena cava or the duodenum. A safe approach is to expose the inferior vena cava in its retropancreatic portion by a Kocher maneuver and to progress cranially. Air embolism

Vascular Isolation Techniques in Liver Resection

83

Figure 2. Inflow control with clamping of the hepatic pedicle.

may occur during transection. A 15 degree Trendelenburg position is recommended in this case to minimize consequences.

Continuous Clamping (Continuous Pringle Maneuver, CPM)

Continuous clamping implies interruption of inflow continuously during the hepatic transection phase, without intermittent release to allow reperfusion. Although conceptually very efficient to control bleeding it is used less frequently as it is not universally effective and has several disadvantages including insufficient control of bleeding, splanchnic congestion and liver and gut ischemia (Table 1). The reduction of intraoperative bleeding is limited by the absence of control of the backflow bleeding. This is particularly relevant to situations in which there is a high CVP due to tricuspid insufficiency or in case of large hepatic tumors compressing hepatic veins associated with multiple venous collaterals or localized near the cavohepatic junction. Interestingly, Smyrniotis et al suggested in a prospective study that this back-flow could contribute to attenuation of hepatic ischemia/perfusion.11 The second drawback of CPM is splanchnic congestion. This phenomenom is related to fluid sequestration in the splanchnic compartment, bowel edema. This can induce difficulties at the time of closure of the abdominal cavity, can induce intra-abdominal hypertension and subsequent abdominal compartment syndrome leading to multi organ failure.12 Development of edema will be detrimental to bowel anastomoses especially in the context of synchronous hepatic resections for colorectal malignancies.13 CPM has shown to induce hyperamylasemia and can lead to clinically significant pancreatitis in some patients.14,15 Interruption of splenic venous return without arterial interruption poses a risk for spontaneous splenic rupture during prolonged continuous clamping.16,17 The last drawback of CPM is prolonged ischemia to the liver. Normal liver can tolerate inflow occlusion under normothermic conditions for up to 60 minutes.4,18 Periods of CPM up to 127 minutes in normal liver and 100 minutes in pathologic livers have been reported with favorable outcomes.19,20 However, diseased livers tolerate smaller duration of ischemia. Hence,

84

Recent Advances in Liver Surgery

Table 1. Hemodynamic changes observed during various methods of clamping for liver resection Clamping Procedures

Portal Pressure

Caval Pressure

Pulmonary Artery Pressure

Cardiac Index

Vascular Resistance

Arterial Pressure

Pedicular clamping

↑↑

#

↓

↓

↑↑

↑

HVE

↑↑

↑

↓↓

↓↓

↑↑

↓

HVE with caval flow preservation

↑↑

#

↓↓

↓

↑↑

#

HVE: hepatic vascular exclusion Severe increase : ↑↑; moderate increase: ↑; severe decrease: ↓↓; moderate decrease: ↓; no change: #.

CPM cannot be applied to diseased livers for long duration. Finally, restoration of blood flow after prolonged clamping can cause reperfusion syndrome characterized by hemodynamic disturbances, due to the release of toxic metabolites and vasodilators from the liver as well as the splanchnic bed.21,22 Consequently, intermittent clamping has been proposed to overcome the drawbacks of continuous clamping.

Intermittent Clamping (Intermittent Pringle Maneuver, IPM)

Intermittent clamping consists of alternative periods of inflow occlusion and of restoration of normal inflow. After a short period of pedicular clamping ranging from 10 to 20 minutes, the inflow is restored during 5 to 10 minutes according to the duration of the transection, to the underlying liver status and to the surgeon’s preference.23 Classically, each cycle comprises 15 minutes of clamping followed by 5 minutes of reperfusion.7,8,24,25 Several modes of clamping/unclamping have been described (20/5, 15/5, 5/1). Recently, Brooks et al,26 studied the variability and the rapid restoration of tissular pH and the liver partial pressure of carbon dioxide (PCO2) after several periods of clamping and unclamping. They showed that after a clamping period of 10 min, a reperfusion of 5 min was sufficient to restore PCO2 and tissue pH. After 20 min of clamping, more than 10 min of reperfusion is required. Based on these results, the authors recommended 10 min period of pedicular clamping combined with a 5 min restoration of inflow. Esaki et al compared 15 min vs 30 min of intermittent clamping and did not show any significant difference in morbidity, transfusion requirements, postoperative liver cytolysis, or liver function.27 Consequently, the optimal duration of hepatic vascular inflow occlusion and reperfusion during liver transection has not been definitely defined. Noteworthy, genuine intermittent clamping requires a true period of unclamping. ‘True’ period of unclamping implies that the surgeon should not continue transection during the period of unclamping. This period during which the surgeon applies gentle compression of the transected surface, can be utilized to reexamine the adequacy of the transection line regarding the vascularization and the carcinological margin. The period of revascularization gives the surgeon an opportunity to visualize the healthy color of the remnant liver. Intra-operative US can be performed to confirm the adequacy of inflow and outflow of the remnant liver as well as to examine the progress and direction of transection in relation to tumor margin. IPM became the most common method of vascular clamping. It has gained wide acceptance as it is technically simple, effective in controlling bleeding, reducing the splanchnic congestion. Moreover, it decreases the ischemic injury of the liver parenchyma and is well tolerated, above all by cirrhotic liver. In a prospective study, Man et al demonstrated significant decrease in blood loss in patients operated with IPM versus those without any vascular control.7 Intermittent clamping in diseased liver has not shown to cause significant deleterious effects even if the cumulative clamping time is up to one hour.25 In a controlled study comparing continuous versus intermittent portal triad clamping we have found that although there was significantly more bleeding in the

Vascular Isolation Techniques in Liver Resection

85

intermittent group during parenchymal transection, there was no statistical difference in the total operative blood loss. The most important result however was the better tolerance of the liver to intermittent clamping.8 Two randomized studies compared intermittent (15 min duration) vs continuous inflow clamping. Mortality and liver failure were higher in the CPM group thought it did not reach statistical significance. The blood loss, number of units transfused or number of patients requiring transfusion was not different.8,28 The application of intermittent clamping in normal livers has prolonged the total clamping duration (up to 3 hours) and has enabled the surgeon to perform even complex hepatic resection with minimal blood loss.29 Safe total ischemic periods of 322 minutes in normal livers and 204 minutes in cirrhotic livers have been reported.25,30 It must be noted that intermittent clamping is the technique of choice in patients undergoing laparoscopic liver resection.31 The wide safety margin of IPM has currently promoted its safe use in donor hepatectomy in living donor liver transplantation. This has neither jeopardized donor safety nor has it compromised graft function.32,33 The use of intermittent clamping enables a bloodless resection and thus it adds to donor safety suggesting that the surgeons should not hesitate to use this during living donation.32,33 To go further into the insight of liver tolerance to ischemia, investigators explore the concept of ‘preconditioning’.

Preconditioning

A newer perspective on inflow vascular clamping has emerged from study of the biological response to ischemia-reperfusion.9,34 The protective effects of a short period of ischemia before inducing a long period of ischemia has been suggested during various conditions such as myocardial or cerebral ischemia.35 In the specific field of liver surgery, similar findings have been described. Experimental data suggested that ischemic preconditioning of the liver not only limits the subsequent negative effects of ischemia on the liver but may also protects distant organs from the systemic effects of organ ischemia. These results led to a study of this technique in humans. Clavien et al revealed that an initial period of ischemia (10 minutes) followed by reperfusion (10 minutes) protects the liver against subsequent prolonged ischemia and postulated that some of the benefit of intermittent clamping may actually result from the impact of the first clamp-unclamp sequence as a preconditioning treatment.9 Preconditioning followed by continuous clamping may have the advantage of avoidance of blood loss during the unclamped period, though no major differences have been shown in terms of blood loss between the continuous vs intermittent clamping approaches. This protective strategy against hepatic ischemia was shown to be efficient, especially in the presence of steatosis in a prospective clinical randomized study.36 The beneficial effect of preconditioning was shown for 30 minutes of continuous clamping and for small volume of liver resection.36 These favorable results have been challenged recently. Azoulay et al failed to demonstrate any benefit in patients undergoing major hepatic resection under vascular exclusion of the liver with ischemic preconditioning.37 In a prospective randomized study, comparing ischemic preconditioning to intermittent selective vascular occlusion, Smyrniotis et al did not find advantages in favor of preconditioning when ischemia time was less than 40 minutes.38 These results have been confirmed in a meta-analysis including the studies of Azoulay et al, Chouker et al and Clavien et al. This analysis showed that there was no difference in mortality, liver failure, blood loss, number of patients needing transfusion, peroperative hemodynamic changes.10 Although, the theoretical advantage of hepatoprotective effect of preconditioning is definitely attractive, in practice this procedure has not shown to have significant advantages over intermittent clamping.

Topical Hypothermia

As hepatic inflow occlusion carries a serious risk of ischemic injury to the remnant liver, induction of hypothermia was proposed to reduce the injury particularly in patients with underlying liver disease.39,40 The adverse effects of systemic hypothermia lead some authors to use topical cooling by placing ice pack or ice slush on the liver surface.41,42 In these studies, ischemic time can be prolonged to more than one hour in diseased livers, especially if hepatic core temperature fell below 30˚ Centigrade.40

86

Recent Advances in Liver Surgery

Selective Inflow Control

Selective inflow control selectively interrupts the arterial and portal venous inflow of the hemiliver to be resected.

Technical Aspects

After encircling the pedicle and performing cholecystectomy, the portal vein is approached posterolaterally from the right to avoid devascularization of the common bile duct. Care must be taken to avoid inadvertent injury to a right hepatic artery arising from the superior mesenteric artery. The main portal vein is dissected caudally to cranially on its anterior surface up to the bifurcation. During the dissection of its posterior surface, the consistent branch from the right posterior face of the right portal vein to the paracaval portion of the caudate lobe is ligated. After isolation and retraction of the right branch of the hepatic artery, the portal bifurcation is identified. The posterior passage of the curved dissector in the bifurcation is facilitated by a slight caudal traction of the main portal trunk. The bifurcation of the portal vein is accessed from the right side usually. When the caudate lobe is preserved, the dissection of the left branch of the portal vein should be accessed from the left side of the portal pedicle, with attention to one or two small portal branches to the left part of the caudate lobe. The right or left branch of the hepatic artery are identified and encircled. We do not advocate extrahepatic biliary dissection before parenchymal transection due to the risk for biliary injury.43 The branches of the portal vein and hepatic artery supplying the liver to be resected can be cross-clamped or ligated. The advantages of this procedure includes (A) a clear demarcation of the limits of resection; (B) the absence of ischemic injury of the remnant liver; (C) the absence of splanchnic congestion and hemodynamic disturbances and (D) the reduction of prolonged periods of ischemic times in cirrhotic liver. Selective inflow control was specifically devised for segmental and subsegmental resections for small hepatocellular carcinoma, in diseased liver.44,45 Additional clamping of the ipsilateral hepatic vein can also be performed along with this procedure for better vascular control46 (Fig. 3). The disadvantage of this technique is continuous bleeding from the controlateral liver due to intrahepatic collaterals leading sometimes to conversion in IPM. With the wider use of intermittent clamping, selective clamping techniques have not gained wide acceptance as this is more technically demanding and has no obvious beneficial effects as compared to genuine intermittent clamping. In a prospective controlled study including patients who underwent minor resection, both techniques were associated with similar blood loss and postoperative complications.47 However, induction of lesser cytolysis was observed in the cirrhotic group who underwent selective clamping.47 There is a relative contraindication to this technique in patients with tumor infiltrating the hilum, having severe adhesions or treated with previous sequential chemo and portal vein embolization. The intrahepatic posterior approach described by Launois allows an extraglissonian vascular control of the right pedicle without dissecting its structures individually.43,48 This technique includes division of the hepatic parenchyma anterior and posterior to the glissonian pedicle. Passage of a large curved clamp encircles the glissonian pedicle allowing its clamping. The caudal traction of the right pedicle facilitates the exposure of the anterior and posterior segmental branches of the right pedicle. This Launois procedure which had a great initial success conserves a place in patients who had previous hilar dissection or inflammation. Segmental selective clamping can be useful for delineating the territory of some tumors which requires difficult segmental or subsegmental resection. Sectoral territories can be delineated by extraparenchymal pedicular control of the respective sectors. Isolated control of single segment is more difficult requiring balloon occlusion of the portal flow with ipsilateral control of one branch of the hepatic artery. Under US guidance, the portal branch is punctured followed by introduction of a balloon catheter. Inflation of the balloon associated with pedicular arterial clamping can delineate the portal territory. The injection of methylene blue into the portal catheter can allow more precise identification of the territory of interest. This technique is mainly indicated for resection of small peripheral hepatocellular carcinoma in order to perform an anatomical carcinologic resection.

Vascular Isolation Techniques in Liver Resection

87

Figure 3. Total vein exclusion (TVE): after complete mobilization of the liver, the IVC is mobilized above and below the liver and encircled. The hepatoduodenal ligament is encircled and clamps are applied in the following order: 1) hepatoduodenal ligament, 2) infrahepatic IVC and 3) suprahepatic IVC.

Inflow and Outflow Vascular Control

Combination of occlusion of vascular inflow and outflow of the liver results in total vascular exclusion. Additionally, this procedure can be performed with or without preserving caval flow.

Total Vascular Exclusion (TVE)

TVE combines total inflow and outflow vascular occlusion of the liver. Total isolation of the liver from the systemic circulation is intended during resection of large tumors adjacent or involving the major hepatic veins and/or the IVC. This procedure can also be considered when significant backflow bleeding occurs due to persistently elevated CVP despite efficient hepatic pedicle clamping (i.e., patient with tricuspid insufficiency). Effective TVE requires a complete mobilization of the liver from its ligamentous attachments and all surrounding adhesions. The IVC is completely freed from the retroperitoneum which requires the ligation of the right adrenal vein. The IVC is mobilized above and below the liver and encircled. The hepatoduodenal ligament is encircled, as described above and a careful search is made for accessory or replaced hepatic arteries (Fig. 4). Clamps are applied in the following order: (1) hepatoduodenal ligament, (2) infrahepatic IVC and (3) suprahepatic IVC. Once the surgeon and the anesthesiologist agree that clamping will be tolerated, clamps are reapplied for a duration up to 60 minutes in patients with normal liver. After completion of the parenchymal transection and prior to removing the clamps, the clamp on the infrahepatic vena cava can be partially released to flush air that might have been trapped and to test for caval integrity. The clamps are then removed in the reverse order of which they were placed. Inadequate TVE technique will result in the progressive congestion of the liver as a result of (A) inadequate clamping of the portal pedicle or the IVC, (B) persistent arterial inflow through an unrecognized left hepatic artery or hypervascular perihepatic adhesions, (C) persistent entry of venous blood into the excluded retrohepatic IVC via anatomical (right adrenal vein) or

88

Recent Advances in Liver Surgery

Figure 4. Hepatic vascular exclusion with caval flow preservation (HVE): the association of inflow occlusion (hepatic pedicle clamping) and outflow occlusion by extraparenchymal clamping of the three main hepatic veins enables complete vascular isolation without interruption of the IVC flow.

pathological veins (tumor adhesions). Patients with huge tumor with diaphragmatic and peritoneal adhesions (who could be the best candidate of TVE) could experience hepatic congestion after suprahepatic caval clamping. This congestion induces increase in liver size, change in color and consistency of the liver and is always associated with hemodynamic intolerance. The release of the suprahepatic clamp immediately restores the hemodynamic condition. This phenomenon is related to the filling of the liver through retrocaval veins that may fill the liver when every connection from the cava to the liver is not controlled.4 Supracaval declamping provides the path of least resistance for blood from the liver toward the heart, rather than backward into the surgical field. Although concomitant supraceliac aortic clamping49 has been proposed in this situation, the technique has not been widely adopted. Three randomized studies50,51 compared TVE with portal pedicle clamping or selective vascular exclusion, showed that both techniques were effective in bleeding control. There was no statistically significant difference in the operative blood loss, number of patients transfused or the number of units transfused.10 There was no difference in mortality between the two groups. However, TVE was associated with significant decrease in mean arterial pressure, mean pulmonary arterial pressure. Postoperative serum creatinine level and length of hospital stay were significantly greater in TVE group.10 Finally, TVE requires prolonged continuous clamping that can be poorly tolerated in patients with diseased liver. Two refinements have been proposed to overcome these drawbacks: (A) TVE with preservation of caval flow in order to minimize the hemodynamic impact and (B) hypothermic perfusion in order to decrease parenchymal lesions related to prolonged warm ischemia.

Vascular Isolation Techniques in Liver Resection

89

Vascular Exclusion with Caval Flow Preservation (HVE)

Historically, extraparenchymal control of the main hepatic veins was considered to be dangerous, as a tear in this part of the vein would risk massive blood loss and air embolism. Better understanding of intrahepatic anatomy and advances in surgical techniques allow many liver surgeons to safely expose and control the three main hepatic veins. In the absence of tumor involvement of the hepatocaval junction, HVE with caval flow preservation can be considered. The association of inflow occlusion (hepatic pedicle clamping) and outflow occlusion by extraparenchymal clamping of the three main hepatic veins (Fig. 5) enables complete vascular isolation without interruption of the IVC flow.52,53 However, the indication of this attractive procedure is restricted to patients without tumor involvement of the hepatocaval junction. In addition, the presence of large veins draining the caudate lobe can make this procedure inefficient. Indeed, caudate lobe veins are not isolated in this technique and can communicate intraparenchymally with other major veins causing persistent backflow bleeding. The technical sequence of HVE with preserved caval flow includes total pedicular clamping with subsequent clamping of the three major hepatic veins at its confluence with the IVC. This clamping procedure can be applied either continuously or intermittently. The extrahepatic control of the right hepatic vein requires a complete mobilization of the right liver. Division of the falciform ligament is extended cranially to the upper peritoneal folds of the right and left triangular ligaments. The gutter between the liver, the right hepatic vein and the middle hepatic vein is dissected free to the anterior surface of the IVC. At this stage, dissection of a major hepatic vein from above is considered very hazardous and should not be continued. After

Figure 5. Isolated inferior caval clamping decreases the central venous pressure (CVP). This technique can be used alone without pedicular clamping or associated with pedicular clamping.

90

Recent Advances in Liver Surgery

mobilization of the right lobe and complete exposure of the right and anterior side of the IVC, the liver is retracted medially and upward. The right half of the IVC is dissected caudally to cranially with ligation of short and small retrohepatic veins. When a significant right inferior hepatic vein is present, it is either encircled or ligated and divided according to type of resection. Before reaching the RHV level, the IVC ligament is encountered. This ligament is dissected and divided between clamps. This ligament, which contains small veins, should be closed with a running suture. Only after this has been completed should the right hepatic vein be encircled and taped. The RHV is easily encircled by a clamp passing on the anterior surface of the IVC toward the space between RHV and MHV. In order to facilitate the subsequent parenchymal dissection, a tape is inserted behind the RHV and passed along the anterior surface of the IVC. Then the right liver is released to lie in its anatomical position. This tape which elevates the precaval space (“hanging maneuver”) facilitates subsequent division and hemostasis of the parenchyma.54 The extrahepatic control of the middle and left hepatic veins requires exposure of left border of IVC. The left upper aspect of the IVC is exposed by division of the peritoneal reflection above the caudate lobe and the ligamentum venosum is ligated and divided exposing the junction of left hepatic vein and the IVC.55 When the left phrenic vein drains directly into the left hepatic vein it is ligated and divided. A dissector is inserted from above in the previously dissected gutter between the right and middle hepatic veins and passed in close contact with the anterior surface of the IVC beneath the middle hepatic vein. The common trunk is then encircled with a tape. When the confluence of the middle and left hepatic veins is extrahepatic, it is possible to separately encircle these two vessels—otherwise the common trunk of the middle and left hepatic veins can be encircled as a unit.

TVE with Refrigeration

Initially described by Fortner,56 this technique has been reevaluated by Azoulay et al, especially when TVE was longer than 60 minutes.57 Compared with standard TVE, this group showed that hypothermic perfusion of the liver was associated with better postoperative liver and renal functions and a lower morbidity especially in patients requiring TVE >60 minutes. In hypothermic conditions, ischemic periods of 121 minutes (maximum: 250) have been reported. The technical aspect requires systematic veno-venous bypass. Refrigeration was performed using 2 to 4 L of UW solution chilled at 4˚C, perfused through the portal vein or the hepatic artery and let out through a cavotomy above the inferior caval clamp. This renewed attractive procedure applicable in difficult and complex liver resection in patients with diseased liver needs to be added to the armamentarium of modern surgery.

Isolated Caval Clamping Infra-Hepatic Caval Clamping

The major impact of caval pressure on blood loss during liver resection has lead some surgeons to propose isolated IVC clamping in order to decrease the CVP (Fig. 5).58,59 Indeed, it induces a decrease of CVP by approximately 4 cm of H2O. This technique is easy to apply. It can be used alone when the liver resection is performed without pedicular clamping or along with pedicular clamping. When it is used in fluid loaded patients, the hemodynamic consequences on arterial pressure and post operative renal function are limited.58 Surgeons should consider this method especially when a low CVP can not be maintained in patients without preoperative renal impairement.

Isolated Total Caval Clamping

Clamping of the infrahepatic vena cava before liver transection can be considered in patients having a persisting high CVP.58 After liver transection, this procedure can be safely applied in patients with tumor involving a part of the vena cava. Total clamping of the vena cava below hepatic veins associated with clamping of the vena cava above renal veins maintains hemodynamic stability while the remnant liver is used as a shunt.60 When a tumor involving the vena cava, spares a suprahepatic venous trunk, total caval clamping is feasible since the hepatic flow is maintained through the remnant liver. This technique of caval clamping is indicated in patients with tumors

Vascular Isolation Techniques in Liver Resection

91

in contact with the venacava or near the cavohepatic junction which necessitates en bloc resection of the IVC or cavo hepatic junction. In this maneuvre, the vena cava alone is clamped leaving the inflow and outflow of the remnant liver intact. This technical procedure requires the control of infra hepatic vena cava and of the uninvolved venous trunk. The initial phase of the procedure consists of parenchymal transection by an anterior approach, usually under intermittent clamping, after ligation of the hepatic pedicle to the tumor bearing hemiliver. When the parenchymal transection reaches the anterior surface of vena cava, the tape which encircle the uninvolved venous trunk is passed behind the supra hepatic IVC. The IVC is clamped at the site of this caval tape after clamping the infra hepatic vena cava. Thus, the vena cava is isolated while the hepatic flow is maintained through the remnant liver. The maintenance of the flow to the suprahepatic vein through the “liver shunt” avoids splanchnic congestion, hemodynamic disturbances and liver ischemia. The total caval clamping without liver ischemia allows comfortable caval resection and reconstruction. This procedure which is especially indicated and efficient when there is involvement and resection of caudate lobe further reduces the indications of TVE to exceptional patients.

No Clamping Technique

The ideal alternative to clamping would be to perform nonbleeding hepatectomy without clamping. This ideal approach is considered by many surgeons faced with major resection on underlying diseased parenchyma, living donor harvesting and combined digestive operation in order to avoid the consequences of splanchnic congestion on bowel anastomoses. Several conditions should be satisfied to perform a hepatectomy without clamping: (A) a low CVP; (B) a complete preserved remnant liver venous drainage assessed preoperatively with CT scan and intra operatively by US Doppler and (C) a possession of modern tools of parenchymal transection. Bleeding from the transection surface is minimized when the remnant liver has a patent venous drainage. Therefore, nonclamping technique should be considered essentially in major anatomic resection which preserves complete venous drainage of the remnant liver. Nonclamping technique increases liver transection time which can be reduced by the use of several technical refinements including ultrasonic dissector, bipolar scissors or water-irrigated bipolar forceps. As minimizing blood loss remains the major objective, the pedicle should be controlled and clamped when the blood loss approaches 20 mL/kg.61 In a prospective randomized study comparing liver resection with and without hepatic pedicle clamping, Capussotti el al showed that liver resection can be safely performed without any vascular occlusion.62

Hemodynamic Response to Different Types of Clamping

The hemodynamic changes are proportional to the type and extent of vascular interruption. They also depend on several factors including the depth of anesthesia, volume and rating of bleeding, vascular filling pressures and cardiovascular ability to face the reduction of venous return. Pedicular clamping is nearly always well tolerated, while addition of caval clamping, is followed by major hemodynamic consequences (Table 1).

Hemodynamic Response to Portal Pedicle Clamping

In humans, hemodynamic consequences of the pedicle clamping are moderate. Systemic arterial pressure consistently increases (10 to 30 %) despite a decrease in cardiac output from around 10 to 15 % caused by a slight decrease in cardiac preload.50,63 This phenomenon is the result of sympathetic stimulation inducing a significant increase in systemic vascular resistance.50,64,65 These hemodynamic changes are depicted in Table 1. Finally, isolated pedicle clamping is usually well tolerated and does not require specific anesthetic management. At the time of declamping, arterial systemic pressure is restored to previous baseline values even for durations of clamping exceeding one hour. However, as duration of clamping increases, vasoconstrictive response can be blunted and systemic hypotension can occur at declamping as surgery progresses. This phenomenon can be observed when the cumulative duration of clamping and thus ischemia exceeds one hour. It could be assimilated to a reperfusion syndrome, related to an extended duration of ischemia of liver parenchyma and splanchnic release of toxic vasodilators. Therefore, it is recommended to

92

Recent Advances in Liver Surgery

increase the duration of unclamping period during each cycle if the cumulative duration exceeds more than one hour, especially in patients with diseased liver.23

Hemodynamic Consequences and Limitations of Total Vascular Exclusion (TVE)

The hemodynamic consequences of the addition of total caval clamping to pedicular clamping are more pronounced (Table 1). The sequence of TVE includes initial inflow occlusion followed by infrahepatic caval clamping and then suprahepatic caval clamping. Clamping of IVC leads to a sudden decrease of mean arterial pressure. TVE associated with caval clamping leads to a decrease of the cardiac preload associated with a 40-50% decrease in cardiac index and 25% decrease in pulmonary artery pressure. Adaptative response includes reflex sympathetic stimulation leading to a 50% increase of heart rate and a very significant increase in systemic vascular resistance. Finally, these modifications are associated with a 10% decrease in mean arterial blood pressure. The increase of portal and IVC pressures before the clamps induces opening of venous portosytemic or cavo-caval shunts that participate in the hemodynamic stabilization. The cardiac response to maintain the blood pressure requires approximately 5 minutes to occur and is facilitated by ‘preloading’ the patient with intravenous fluids. These hemodynamic changes can vary greatly between individuals. Tolerance to TVE depends on circulating blood volume, cardiac function and development of collateral circulation. These variations are impredictable and justify the realization of a test. Before TVE, optimization of the volemia with fluid loading is mandatory. Tolerance is evaluated after a 5 minutes period of TVE according to the variation of arterial pressure. Decrease of PAM under 30% of the baseline values or systolic arterial pressure less than 80 mmHg are usually considered as a criteria for nontolerance. Instability despite adequate fluid loading before clamping can occur in approximatively 10% of the cases. Causes of this hemodynamic intolerance to TVE include: (A) inadequate fluid loading; (B) hepatic congestion due to persistent inflow and (C) inadequate cardiovascular response. Hypotension related to relative hypovolemia is likely to occur when unexpected need for caval occlusion and absence of anticipation with correct volume infusion before clamping.66,67

Anesthetic Considerations

During major hepatic surgery, intravascular volume expansion is constantly required but the fluid management is critical. Indeed, the critical influence of central venous pressure on blood loss during liver surgery has been recently stressed.

Low Central Venous Pressure Anesthesia

CVP directly influences the occurrence of backward bleeding during liver inflow occlusion. In a retrospective study, Smyrniotis et al showed that Pringle maneuver associated with CVP of 6 mmHg or more is associated with greater blood loss, than maneuver with CVP of 5 or less.68 Thus the concept of low CVP anesthesia for hepatectomy has emerged. Maintaining a low CVP during hepatic transection reduces the distension of hepatic veins and thus significantly decreases bleeding.69 It also avoids vena caval distension and thus facilitates safe dissection of retrohepatic vena cava and major hepatic veins. As the blood loss resulting from a vascular injury is proportional to the pressure gradient across the vessel wall as well as the fourth power of the radius of the injury, lowering the CVP to one-fifth will decrease the blood loss by a factor greater than 5.70 Low central venous pressure during liver transection is consistently associated with reduced blood loss.69-74 Moreover, in retrospective studies, low CVP tended to be associated with lower postoperative morbidity and reduction of hospital stay.68,72 The two potentials drawbacks of low CVP anesthesia are perioperative occurrence of air embolism and consequence of hypovolemia on post operative renal function. During hepatectomy, transoesophagel echocardiography always detects small volumes of air embolism.75 However, the incidence of clinically significant events related to air embolism is not known. Zhou et al found an incidence of 3 cases for 110 liver resections performed with inflow occlusion.76 According to the volume and the rate of air admission in the venous circulation, clinical

Vascular Isolation Techniques in Liver Resection

93

consequences vary from a slight decrease of end-tidal CO2 concentration to sudden pulmonary hypertension leading to cardiac arrest.77 Moreover, systemic paradoxal air embolisms have been described related to intracardiac shunt such as patent foramen ovale or intrapulmonary arterio-venous shunt.78 The risk of postoperative renal failure linked to low PVC anesthesia has been suggested in the setting of liver transplantation.79 During liver resection, the incidence of postoperative renal dysfunction related to intraoperative volemia is not clearly described. Based on retrospective studies, it does not appear that postoperative renal dysfunction increases significantly.70,73,80 Conversely, renal failure requiring extra-renal therapy has been occasionally described in case of hemorrhage in a patient who could not be rapidly brought back to normovolemia.81 Therefore, no specific recommendation can be derived from these studies at the present time.

How to Maintain Low CVP

The anesthesiologist can maintain a low CVP by several methods. Fluid restriction during induction and liver transection is the most commonly used methods. Intravenous fluids are given at a rate of 0.5 to 1 mL/kg/hr until the hepatic resection is completed. The patient is brought back to normovolemia at the end of surgery and hemostasis is ensured. Other methods commonly employed are the use of anaesthetic gases such as isoflurane which has systemic vasodilatory properties with minimal cardiac depression82 and the use of certain drugs with vasodilatory effects. Although, low tidal volume ventilation was considered to reduce the back flow bleeding, there is no evidence that this maneuver reduces the quantity of blood loss during hepatic transection phase.83 The surgeon can decrease the central venous pressure by lateral clamping the infrahepatic inferior vena cava which leads to decrease venous return and has been shown to have no deleterious effect on renal function, even with a clamping time of up to one hour.58 The ideal tool for hemodynamic monitoring under these circumstances remains to be determined. Transoesophageal echocardiography, pulmonary artery catheterization can be used.66 Intraoperative monitoring of fluid responsiveness could also be implemented non-invasively using respiratory variations in arterial pulse pressure ore monitoring of peripheral venous pressure.84,85 In centers with extensive experience, CVP monitoring did not show any significant influence on perioperative.86

Considerations during TVE

Application of vascular isolation techniques mandates a high level of anesthetic expertise. When a major hepatectomy using TVE is planned, anaesthetic management is adjusted to anticipate the reduction in venous return, sudden decrease in cardiac output and increase in afterload. Volume expansion is usually required for patients undergoing TVE. This is achieved by rapid infusion of 500 ml of colloids before the cross clamping of the vena cava. In patients who do not tolerate caval cross-clamping, even after volume expansion, vasopressor agents like dopamine or noradrenaline can be added.86 Persistent hypotension and/or low cardiac index, which can occur in 10-20% of patients should be considered as intolerance to TVE and is an indication of caval declamping or to consider the use of veno-venous bypass or supra celiac aortic clamping.81

Conclusions

Each vascular occlusion technique has a place in major and minor hepatic resectional surgery, based on the tumor location, presence of associated underlying liver disease, patient cardiovascular status and experience of the operating surgeon. Understanding of the potential application of different techniques, anticipation of the expected and potential hemodynamic responses and knowledge of the limitations of each technique are fundamental to appropriate surgical planning adapted to each patient. Experience with the various clamping methods enables an aggressive but safe approach to surgical treatment of hepatobiliary diseases, with acceptable blood loss and transfusion requirements. In all cases, surgical strategy should be defined with the anesthesiologist, particularly in regard to hemodynamic monitoring, in order to optimize perioperative patient management and to minimize the risk for complications such as bleeding and air embolism. Importantly, randomized studies have shown that the dissection, operative and postoperative risks associated with TVE are not balanced by decreased blood loss compared with hepatic

94

Recent Advances in Liver Surgery

pedicle clamping, except in exceptional cases when tumors involve the major hepatic veins or vena cava. In addition, dissection in preparation for clamping may be used as safe approach techniques to tumors in difficult locations, even when eventual clamping is not performed. Similarly, the liver-hanging maneuver enables resection without mobilization, compression and manipulation of large tumors.

References

1. Poon RT, Fan ST, Ng IO et al. Significance of resection margin in hepatectomy for hepatocellular carcinoma: A critical reappraisal. Ann Surg 2000; 231:544-51. 2. Asahara T, Katayama K, Itamoto T et al. Perioperative blood transfusion as a prognostic indicator in patients with hepatocellular carcinoma. World J Surg 1999; 23:676-680. 3. Blumberg N, Heal JM, Murphy P et al. Association between transfusion of whole blood and recurrence of cancer. Br Med J (Clin Res Ed) 1986; 30(293):530-533. 4. Huguet C, Gavelli A, Addario Chieco A et al. Liver ischemia for hepatic resection: where is the limit? Surgery 1992; 111:251–259. 5. Poon RT, Fan ST, Lo CM et al. Extended hepatic resection for hepatocellular carcinoma in patients with cirrhosis: is it justified? Ann Surg 2002; 236:602-611. 6. Belghiti J, Hiramatsu K, Benoist S et al. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 2000; 191:38-46. 7. Man K, Fan ST, Ng IO et al. Prospective evaluation of pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg 1997; 226:704-711. 8. Belghiti J, Noun R, Malafosse R et al. Continuous versus intermittent portal triad clamping for liver resection: a controlled study. Ann Surg 1999; 229:369–375. 9. Clavien PA, Yadav S, Sindram D et al. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg 2000; 232:155-62. 10. Gurusamy KS, Kumar Y, Sharma D et al. Methods of vascular occlusion for elective liver resections. Cochrane Database Syst Rev 2007; 17(4):CD006409. 11. Smyrniotis V, Kostopanagiotou G, Lolis E et al. Effects of hepatoprotective backflow on ischemic-reperfusion injuries in liver resections with the pringle maneuver. J Am Coll Surg 2003; 197:949-954. 12. Moore AF, Hargest R, Martin M et al. Intra-abdominal hypertension and the abdominal compartment syndrome. Br J Surg 2004; 91:1102-1110. 13. Elias D, Detroz B, Lasser P et al. Is simultaneous hepatectomy and intestinal anastomosis safe? Am J Surg 1995; 169:254-260. 14. Miyagawa S, Makuuchi M, Kawasaki S et al. Changes in serum amylase level following hepatic resection in chronic liver disease. Arch Surg 1994; 129:634-638. 15. Miyagawa S, Makuuchi M, Kawasaki S et al. Serum amylase elevation following hepatic resection in patients with chronic liver disease. Am J Surg 1996; 171:235-238. 16. Emre S, Schwartz ME, Katz E et al. Liver resection under total vascular isolation. Variations on a theme. Ann Surg 1993; 217:15-19. 17. Ouaïssi M, Benoist S, Penna C et al. How to manage splenic rupture during major liver resection. Gastroenterol Clin Biol 2006; 30:1311-1312. 18. Delva E, Camus Y, Nordlinger B et al. Vascular occlusions for liver resections: operative management and tolerance to hepatic ischemia: 142 cases. Ann Surg 1989; 209:211-218. 19. Hannoun L, Borie D, Delva E et al. Liver resection with normothermic ischaemia exceeding 1 h. Br J Surg 1993; 80:1161–1165. 20. Midorikawa Y, Kubota K, Takayama T et al. A comparative study of postoperative complications after hepatectomy in patients with and without chronic liver disease. Surgery 1999; 126:484-491. 21. Kim YI, Song KE, Ryeon HK et al. Enhanced inflammatory cytokine production at ischemia/reperfusion in human liver resection. Hepatogastroenterology 2002; 49:1077-1082. 22. Kim YI. Ischemia-reperfusion injury of the human liver during hepatic resection. J Hepatobiliary Pancreat Surg 2003; 10:195-199. 23. Imamura H, Seyama Y, Kokudo N et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg 2003; 138:1198-1206. 24. Hardy KJ, Tancheroen S, Shulkes A. Comparison of continuous versus intermittent ischaemia-reperfusion during liver resection in an experimental model. Br J Surg 1995; 82:833-836. 25. Takayama T, Makuuchi M, Inoue K et al. Selective and unselective clamping in cirrhotic liver. Hepatogastroenterology 1998; 45:376-380.

Vascular Isolation Techniques in Liver Resection

95

26. Brooks AJ, Hammond JS, Girling K et al. The effect of hepatic vascular inflow occlusion on liver tissue pH, carbon dioxide and oxygen partial pressures: defining the optimal clamp/release regime for intermittent portal clamping. J Surg Res 2007; 141:247-251. 27. Esaki M, Sano T, Shimada K et al. Randomized clinical trial of hepatectomy using intermittent pedicle occlusion with ischaemic intervals of 15 versus 30 minutes. Br J Surg 2006; 93:944-951. 28. Capussotti L, Nuzzo G, Polastri R et al. Continuous versus intermittent portal triad clamping during hepatectomy in cirrhosis: results of a prospective, randomized clinical trial. Hepatogastroenterology 2003; 50:1073-1077. 29. Sakamoto Y, Makuuchi M, Takayama T et al. Pringle’s maneuver lasting 322 min. Hepatogastroenterology 1999; 46:457-458. 30. Wu CC, Hwang CR, Liu TJ et al. Effects and limitations of prolonged intermittent ischaemia for hepatic resection of the cirrhotic liver. Br J Surg 1996; 83:121-124. 31. Chang S, Laurent A, Tayar C et al. Laparoscopy as a routine approach for left lateral sectionectomy. Br J Surg 2007; 94:58-63. 32. Imamura H, Takayama T, Sugawara Y et al. Pringle’s manoeuvre in living donors. Lancet 2002; 360:2049-2050. 33. Imamura H, Kokudo N, Sugawara Y et al. Pringle’s maneuver and selective inflow occlusion in living donor liver hepatectomy. Liver Transpl 2004; 10:771-778. 34. Hardy KJ, McClure DN, Subwongcharoen S. Ischaemic preconditioning of the liver: a preliminary study. Aust N Z J Surg 1996; 66:707-710. 35. Zhao H. The protective effect of ischemic postconditioning against ischemic injury: from the heart to the brain. J Neuroimmune Pharmacol 2007; 2:313-318. 36. Clavien PA, Selzner M, Rüdiger HA et al. A prospective study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg 2003; 238:843-852. 37. Azoulay D, Lucidi V, Andreani P et al. Ischemic preconditioning for major liver resection under vascular exclusion of the liver preserving the caval flow: a randomized prospective study. J Am Coll Surg 2006; 202:203-211. 38. Smyrniotis V, Theodoraki K, Arkadopoulos N et al. Ischemic preconditioning versus intermittent vascular occlusion in liver resections performed under selective vascular exclusion: a prospective randomized study. Am J Surg 2006; 192:669-674. 39. Kim YI, Kobayashi M, Nakashima K et al. In situ and surface liver cooling with prolonged inflow occlusion during hepatectomy in patients with chronic liver disease. Arch Surg 1994; 129:620-624. 40. Kim YI, Hwang YJ, Lee JW et al. 101 hepatectomies under continuous inflow occlusion following simple in-situ liver cooling in patients with chronic liver diseases. Hepatogastroenterology 2004; 51:1093-1098. 41. Yamanaka N, Dai CL, Okamoto E. Historical evolution of hypothermic liver surgery. World J Surg 1998; 22:1104-1107. 42. Imakita M, Yamanaka N, Kuroda N et al. Does topical cooling alleviate ischemia/reperfusion injury during inflow occlusion in hepatectomy? Results of an experimental and clinical study. Surg Today 2000; 30:795-804. 43. Launois B, Jamieson GG. The posterior intrahepatic approach for hepatectomy or removal of segments of the liver. Surg Gynecol Obstet 1992; 174:155-158. 44. Shimamura Y, Gunvén P, Takenaka Y et al. Selective portal branch occlusion by balloon catheter during liver resection. Surgery 1986; 100:938-941. 45. Castaing D, Garden OJ, Bismuth H. Segmental liver resection using ultrasound-guided selective portal venous occlusion. Ann Surg 1989; 210:20-23. 46. Makuuchi M, Mori T, Gunvén P et al. Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet 1987; 164:155-158. 47. Figueras J, Llado L, Ruiz D et al. Complete versus selective portal triad clamping for minor liver resections: a prospective randomized trial. Ann Surg 2005; 241:582-590. 48. Launois B, Jamieson GG. The importance of Glisson’s capsule and its sheaths in the intrahepatic approach to resection of the liver. Surg Gynecol Obstet 1992; 174:7-10. 49. Stephen MS, Gallagher PJ, Ross Sheil AG et al. Hepatic resection with vascular isolation and routine supraceliac aortic clamping. Am J Surg 1996; 171:351-355. 50. Belghiti J, Noun R, Zante E et al. Portal triad clamping or hepatic vascular exclusion for major liver resection: a controlled study. Ann Surg 1996; 224:155-161. 51. Chen XP, Zhang ZW, Zhang BX et al. Modified technique of hepatic vascular exclusion: effect on blood loss during complex mesohepatectomy in hepatocellular carcinoma patients with cirrhosis. Langenbecks Arch Surg 2006; 391:209-215. 52. Elias D, Lasser P, Debaene B et al. Intermittent vascular exclusion of the liver (without vena cava clamping) during major hepatectomy. Br J Surg 1995; 82:1535-1539.

96

Recent Advances in Liver Surgery

53. Cherqui D, Malassagne B, Colau PI et al. Hepatic vascular exclusion with preservation of the caval flow for liver resections. Ann Surg 1999; 230:24-30. 54. Belghiti J, Guevara OA, Noun R et al. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 2001; 193:109-111. 55. Majno PE, Mentha G, Morel P et al. Arantius’ ligament approach to the left hepatic vein and to the common trunk. J Am Coll Surg 2002; 195:737-739. 56. Fortner JG, Shiu MH, Kinne DW et al. Major hepatic resection using vascular isolation and hypothermic perfusion. Ann Surg 1974; 180:644-652. 57. Azoulay D, Eshkenazy R, Andreani P et al. In situ hypothermic perfusion of the liver versus standard total vascular exclusion for complex liver resection. Ann Surg 2005; 241:277-285. 58. Otsubo T, Takasaki K, Yamamoto M et al. Bleeding during hepatectomy can be reduced by clamping the inferior vena cava below the liver. Surgery 2004; 135:67-73. 59. Abdalla EK, Noun R, Belghiti J. Hepatic vascular occlusion: which technique? Surg Clin North Am 2004; 84:563-585. 60. Varma D, Ogata S, Belghiti J. Isolated total caval clamping with “preserved remnant liver perfusion” for combined hepatic and venacaval resection in tumors involving venacava. Surgery 2007; 141:112-116. 61. Scatton O, Massault PP, Dousset B et al. Major liver resection without clamping: a prospective reappraisal in the era of modern surgical tools. J Am Coll Surg 2004; 199:702-708. 62. Capussotti L, Muratore A, Ferrero A et al. Randomized clinical trial of liver resection with and without hepatic pedicle clamping. Br J Surg 2006; 93:685-689. 63. Delva E, Camus Y, Paugam C et al. Hemodynamic effects of portal triad clamping in humans. Anesth Analg 1987; 66:864-868. 64. Delva E, Barberousse JP, Nordlinger B et al. Hemodynamic and biochemical monitoring during major liver resection with use of hepatic vascular exclusion. Surgery 1984; 95:309-318. 65. Decailliot F, Cherqui D, Leroux B et al. Effects of portal triad clamping on haemodynamic conditions during laparoscopic liver resection. Br J Anaesth 2001; 87:493-496. 66. Eyraud D, Richard O, Borie DC et al. Hemodynamic and hormonal responses to the sudden interruption of caval flow: insights from a prospective study of hepatic vascular exclusion during major liver resections. Anesth Analg 2002; 95:1173-1178. 67. Delva E, Huguet C, Camus Y et al. Hemodynamic effects of suprahepatic inferior vena cava clamping with hepatic vascular exclusion. Anesthesiology 1986; 65:A409. 68. Smyrniotis V, Kostopanagiotou G, Theodoraki K et al. The role of central venous pressure and type of vascular control in blood loss during major liver resections Am J Surg 2004; 187:398-402. 69. Jones RMcL, Moulton CE, Hardy KJ. Central venous pressure and its effect on blood loss during liver resection. Br J Surg 1998; 85:1058-1060. 70. Melendez JA, Arslan V, Fischer ME et al. Perioperative outcomes of major hepatic resections under low central venous pressure anaesthesia: blood loss, blood transfusion and the risk of preoperative renal dysfunction. J Am Coll Surg 1998; 187:620-625. 71. Cunningham JD, Fong Y, Shriver C et al. Our hundred consecutive hepatic resections: blood loss, transfusion and operative technique. Arch Surg 1994; 129:1050-1056. 72. Chen H, Merchant NB, Didolkar MS. Hepatic resection using intermittent vascular inflow occlusion and low central venous pressure anesthesia improves morbidity and mortality. J Gastrointest Surg 2000; 4:162-167. 73. Wang WD, Liang LJ, Huang XQ et al. Low central venous pressure reduces blood loss in hepatectomy. World J Gastroenterol 2006; 12:935-939. 74. Eid EA, Sheta SA, Mansour E. Low central venous pressure anesthesia in major hepatetic resection. Middle East J Anesthesiol 2005; 18:367-377. 75. Schmandra TC, Mierdl S, Bauer H et al. Transoesophageal echocardiography shows high risks of gas embolism during laparoscopic hepatic resection under carbon dioxide pneumoperitoneum. Br J Surg 2002; 89:870-876. 76. Zhou W, Li A, Pan Z et al. Selective hepatic vascular exclusion and Pringle maneuver: a comparative study in liver resection. Eur J Surg Oncol 2008; 34:49-54. 77. Adachi UY, Doi M, Sato S. Cardiac arrest by venous air embolism during hepatic resection using the Cavitron Ultrasonic Surgical Aspirator. Anesth Analg 2006; 103:493-494. 78. Lee SY, Choi BI, Kim JS et al. Paradoxical air embolism during hepatic resection. BR J Anaesth 2002; 88:136-138. 79. Schroeder RA, Collins BH, Tuttle-Newhall E et al. Intraoperative fluid management during orthotopic liver transplantation. J Cardiothor Vasc Anesth 2004; 18:438-441. 80. Moug SF, Smith D, Leen E et al. Selective continuous vascular occlusion and perioperative fluid restriction in partial hepatectomy. Outcomes in 101 consecutive patients. Eur J surg Oncol 2007; 33:1036-1041.

Vascular Isolation Techniques in Liver Resection

97

81. Redai I, Emond J, Brentjens T. Anesthetic considerations during liver surgery. Surg Clin North Am 2004; 84:401-411. 82. Gatecel C, Losser MR, Payen D. The postoperative effects of halothane versus isoflurane on hepatic artery and portal veine blood flow in humans. Anesth Analg 2003; 96:740-745. 83. Hasegawa K, Takayama T, Orii R et al. Effect of hypoventilation on bleeding during hepatic resection: a randomized controlled trial. Arch Surg 2002; 137:311-315. 84. Solus-Biguenet H, Fleyfel M, Tavernier B et al. Non invasive prediction of fluid responsiveness during major hepatic surgery. Br J Anaesth 2006; 97:808-816. 85. Choi SJ, Gwak MS, Ko JS et al. Can peripheral venous pressure be an alternative to central venous pressure during right hepatectomy in living donors? Liver Transpl 2007; 13:1414-1421. 86. Niemann CU, Feiner J, Behrends M et al. Central venous pressure monitoring during living right donor hepatectomy. Liver Transpl 2007; 13:266-271.

Chapter 8

Preoperative Portal Vein Embolization for Hepatocellular Carcinoma Taku Aoki, Hiroshi Imamura, Takuya Hashimoto, Norihiro Kokudo and Masatoshi Makuuchi*

Abstract

P

reoperative portal vein embolization (PVE) has been introduced to increase the safety of major hepatic resection for hepatocellular carcinoma (HCC). PVE induces atrophy of the embolized portion of the liver to be resected with compensatory hypertrophy of the preserved liver remnant, even in chronically diseased liver. In addition, PVE induces an abrupt increase in portal flow/pressure in the nonembolized liver segments, leading to an improved patient tolerance to these changes after major hepatic resection. Transcatheter arterial chemoembolization (TACE) is a feasible preparation prior to PVE for HCC patients because it would strengthen the effect of PVE by stopping arterio-portal shunts arising from HCC as well as preventing migration of the embolic material to the feature remnant part of the liver and stopping any tumor progression during the waiting period. PVE can widen the indications for liver resection for HCC patients who are otherwise poor candidates for hepatectomy because of inadequate estimated liver size and function and favorable long-term results after hepatic resections have been reported.

Introduction

Although recent advances in surgical techniques and perioperative care have significantly improved both short- and long-term outcomes after hepatic resections,1-3 liver failure is still a major concern after a major hepatic resection (the resection of three or more Couinaud segments4). Both the small size of the remnant liver parenchyma and sinusoidal injury following an abrupt increase in portal venous flow/pressure have been supposed to induce postoperative liver failure after an extensive hepatic resection.5 This concern is even more relevant in patients with obstructive jaundice or underlying liver disease. Preoperative portal vein embolization (PVE) has been introduced in an attempt to extend the indications for major hepatic resections and to increase the safety of this procedure. First reported by Makuuchi et al6,7 the aim of PVE is to induce the atrophy of the segments to be resected and encourage a compensatory hypertrophy of the nonembolized future liver remnant (FLR).8 This technique was first applied to patients with hilar bile duct tumors (Klatskin tumors)6-9 and its indication were subsequently extended to patients with metastatic liver tumors10-12

Preoperative PVE for HCC

Currently, hepatic resection is considered to be the only curative treatment for large hepatocellular carcinoma (HCC), since liver transplantation or ablative therapy is not indicated for most of these tumors. In the patients with large HCC, a major hepatic resection is often required for *Corresponding Author: Masatoshi Makuuchi—Department of Surgery, Japanese Red Cross Medical Center, 4-1-22 Hiro-o, Shibuya-ku, Tokyo 150-8935, Japan. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Preoperative Portal Vein Embolization for Hepatocellular Carcinoma

99

curative resection. Likewise, since HCC frequently metastasizes via the portal venous system, segment-oriented anatomic hepatic resection including a right or left hemihepatectomy, is recommended to obtain better long term results.13-16 However, most patients with HCC have impaired hepatic functional reserves because of hepatitis B or C virus—associated liver cirrhosis. Consequently, the amount of liver parenchyma that can be safely resected in these patients is extremely limited. This dilemma limits the number of HCC patients who can benefit from hepatic resections and results in a low resectability rate.17,18 To overcome this dilemma, preoperative PVE has been applied to HCC patients as the treatment of choice when the scheduled FLR is small. Major hepatectomy produces a volume reduction of the liver and an abrupt increase in the portal venous pressure immediately after the operation. Preoperative PVE induces a rapid increase in the portal venous flow while preserving the liver volume, causing an early change in portal hemodynamics similar to that observed after a major hepatic resection. Accordingly, PVE may improve the patient’s tolerance of major resections, leading to the safety of hepatic resection. On the other hand, the indications for PVE in patients with HCC continue to be debated for the following reasons: (1) the livers of most HCC patients are compromised by an underlying liver disease and the capacity for liver regeneration after PVE may be impaired under such conditions,19-21 making it difficult to predict whether sufficient hypertrophy of the future remnant liver segments can be achieved after PVE; (2) because most HCCs are hypervascular tumors fed mainly by arterial blood flow, cessation of the portal flow induces a compensatory increase in arterial blood flow in the embolized segments,22 resulting in the rapid progression of the tumors after PVE; and (3) arterio-portal shunts are frequently found in cirrhotic liver and HCC and these shunts may attenuate the effects of PVE and even increase the risk of the embolic material spreading to the FLR.

Sequential TACE and PVE

Since the mid-1980s, we have combined selective transcatheter arterial chemoembolization (TACE) prior to PVE before performing a major hepatic resection in HCC patients.23,24 These two preparatory steps aim to (1) utilize TAE to prevent tumor progression during the period between PVE and the planned hepatectomy, in view of the fact that most HCCs are hypervasular tumors fed exclusively by arterial blood flow; and (2) enhance the effect of PVE by first embolizing possible arterio-portal shunts, which are frequently found in cirrhotic liver and HCC. This double preparation has also been advocated by other groups.25-27 The interval between TACE and PVE varies from one week 24 to six weeks.25,27 In patients with impaired liver function, much time is required to obtain a sufficient FLR volume after PVE, often requiring six weeks to several months. In our series, we evaluated tumor progression during the period when the TACE, PVE and hepatic resection procedures were successively performed; tumor progression was evaluated according to the tumor volume, the serum alpha-fetoprotein level and the plasma des-γ-carboxy prothrombin level (Fig. 1).24 The tumor volume tended to decrease after PVE, though the difference did not reach significance. The serum AFP levels between the TACE and PVE procedures and between the PVE and hepatectomy procedures were significantly lower than the AFP levels before TACE (P = 0.001 and 0.003, respectively). The plasma DCP level between the TACE and PVE procedures decreased significantly (P = 0.002), while the DCP level between the PVE and the hepatectomy procedures showed a decrease of borderline significance (P = 0.02). Two previous reports have confirmed that, compared with PVE alone, the combination of PVE with TACE resulted in superior FLR hypertrophy.27,28

Indications for Preoperative PVE in Patients with HCC

The general indications for PVE are based on the size of the FLR, the expected function of the remnant liver segments and the extent or complexity of the procedure. However, few data exist regarding the hepatic mass or volume required to support life and to prevent complications. The general consensus is that, for normal livers, 25% of the total hepatic volume needs to be preserved to ensure a safe resection.29-31 A larger remnant volume is required to avoid posthepatectomy

100 Recent Advances in Liver Surgery

Figure 1. Changes in tumor volume (A) before TACE and PVE and before hepatectomy and changes in the serum alpha-fetoprotein (AFP) level (B) and the plasma des-γ-carboxy prothrombin (DCP) level (C) before TACE, before PVE (after TACE) and before hepatectomy (after PVE). Data are expressed as the mean ± SEM and the levels of AFP and DCP were compared after logarithmic transformation (reproduced from ref. 24 with permission. Copyright ©2004, American Medical Association. All Rights reserved.). ∗P = 0.001, ∗∗P = 0.003, ∗∗∗P = 0.002.

Preoperative Portal Vein Embolization for Hepatocellular Carcinoma

101

insufficiency or failure in patients with compromised liver function. Recent studies suggest that 40% of the total hepatic volume should be preserved in patients whose liver function has been compromised by underlying chronic liver disease12,23,24 or high-dose chemotherapy 32 to minimize complications. We advocate PVE for (1) patients with a normal liver, i.e., an indocyanine green retention rate at 15 minutes (ICG R15) ≤ 10%, if the FLR volume/total liver volume (TLV) is < 40%; and (2) patients with an injured liver, i.e., 10% < ICG R15 ≤ 20%, if the FLR volume/TLV is < 50%. If the ICG R15 exceeds 20%, a major hepatectomy is contraindicated even after PVE (Fig. 2).23 In our series, preoperative PVE was mainly scheduled when (1) a large tumor was present in the right liver, (2) multiple tumors were present in the right liver, (3) the tumor was close to the bifurcation of the right portal vein and (4) macroscopic vascular invasion (not tumor thrombus) to the first-ordered branches of the portal vein or bile duct was observed. Accordingly, although the indications for preoperative TACE and PVE are determined by the imbalance between the volumetric ratio of the FLR and the hepatic functional reserve, preoperative TACE and PVE are often indicated for advanced HCC.24

Technique of PVE Approach

Two major techniques have emerged to access the portal vein: direct catheterization of the ileocolic vein6, 7, 33 and the percutaneous approach.6, 7, 34 The former involves an open technique in which the ileocolic vein is cannulated at laparotomy. This method allows the extent of the tumor, including peritoneal dissemination and hilar lymph node metastases, to be evaluated at the time of PVE.12 The catheterization of all portal branches is simple, even in cases with anatomical variations and can be applied when the transhepatic approach is difficult because of the location of the tumor. However, an open laparotomy under general anesthesia is required, with the attendant risks of these procedures; thus this technique is not recommended in cases with a history of prior lower abdominal surgery. Bowel obstruction has been reported to occur.12 The transhepatic procedure can be performed under local anesthesia with or without intravenous sedatives. The contralateral approach (access through the FLR) is technically easier than the ipsilateral approach (access through

Figure 2. Algorithm of PVE for HCC patients.

102

Recent Advances in Liver Surgery

the portion of the liver to be resected), especially in the presence of anatomical variations.9,11 The shortcoming of this method is that the portal vein in the FRL is punctured. Iatrogenic lesions of the FLR, including hematoma, portal vein wall dissection and portal vein thrombosis, were described in a multicenter review.35,36 The ipsilateral approach was proposed as a means of possibly avoiding FLR injury.37 Embolization materials can be placed along the puncture line at the completion of the procedure to prevent postPVE hemorrhage. This approach is theoretically superior to the contralateral procedure in terms of safety but is technically demanding, particularly when a severe angulation exists between the right portal branches. The rate of recanalization is higher than with the contralateral approach and an appropriate puncture line sometimes can not be secured because of the location of the liver tumor. Furthermore, postPVE portography or portal pressure measurements to confirm the efficacy of embolization can not be performed after this procedure.36 Figure 3A-3E demonstrates each step of TACE and right liver PVE via an ipsilateral transhepatic approach. About 1 week after the TACE, the portal branch of the right lateral sector (P6) was punctured under ultrasonic and fluoroscopic guidance and a balloon occlusion catheter was advanced through an introducer under fluoroscopic control. At first, the tip of the catheter was placed in the main portal trunk and a direct portography was obtained. In addition, the portal venous pressure before PVE was measured. Then the catheter was advanced to the right paramedian sector branches and these branches were embolized from the distal portion using gelatin sponge and thrombin. These products were mixed with contrast material. Then, the right paramedian portal branch was bunged using metallic coils. Next, the catheter was pulled back into the right lateral sector branches and these branches were also embolized in their proximal portion using balloon occlusion. Particular attention was paid to whether or not the second-order branches originated independently or close to, the main portal trunk.36 A right anterolateral view using fluoroscopy was recommended during the embolization of the branches to the right lateral sector (segments 6 and 7). The success of this technique is nearly 100%. Rare technical failures are usually associated with difficulty during catheterization as a result of severe angulations between the portal branches and the migration of embolization materials to the FLR. The use of a balloon-tipped catheter is advocated to avoid the latter complication.36

Embolization Materials

Various substances have been used for embolization and there has been no general consensus regarding the ideal embolization material to be used for PVE (Table 1). The substances can be roughly divided into biomaterials and synthetic materials. Biomaterials include gelatin sponge particles with thrombin12,38 and fibrin glue (a combination of fibrinogen and thrombin).37 Synthetic materials include synthetic glue (n-butyl-2-cyanoacrylate),11 synthetic embolization particles (polyvinyl alcohol),43 coils, iodized oil, absolute ethanol39 and liquid embolic material (EMBOl-78).42 Biomaterials are absorbable and thus allow recanalization, a theoretical drawback associated with these substances. Conversely, unwanted outcomes induced by the migration of embolization materials into portal branches of the FLR are minimal or absent.12 N-butyl-2-cyanoacrylate has a permanent embolizing effect and has been used to obliterate the gastric coronary vein and esophageal varices.44 As it immediately polymerizes upon contact with blood, this agent can not be used for ipsilateral transhepatic procedures because it would be impossible to remove the catheter. Despite a long-lasting embolization effect, accompanying inflammatory reaction and fibrosis of the perivascular connective tissue and portal vein casting may lead to difficulties during hilar dissection or discriminating tumor invasion.11,45 Polyvinyl alcohol particles have a smaller diameter (150-100 um) than gelatin sponge (500-100 um). This material has been selected because of its safety, minimal periportal reaction and its enduring embolization effect when used in combination with coils.45 Coils and iodized oil are usually used in combination with these materials. In particular, iodized oil produces a long-lasting “portal cast” that can be viewed on follow up CT scans. All of these agents reportedly yield a similar extent of hypertrophy in the FLR, 2-4 weeks after PVE (Table 1). PVE with absolute ethanol may be particular useful in the treatment of hepatocellular carcinoma, although a greater alteration in measured liver function occurs following embolization with alcohol, compared with other substances.46,47 Alcohol also leads to significant

Author

Year

Makuuchi et al38

1991

No. HCC Patients

TACE Prio to PVE Embolization Material

Interval between PVE Volume Increment and Hepatectomy (Weeks) of FRL (%)

32

-

Gelatin sponge

2-3

14.1

Shimamura et al39 1997

7

7/7

Absolute ethanol

4

27

Imamura et al12

1999

10

10/10

Gelatin sponge and thrombin

2

-

Azoulay et al

2000

10

9/10

Cyanoacrylate and iodinized oil

9

16

Tanaka et al40

2000

33

-

Fibrin glue and iodinozed oil

2

12

26

28

Sugawara et al

2002

66

47/66

Gelatin sponge

2-3

13

Wakabayashi et al41

2002

26

-

Gelatin sponge

3

9

Hemming et al31

2003

15

0/15

Polyvinyl alcohol particle and coil

4-6

8.4

Aoki et al

2004

17

17/17

Gelatin sponge and thrombin

2

11

Ogata et al27

2006

18

18/18

Cyanoacrylate and iodinized oil

4-8 (mean 5.3)

12 ± 5

18

0/18

Cyanoacrylate and iodinized oil

4-8 (mean 5.7)

Seo et al42

2007

32

17/32

Liquid embolic material (Embol-78) 2-10 (median 3)

23

Preoperative Portal Vein Embolization for Hepatocellular Carcinoma

Table 1. Preoperative PVE for HCC

8±4 9.3

103

104 Recent Advances in Liver Surgery

Figure 3. Each step in TACE and right liver PVE via the ipsilateral transhepatic approach. A) TACE is performed for an HCC located in Segments 7 and 8 of the right liver. B) The portal branch of Segment 6 is punctured and a portography is obtained. Lipiodol accumulation in the tumor is visualized. C) The right paramedian sector branches (P5 and P8) are embolized with gelatin sponge, thrombin and coils. D) Next, the right lateral sector branches (P6 and P7) are embolized. E) Fluoroscopy after the completion of PVE.

Preoperative Portal Vein Embolization for Hepatocellular Carcinoma

105

periportal necrosis and fibrosis, but recanalization is rare47 and hypertrophy may be greatest with this substance.39

Portal Venous Pressure after PVE

The total portal venous flow volume is thought remain unchanged before and after PVE because the liver does not have an intrinsic ability to modulate portal flow, which is a function of extrahepatic and systemic factors. Consequently, the same volume of portal venous flow as that prior to PVE enters the nonembolized liver segments after PVE, with the result that portal venous pressure in the nonembolized liver is elevated immediately after PVE. A similar increase was observed in cirrhotic patients, who have a higher baseline portal pressure.24 We believe that this phenomenon may increase the tolerance of the patients to high portal venous flow/pressure after extensive hepatic resection, resulting in an attenuation of liver damage after the subsequent hepatectomy. The elevation of portal pressure is thought to be transient, with pressure gradually returning to the baseline value in 2-3 weeks, as indicated by changes in a surrogate index (portal flow velocity) measured using Doppler ultrasound.48

Clinical Course after PVE

Postembolization syndrome, including pain, fever, nausea and vomiting, are usually minimal after PVE. Most patients experience a mild fever following PVE, which subsides within 2-3 days. Likewise, changes in liver function -as reflected by an increased total bilirubin value and prolonged prothrombin time- are mild and transient, returning to their baseline values 2-3 days after PVE. The serum AST and ALT values are stable in around 50% of patients and are mildly elevated on day 1, returning to baseline values in 4-7 days after PVE.12 In contrast, a marked elevation of liver enzymes are observed when absolute ethanol is used for embolization39 and when sequential TACE and PVE is carried out.24,27 In our series, these elevations emerged within 3 days after PVE following TACE but returned to their baseline values by two weeks before the scheduled hepatectomy (Fig. 4). Reported complications of PVE are few (0-10%) and include the need for re-embolization, transient hemobilia and small bowel obstruction.45 No major complication have been reported. After PVE using biomaterials and metallic coils, Doppler ultrasound is carried out every 3-4 days. When recanalization of the portal branches are found with ultrasound, the relavant portal branches are punctured percutaneously and absolute ethanol is injected slowly until the blood flow is stopped.

Volumetric Changes after PVE

A CT scan with contrast enhancement is the most commonly used method of calculating noncancerous total liver and FLR volumes.49 The ratio of “FLR volume/TLV-tumor volume” (the FLR volume/TLV ratio) is a widely used parameter to determine the need for preoperative PVE and to evaluate the degree of FLR hypertrophy. PVE induces significant hypertrophy of the nonembolized liver and atrophy of the embolized portion of the liver, even in HCC patients with chronically diseased liver. It has been reported that the FLR volume/TLV ratio increased 8-27% after a waiting period of 2-9 weeks after PVE (Table 1). The hypertrophy ratio of the FLR has been reported to be around 20% and this figure is less than that of a normal liver (approximately 30%).8,12 Other factors, such as diabetes, obstructive jaundice, the baseline FLR volume before PVE and embolization materials have been reported to affect hypertrophy/atrophy. Absolute alcohol was reported to achieve the highest degree of regeneration with marked increases in AST and ALT levels, secondary to liver necrosis. The interval between PVE and hepatic resection differs among previous reports. In our series, the interval was 2 weeks,24 which is shorter than that reported in Western series.26,27,31 In an earlier Western series, hepatic resections were attempted once complete hypertrophy of the nonembolized liver had been obtained or once the time-liver volume curve of the nonembolized segments had reached a plateau. As described above, preoperative PVE improves the patient’s tolerance to major resections as a

106

Recent Advances in Liver Surgery

Figure 4. Time courses of changes in aspartate transaminase (AST; A), alanine transaminase (ALT; B) and total bilirubin (T.B.; C) values after sequential TACE and PVE. Data are expressed as the mean ± SEM. AST and ALT values increased within 3 days after TACE (AST: P < 0.0001; ALT: P = 0.004) and returned to their baseline value after 1 week. After PVE, the values increased again within 3 postoperative days and returned to their prePVE values within 2 weeks. The T.B. value showed a significant change soon after TACE but returned to within the normal range after 1 week; the T.B. value remained stable after the PVE (reproduced from ref. 24 with permission. Copyright©2004, American Medical Association. All Rights reserved.).

Preoperative Portal Vein Embolization for Hepatocellular Carcinoma

107

form of preconditioning: as a result, major hepatic resections can be safely performed after a relatively short waiting period, when the nonembolized liver segments are not yet fully hypertrophied.

Histological Changes after PVE

Harada et al have reported histological changes after PVE.50 In the nonembolized part, many hepatocytes had basophilic cytoplasm. There were numerous small or binuclear hepatocytes, i.e., proliferative hepatocytes and mitotic figures were found occasionally, but apoptotic hepatocytes were rare. In the embolized part, hepatocyte atrophy was observed and the sinusoidal areas appeared to be increased, especially in the pericentral field; this observation can be explained as a consequence of hepatocyte deletion. The cytoplasm was more eosinophilic than normal, but the hepatocytes still had clear cell lines showing no inflammatory responses or necrotic changes. Apoptotic cells were detected, predominantly in the perivenular area. Based on these findings, they concluded that PVE induces hepatocyte apoptosis and hepatocyte deletion, leading to the atrophy of the embolized part; the cells in the nonembolized part enter a highly active phase of proliferation within two weeks after PVE. The theoretical drawback of sequential TACE and PVE is the risk of liver parenchyma necrosis induced by the double occlusion of the blood supply. However, an interval of one week between the TACE and PVE is supposed to reduce the risk and we have confirmed that although the tumor necrosis was extensive after sequential TACE and PVE, the extent of the necrosis of the noncancerous liver parenchyma was minimal.23

Effect of PVE on Hepatic Functional Reserve

Cellular hyperplasia and the resulting partial hypertrophy do not necessarily signify functional gain in the corresponding part of the liver.36 Various methods, including the clearance of antipyrine,51 concentrations of adenine nucleotides and hepatic energy charge levels52 and technetium -99m-galactosyl human serum albumin (99mTc-GSA) scintigraphy,53,54 were used to evaluate the function of the whole liver and/or nonembolized liver segments. All these studies demonstrated that the volume increase in the nonembolized part was accompanied by a parallel increment in liver function in the corresponding part. We have evaluated the hepatic functional reserve using ICG R15 values before and after sequential preoperative TACE and PVE. In most cases, the ICG R15 values were comparable to those obtained at baseline; in some cases, however, hepatic resection was abandoned or a smaller extent of hepatic resection was performed because of a deterioration in the hepatic functional reserve. In such cases, the baseline portal venous pressure was usually high, suggesting that severe cirrhosis was present.24

Results of Hepatic Resections following PVE

The main aim of preoperative PVE is to extend the indications for hepatic resection and to avoid postoperative liver failure in those patients in whom resection would otherwise be borderline indicated without PVE.23,55 Previous reports have documented that over 90% of the patients who underwent preoperative PVE went on to receive hepatic resections.24,26-28,40,42 The reported mortality and morbidity rates ranged from 0 to 11% and 19 to 45%, respectively; these figures are comparable to those obtained after major hepatic resection without preoperative PVE (Table 2). Recently, the long-term results after major hepatic resections following PVE have been documented. The 5-year disease-free and overall survival rates ranged from 19 to 46.7% and 31 to 71.9%, respectively. Whether preoperative PVE itself can improve the surgical outcome is controversial. Although the number of patients is limited, three retrospective studies have compared the surgical results after a right hepatectomy with or without preoperative PVE. One report documented a favorable overall survival rate after a right hepatectomy following PVE, compared with that without PVE;40 the other two reports did not find any differences.26,56 It is unethical to conduct a randomized controlled trial to evaluate the effect of PVE on patient survival, because in marginally indicated HCC patients, postoperative liver failure is thought to be highly possible if they do not undergo preoperative PVE. Anyway, from the point of view that PVE extends the operability and

108

Table 2. Outcome after hepatectomy following PVE for HCC Disease-Free Survival Rate (%)

Overall Survival Rate (%)

No. of Patients Undergoing PVE

2000

10

9

0

45

Tanaka et al

2000

-

33

3

-

38

35

55

50

Sugawara et al28

2002

66

61

0

-

44.1

37.9

81.2

58.9

Aoki et al

2004

17

16

0

25

46.7

46.7

55.6

55.6

Ogata et al27

2006

18(TACE +)

18

11

39

37

37

54

43

18(TACE –)

18

11

55

19

19

31

31

Seo et al42

2007

32

32

0

19

40

37.2

71.9

71.9

Author Azoulay et al26 40

23

Mortality (%)

Morbidity (%)

3-year

5-year

3-year

5-year

64

21

67

44

Recent Advances in Liver Surgery

Year

No. of Patients Undergoing Hepatectomy

Preoperative Portal Vein Embolization for Hepatocellular Carcinoma

109

safety of hepatic resections for HCC patients, PVE likely does improve the long-term prognosis of advanced HCC patients. Sequential TACE and PVE may improve the surgical results after hepatectomy. Ogata et al compared patients who underwent sequential TACE and PVE with those who underwent PVE alone.27 The short-term results, including morbidity and mortality, of these two groups were comparable; however, the disease-free survival rate of the patients undergoing sequential TACE and PVE was significantly higher than that of patients treated with PVE alone. They concluded that this double preparation could achieve a higher complete necrosis rate of the tumor and a longer recurrence free survival. The difference in overall survival did not reach a significant level, but the difference was 12% between these two groups.

Conclusions

PVE induces the atrophy of the embolized liver to be resected with a compensatory hypertrophy of the contralateral part of the liver to be preserved, even in HCC patients with chronic liver disease. Double preparations using sequential TACE and PVE can strengthen the atrophy-hypertrophy process. PVE is thought to widen the indications for liver resection for HCC patients who would otherwise be poor candidates for hepatectomy. The accumulation of further patients undergoing preoperative PVE and subsequent major hepatic resection would clarify the long-term benefits obtained by PVE.

References

1. Fan ST, Lo CM, Liu CL et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg 1999; 229:322-330. 2. Grazi GL, Ercolani G, Pierangeli F et al. Improved results of liver resection for hepatocellular carcinoma on cirrhosis give the procedure added value. Ann Surg 2001; 234:71-78. 3. Imamura H, Seyama Y, Kokudo N et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg 2003; 138:1198-1206. 4. Couinaud C. Le Foie, Etude Anatomiques et Chirurgicales. Paris: Masson; 1957. 5. Panis Y, McMullan DM, Emond JC. Progressive necrosis after hepatectomy and the pathophysiology of liver failure after massive resection. Surgery 1997; 121:142-149. 6. Makuuchi M, Takayasu K, Takuma T et al. Preoperative transcatheter embolization of the portal venous branch for patients receiving extended lobectomy due to the bile duct carcinoma. J Jpn Soc Clin Surg 1984; 45:14-20. 7. Makuuchi M, Thai BL, Takayasu K et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990; 107:521-527. 8. Kawasaki S, Makuuchi M, Miyagawa S et al. Radical operation after portal embolization for tumor of hilar bile duct. J Am Coll Surg 1994; 178:480-486. 9. Nagino M, Nimura Y, Kamiya J et al. Changes in hepatic lobe volume in biliary tract cancer patients after right portal vein embolization. Hepatology 1995; 21:434-439. 10. Kawasaki S, Makuuchi M, Kakazu T et al. Resection for multiple metastatic liver tumors after portal embolization. Surgery 1994; 115:674-677. 11. De Baere T, Roche A, Elias D et al. Preoperative portal vein embolization for extension of hepatectomy indications. Hepatology 1996; 24:1386-1391. 12. Imamura H, Shimada R, Kubota M et al. Preoperative portal vein embolization: an audit of 84 patients. Hepatology 1999; 29:1099-1105. 13. Makuuchi M, Hasegawa H, Yamazaki S. Ultrasonically guided subsegmentectomy. Surg Gynecol Obstet 1985; 161:346-350. 14. Imamura H, Matsuyama Y, Miyagawa Y et al. Prognostic significance of anatomical resection and des-γ-carboxy prothrombin in patients with hepatocellular carcinoma. Br J Surg 1999; 86:1032-1038. 15. Regimbeau JM, Kianmanesh R, Farges O et al. Extent of liver resection influences the outcome in patients with cirrhosis and small hepatocellular carcinoma. Surgery 2002; 131:311-317. 16. Hasegawa K, Kokudo N, Imamura H et al. Prognostic impact of anatomic resection for hepatocellular carcinoma. Ann Surg 2005; 242:252-259. 17. Fan ST, Lo CM, Liu CL et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg 1999; 229:322-330. 18. Arii S, Okamoto E, Imamura M. The Liver Cancer Group of Japan. Registries in Japan: current status of hepatocellular carcinoma in Japan. Semin Surg Oncol 1996; 12:204-211.

110

Recent Advances in Liver Surgery

19. Nagasue N, Yukaya H, Ogawa Y et al. Human liver regeneration after major hepatic resection: a study of normal liver and livers with chronic hepatitis and cirrhosis. Ann Surg 1987; 206:30-39. 20. Chen MF, Hwang TL, Hung CF. Human regeneration after major hepatectomy: a study of liver volume by computed tomography. Ann Surg 1991; 213:227-229. 21. Yamanaka N, Okamoto E, Kawamura E et al. Dynamics of normal and injured human liver regeneration after hepatectomy as assessed on the basis of computed tomography and liver function. Hepatology 1993; 18:79-85. 22. Nagino M, Nimura Y, Kamiya J et al. Immediate increase in arterial blood flow in embolized hepatic segments after portal vein embolization: CT demonstration. AJR Am J Roentgenol 1998; 171:1037-1039. 23. Kubota K, Makuuchi M, Kusaka K et al. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology 1997; 26:1176-1181. 24. Aoki T, Imamura H, Hasegawa K et al. Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma. Arch Surg 2004; 139:766-774. 25. Yamakado K, Takeda K, Matsumura K et al. Regeneration of the un-embolized liver parenchyma following portal vein embolization. J Hepatol 1997; 27:871-880. 26. Azoulay D, Castaing D, Krissat J et al. Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver. Ann Surg 2000; 232:665-672. 27. Ogata S, Belghiti J, Farges O et al. Sequential arterial and portal vein embolizations before right hepatectomy in patients with cirrhosis and hepatocellular carcinoma. Br J Surg 2006; 93:1091-1098. 28. Sugawara Y, Yamamoto J, Higashi H et al. Preoperative portal embolization in patients with hepatocellular carcinoma. World J Surg 2002; 26:105-110. 29. de Baere T, Roche A, Elias D et al. Preoperative portal vein embolization for extension of hepatectomy indications. Hepatology 1996; 24:1386-1391. 30. Vauthey JN, Chaoui A, Do KA et al. Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery 2000; 127:512-519. 31. Hemming AW, Reed AI, Howard RJ et al. Preoperative portal vein embolization for extended hepatectomy. Ann Surg 2003; 237:686-693. 32. Azoulay D, Castaing D, Smail A et al. Resection of nonresectable liver metastases from colorectal cancer after percutaneous portal vein embolization. Ann Surg 2000; 231:480-486. 33. Azoulay D, Raccuia JS, Castaing D et al. Right portal vein embolization in preparation for major hepatic resection. J Am Coll Surg 1995; 181:266-269. 34. Kinoshita H, Sakai K, Hirohashi K et al. Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg 1986; 10:803-808. 35. Di Stefano DR, de Baere T, Denys A et al. Preoperative percutaneous portal vein embolization: evaluation of adverse events in 188 patients. Radiology 2005; 234:625-630. 36. Imamura H, Takayama T, Makuuchi M. Portal vein embolization: place of portal vein embolization. In: Blumgart Lh, Beligi J eds. Surgery of the Liver, Biliary Tract and Pancreas. 4th edition, New York: WB Saunders; 2006:1452-1460. 37. Nagino M, Nimura Y, Kamiya J et al. Selective percutaneous transhepatic embolization of the portal vein in preparation for extensive liver resection: the ipsilateral approach. Radiology 1996; 200:559-563. 38. Makuuchi M, Kosuge T, Lygidakis NJ. New possibilities for major liver surgery in patients with Klatskin tumors or primary hepatocellular carcinoma- an old problem revisited. Hepatogastroenterology 1991; 38:329-336. 39. Shimamura T, Nakajima Y, Une Y et al. Efficacy and safety of preoperative percutaneous transhepatic portal embolization with absolute ethanol: a clinical study. Surgery 1997; 121:135-141. 40. Tanaka H, Hirohashi K, Kubo S et al. Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma in patients with impaired hepatic function. Br J Surg 2000; 87:879-882. 41. Wakabayashi H, Ishimura K, Okano K et al. Application of preoperative portal vein embolization before major hepatic resection in patients with normal or abnormal liver parenchyma. Surgery 2002; 131:26-33. 42. Seo DD, Lee HC, Jang MK et al. Preoperative portal vein embolization and surgical resection in patients with hepatocellular carcinoma and small future liver remnant volume: comparison with transarterial chemoembolization. Ann Surg Oncol 2007; 14:3501-3509. 43. Abdalla EK, Barnett CC, Doherty D et al. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg 2002; 137:675-681. 44. Lunderquist A, Vang J. Transhepatic catheterization and obliteration of the coronary vein in patients with portal hypertension and esophageal varices. N Engl J Med 1974; 291:646-649.

Preoperative Portal Vein Embolization for Hepatocellular Carcinoma

111

45. Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future prospects. Br J Surg 2001; 88:165-175. 46. Yamakado K, Takeda K, Nishibe Y et al. Portal vein embolization with steel coils and absolute ethanol: a comparative experimental study with canine liver. Hepatology 1995; 22:1812-1818. 47. Ogasawara K, Uchino J, Une Y et al. Selective portal vein embolization with absolute ethanol induces hepatic hypertrophy and makes more extensive hepatectomy possible. Hepatology 1996; 23:338-345. 48. Goto Y, Nagino M, Nimura Y. Doppler estimation of portal blood flow after percutaneous transhepatic portal vein embolization. Ann Surg 1998; 228:209-213. 49. Kawasaki S, Makuuchi M, Matsunami H, et al. Preoperative measurement of segmental liver volume of donors for living related liver transplantation. Hepatology 1993; 18:1115-1120. 50. Harada H, Imamura H, Miyagawa S et al. Fate of human liver after hemihepatic portal vein embolization: cell kinetics and morphometric study. Hepatology 1997; 26:1162-1170. 51. Shimada R, Imamura H, Nakayama A et al. Changes in blood flow and function of the liver after right portal vein embolization. Arch Surg 2002; 137:1384-1388. 52. Chijiiwa K, Saiki S, Noshiro H et al. Effect of preoperative portal vein embolization on liver volume and hepatic energy status of the nonembolized liver lobe in humans. Eur Surg Res 2000; 32:94-99. 53. Hirai I, Kimura W, Fuse A et al. Evaluation of preoperative portal vein embolization for safe hepatectomy, with special reference to assessment of nonembolized lobe function with 99mTc-GSA SPECT scintigraphy. Surgery 2003; 133:495-506. 54. Nishiguchi S, Shiomi S, Sasaki N et al. Course before and after percutaneous transhepatic portal vein embolization of a patient with cholangiocarcinoma monitored by scintigraphy with Tc-99m galactosyl human serum albumin. Ann Nucl Med 2000;14:231-234. 55. Makuuchi M, Kosuge T, Takayama T et al. Surgery for small liver cancers. Sem Surg Oncol 1993; 9:298-304. 56. Wakabayashi H, Ishimura K, Okano K et al. Is preoperative portal vein embolization effective in improving prognisis after major hepatic resection in patients with advanced-stage hepatocellular carcinoma? Cancer 2001; 92:2384-2390.

Chapter 9

Vascular Embolotherapy in Hepatocellular Carcinoma

Saad M. Ibrahim, Gianpaolo Carrafiello, Robert J. Lewandowski, Robert K. Ryu, Kent T. Sato, Reed A. Omary and Riad Salem*

Abstract

T

reatment options for hepatocellular carcinoma, that cannot be resected or ablated, are based on trans arterial techniques. These include drug delivery in the form of traditional chemoembolization, bland embolization, radioembolization and drug-eluting beads. These technologies are rapidly being adopted in the medical community as an adjunctive therapeutic tool in the management of hepatocellular carcinoma. This chapter discusses these four treatment modalities that represent the mainstay of trans-arterial therapy for hepatocellular carcinoma.

Introduction

The majority of patients diagnosed with hepatocellular carcinoma (HCC) are not amenable to surgical cure. Reasons for this include the advanced nature of disease or other underlying comorbidities.1 For those who undergo surgical resection, recurrence rates of 50-80% at 5 years have been reported.2-5 Consequently, various transarterial therapies have been investigated in an effort to improve the quality of life and survival outcomes in patients with inoperable disease. Within the last decade, minimally invasive intra-arterial therapies have revolutionized the treatment for unresectable HCC. The basis underlying intra-arterial targeting of tumor is that hepatic neoplasms preferentially derive blood from an arterial source, whereas the majority of noncancerous liver is supplied by the portal vein.6-8 Taking advantage of this differential contribution, a number of image-guided catheter based therapies have become increasingly important in treating this patient population. Therapies such as transcatheter arterial chemoembolization (TACE), transarterial embolization (TAE), radioembolization using yttrium-90 (Y90), and most recently, drug eluting beads (DEB) have all shown to provide survival benefits in selected patients. The objective of these liver directed therapies is to inflict lethal injury to the tumor while preserving normal liver parenchyma. In some instances, these therapies have been employed to bridge or downstage patients, otherwise deemed unresectable, to resection and transplantation.

Technique

The process begins with determining patient eligibility. For this, clinical history, physical examination, laboratory values and performance status are typically evaluated. Patients are generally expected to have adequate liver and renal reserve and not be at risk of rapid onset of liver failure. Common to all catheter based intra-arterial therapies is the technique by which hepatic neoplasms are targeted. Since the anatomy of the mesenteric system has been shown to have a *Corresponding Author: Riad Salem—Department of Radiology, Director, Interventional Oncology, Robert H Lurie Comprehensive Cancer, Department of Radiology, 676 N St Clair, Suite 800, Chicago, IL 60611, USA. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Vascular Embolotherapy in Hepatocellular Carcinoma

113

considerable degree of variation, angiographic studies are instrumental in delineating the arterial conduits that feed the tumor. The angiographic evaluation is performed primarily to document visceral anatomy, identify anatomic variants and isolate the hepatic circulation by occluding the extrahepatic vessels.9 The first step involves cannulating the right common femoral artery using Seldinger technique. Next, a diagnostic abdominal aortogram followed by a superior mesenteric arteriogram is carried out. This assesses for hepatic variants arising from the superior mesenteric artery. During the procedure the patency of the portal vein is determined. The final step of angiography involves selectively catheterizing the celiac trunk and evaluating the hepatic arterial supply. In its evaluation, the origins of the right and left hepatic arteries are identified as well as variant mesenteric anatomy. During the angiographic assessment, all hepatic vessels are interrogated. Given the propensity for neoplasms to parasitize blood flow from vessels other than from its location, catheterization and interrogation helps to identify this occurrence. The failure to recognize this phenomenon typically results in the incomplete tumor coverage. Before proceeding with any intra-arterial therapy it may become necessary to prophylactically embolize the supraduodenal, retroduodenal, left inferior phrenic, accessory left gastric and inferior esophageal arteries.10 Prophylactically embolizing the aforementioned vessels aids in isolating the hepatic vasculature. This prevents the inadvertent delivery of the therapeutic agents to nontarget areas. Complications of unplanned administration to the cutaneous, cystic, gastrointestinal and phrenic arterial beds have been previously published.11-17 Next, the tumor is targeted by either whole liver, selective (lobar), or superselective (segmental) approaches, depending on the location of the tumor and the origins of tumor-feeding vessels. Patients are routinely admitted for in-house observation and managed for the so-called post embolization syndrome (PES). This syndrome is common to all embolic therapies, with the exception of radioembolization. Since pain is not commonly encountered with radioembolization, this therapy is usually carried out on an outpatient basis.

Transarterial Embolization

Transarterial embolization, also referred to as “bland” or “particle” embolization, is a procedure by which the hepatic arteries feeding a hepatoma are embolized. The principle underlying this therapy is to completely occlude the tumor-feeding arteries, thereby inciting extensive tumor necrosis and cell death. The concept of treating liver malignancies by interrupting the blood supply was first introduced in 1952 and is the basis of TAE.18 A common complication of most intra-arterial embolic therapies occluding the hepatic artery is a PES consisting of; abdominal pain, fever, nausea and vomiting. The degree of PES is generally related to the size of the particles used and extent of the liver embolized. The inclusion and exclusion criteria varies from center to center. Patients are excluded from therapy based on uncontrolled liver disease (gastrointestinal bleeding, encephalopathy), bacterial infection, liver compromise, complete portal vein thrombosis and for arterial access contraindications (platelet count <70,000/mm3, prothrombin <50%).19,20 In a meta-analysis of 3 randomized controlled trials consisting of 412 patients, Marelli et al compared the results of TACE versus TAE.21 The authors concluded that TACE failed to demonstrate a survival difference compared to TAE alone.22-24 Additionally, the observed tumor response and survival benefits observed with TACE may have been the result of the induced ischemia rather than the cytotoxic effects of chemotherapy. Covey et al reported on the use of bland embolization in 45 patients with postsurgical disease recurrence.25 Of the 45 patients treated, 97% had Okuda stage I disease. The authors reported a median survival of 46 months after treatment. The 1, 2 and 5 year actuarial survivals were 86, 74 and 47%, respectively. In a retrospective review, Brown et al evaluated the survival outcomes in 46 patients treated with polyvinyl alcohol over a four year period.26 The heterogeneous cohort underwent 86 sessions in which 81% developed PES postprocedurally. The authors concluded that particle embolization

114

Recent Advances in Liver Surgery

for HCC was well tolerated and demonstrated actuarial survivals of 50% and 33% at 1 and 2 years, respectively. In a prospective randomized control trial, Bruix et al reported on 80 patients treated with bland embolization.27 The cohort was equally split into treatment and control groups. The investigators concluded that despite TAE’s ability to retard tumor growth, no survival benefit was observed between the two groups. In fact, the authors suggested abandoning this mode of therapy for HCC. Loewe et al reported on 36 patients treated with cyanoacrylate and lipiodol with the intent to occlude the tumor feeding vessels.19 The investigators of this study reported PES in 86%, a 30-day perioperative mortality rate of 2.7% and median survival of 26 months. The authors observed, at follow-up arteriography, multiple small-caliber collateral vessels supplying both the tumor and liver. Maluccio and colleagues published a comparison of surgical resection with TAE and ablation in patients with HCC.28 In the study, 40 patients underwent surgical resection and 33 patients underwent embolization and ablation. Age, gender and size of the treated lesion were not significantly different between the groups. There were more patients classified as Okuda stage II in the embolization/ablation group (P < 0.001). A longer median recurrence-free survival rate was reported in the surgical group (53.1 versus 25.1 months). With a median follow-up of 23 months, the 1, 3 and 5-year actuarial survival rates were 97, 77 and 56%, for the embolization/ablation group and 81, 70 and 58% for the surgical group, respectively. There was no statistical difference in the overall survival rates (P = 0.20). The authors concluded that bland arterial embolization in combination with ablation is effective in treating solitary HCC lesions up to 7 cm and achieves similar overall survival compared to surgical resection in selected patients.

Transarterial Chemoembolization

The results of systemic chemotherapy for the treatment of HCC have been largely disappointing.29-31 The toxicities coupled with a lack of survival benefits associated with systemic treatment have resulted in the development of novel therapies. Transarterial chemoembolizations (TACE) refers to the administration of potent chemotherapeutic agent/s into tumor feeding arteries. This device exposes tumors to high drug concentrations while minimizing the bioavailability systemically. The intended purpose of embolization is two-fold: to prevent washout of the drug at the site of tumor and to induce ischemic necrosis. Transarterial chemoembolization is the mainstay and standard of care for treating patients with unresectable HCC. Vast variations of this technique have been demonstrated throughout the world and no standard protocol has been uniformly adopted. Centers have differed in the characteristics of the patients treated, the choice of the embolizing agent used, the choice/dose of the anticancer agents and the schedule/interval for retreatment.21 In treating these patients, single agent doxorubicin is the most commonly used agent worldwide whereas the combination regimen of mitomycin C, doxorubicin and cisplatin is the preferred regimen in the United States. Irrespective of the agent used, the chemotherapeutic agent is generally emulsified in lipiodol. Lipidol is an oily contrast agent believed to increase intratumoral retention of the cytotoxic agent.32-34 Immediately following the chemotherapeutic infusion, the target vessels are embolize. The most commonly applied embolizing agent is gelatin sponge,21 although other agents such as polyvinyl alcohol (PVA)35 and autologous blood clots36,37 have been used. In general, absolute contraindications to TACE include the absence of hepatopetal flow or compensatory collaterals, encephalopathy and biliary obstruction. The relative contraindications include serum bilirubin (>2 mg/dL), lactate dehydrogenase (>425 U/L), aspartate aminotransferase (>100 U/L), tumor burden exceeding >50% of the liver, ascites, bleeding varices, thrombocytopenia, or cardiac or renal insufficiency. Common side effects include a PES characterized by transient right upper quadrant abdominal pain, nausea, vomiting, fever and elevated transaminases. This is usually self-limiting and typically resolves in 7-10 days. Severe complications of this procedure include treatment induced ischemic damage to nontarget tissue such as normal liver parenchyma. Additionally, less common but severe

Vascular Embolotherapy in Hepatocellular Carcinoma

115

treatment related side-effects reported include liver abscess, acute liver failure, acute cholecystitis, bile duct injury, renal dysfunction, gastrointestinal bleeding and cardiac toxicity.38,39 Unless postprocedural complications arise, the treatment typically necessitates 1-2 days of inpatient observation. Until 2002, various investigators cited the lack of compelling data for the use of TACE demonstrating limited or the absence of survival benefits.40-42 In 2002, however, two landmark studies showed a statistically significant survival advantage with TACE versus less optimal therapeutic interventions in selected patients with well preserved liver functions.22,43 Llovet et al prospectively studied the survival outcomes in patients treated with fixed interval (intention to treat) chemoembolization, embolization and conservative measures.22 Survival outcomes for the 3 arms showed a survival benefit in stringently selected patients treated with chemoembolization and embolization, versus those treated conservatively. In a second randomized control trial Lo et al reported on a select group of patients with unresectable HCC treated with TACE or supportive care.43 The authors of this study concluded that TACE significantly improves survival in select patients with HCC. A recent meta-analysis of seven published randomized controlled trials concluded that TACE was an effective palliative treatment for HCC.44 Although embolization of the tumor feeding vessels has been shown to induce tumor necrosis, recent research suggests that tumor ischemia and hypoxia may stimulate neoangiogenesis by upregulating vascular endothelial growth factor (VEGF) and hypoxia induced factor-1 (HIF-1).45,46 Hypoxia has been further associated with metastasis and poor-outcomes, although the mechanism remains unclear.47 To date, evidence is lacking for the superiority of one anti-cancer agent over another in treating HCC. Additionally, although it has been shown that repeat chemoembolizations provide the greatest tumor response, there are no prospective studies highlighting the best retreatment intervals. Despite these limitations, chemoembolization continues to be used worldwide as the preferred treatment modality in patients with inoperable HCC.

Yttrium-90 Radioembolization

The use of external beam irradiation has historically played a limited role in the treatment of HCC due to the radiosensitive nature of normal hepatic tissue.48 With radiation doses exceeding 35 Gy, a clinical syndrome consisting of anicteric ascites, hepatomegaly and elevated liver enzymes has been observed weeks to months following therapy.48,49 Given this limitation and the need for higher doses to achieve tumoricidal effects, a minimally embolic intra-arterial device has emerged with the capacity to deliver radiation doses as high as 150 Gy without developing the clinical complications seen with external beam therapy.50-53 Yttrium-90 radioembolization (Y90) refers to the deployment of glass or resin particles, incorporating the radioactive isotope 90Y, directly into the arterial channels that perfuse tumor. Although this was first used in human subjects in the early 1960’s,54 only within the last decade has it gained increasing awareness and usage.55 90 Y is a pure beta emitter and decays to stable Zr-90 with a physical half-life of 64.2 hours.56-59 The emissions generated have a mean tissue penetration of 2.5 mm with a maximum reach of 11 mm. There are 2 commercially available Y90 devices: resin and glass microspheres. These 2 devices have unique characteristic differences that have been previously reported. In general, resin microspheres (20-60 microns in diameter) differ from glass microspheres (20-30 microns in diameter) in that resin microspheres have a lower specific activity, lower specific gravity and higher number of particles per treatment.60 Unique to radioembolization is the need to perform a pretreatment nuclear scan with a radioactive tracer: technetium-99 labeled macroaggregated albumin. This scan helps determine the percentage of hepatopulmonary and hepatogastrointestinal shunting in a given patient. In the event a shunt to the gastrointestinal tract is identified, it becomes imperative to embolize the vessels to mitigate the risks associated with nontarget radiation.

116

Recent Advances in Liver Surgery

After the scan, computed tomography (CT) or magnetic resonance imaging (MRI) is used to calculate the dosage required for treatment. Microsphere administration varies according to the type, size and number of microspheres delivered per treatment. Absolute Y90 contraindications include the demonstration that a given patient would receive >30 Gy to the lung in a single treatment session, or >50 Gy over multiple sessions as a result of significant hepatopulmonary shunting.61,62 Additionally, a patient is contraindicated from treatment if the deposition of microspheres into the gastrointestinal tract cannot be averted using catheter techniques. As with all other intra-arterial therapies relative contraindications include compromised pulmonary function, inadequate liver reserve, serum creatinine >2.0 mg/dl and a platelet count < 70,000/mm3. Common toxicities observed radioembolization include a mild post-embolic syndrome consisting of nausea and vomiting, fatigue and vague abdominal pain.63-65 Complications of nontarget radiation include radiation cholecystitis, pleural effusion, pancreatitis, gastroduodenitis, gastric ulceration, radiation pneumonitis and radiation hepatitis.64,66-70 In a study by Carr and collegues, 65 patients with biopsy proven HCC underwent Y90 radioembolization.71 Toxicities included vague abdominal pain, cholecystitis and elevated liver enzymes in 9,2 and 25 patients, respectively. Seventy-five percent of patients demonstrated lymphopenia without clinical sequelae. Median survival was 21.6 and 10.1 months for Okuda I (65%) and Okuda II patients (35%), respectively. The use of radioembolization in 15 patients with portal vein thrombosis and inoperable disease was recently reported.72 Two patients demonstrated bilirubin toxicities and disease progression. No serious adverse events related to treatment were reported. Eight patients showed stable or improved liver function following therapy. This study demonstrated the safety and efficacy of Y90 in treating HCC patients with PVT. Geshwind et al reported on 80 patients treated with Y90 microspheres using segmental, regional and whole liver approaches.73 The patients were stratified according to Child Pugh, Okuda and Clip scoring systems. Median survival for Okuda I (68%) and Okuda II (38%) was 20.1 and 10.8 months, respectively. In a retrospective review, Goin et al reported on 121 patients, with advanced disease, treated with Y90.74 The cohort consisted of 57, 39 and 23%, Okuda stage I, II and III respectively. Liver related toxicities ere observed in 14 patients. Severe treatment related adverse events included one case each of radiation pneumonitis and gastrointestinal bleeding. Salem et al reported on the safety, tumor response and survival of 43 consecutive patients treated with Y90 over a 4 year period.63 Forty-seven percent demonstrated an objective tumor response. The median survival for low and high risk patients were 20.8 and 11.1 months, respectively. The authors reported no procedure related life threatening events. Sangro et al reported on 24 Child-Pugh A patients who underwent Y90 radioembolization. The authors observed tumor reduction in 79% of treated patients.75 There were no cases of PES and all patients were discharged within 24 hours of treatment. The authors reported 2 fatal events attributable to therapy. There were no cases of progression at 12.5 months post-treatment. Kamel et al reported on 13 patients prospectively enrolled and treated with Y90 microspheres.76 Twenty-two and 25% of targeted tumors demonstrated mean decreases in arterial and venous enhancements, of 22, respectively. Median survival of 12 months was reported from the time of diagnosis. Kulik et al reported on 21 patients who underwent Y90 radioembolization and were subsequently bridged to transplantation.77,78 The most common treatment related symptom was fatigue, observed in 42% of patients. Complete necrosis was noted in 14 of 21 (66%) explants by pathologic exam. Four of 21 patients had disease recurrence after resection. Most recently, Kulik et al reported on the safety of Y90 in 37 of 108 patients with imaging documented PVT.79 Patients were stratified by Okuda, Child-Pugh, bilirubin, performance status, presence of cirrhosis and location of PVT. Liver related adverse events reported were increases in bilirubin (40%), ascites (18%) and hepatic encephalopathy (4%) in the majority presenting with

Vascular Embolotherapy in Hepatocellular Carcinoma

117

main PVT and cirrhosis. Median survival for those without PVT was 27.1 months. For those with cirrhosis, PVT and both PVT/cirrhosis the median survival were 12.8, 4.5 and 3.4 months, respectively. The authors concluded that treatment with Y90 in patients with PVT or cirrhosis did not increase the risk of liver failure.

Drug Eluting Beads

Drug eluting beads (DEB) represent a relatively new and novel mechanism of enhancing the delivery of potent anti-cancer agents using transarterial percutaneous techniques. The unique properties of the beads allow for fixed dosing and the ability to release the chemotherapeutic drugs in a sustained and controlled manner. The microspheres (diameter 100-900 μm) are composed of polyvinyl alcohol polymers modified with sulfonate groups. The sulfonate groups interact with the protonated amine groups of doxorubicin hydrochloride by an ion exchange process, which actively sequesters doxorubicin from solution, until an equilibrium is reached.80 The bead reportedly sequesters a maximum bound 40 mg/mL of doxorubicin and 4 mL of beads are necessary to produce the necessary embolic outcome.80 Investigators have shown the plasma concentration of the drug to remain at a level that is both steady and lower than traditional TACE.81 Although a relatively new addition in the armamentarium of treatment options for unresectable HCC, the applicability of this process in recent reports appear promising.82-84 Varela et al reported on 27 patients who underwent DEB to assess the applicability, safety and efficacy of the procedure.82 A typical PES was observed in 41 and 18% of treated patients after the first and second treatment, respectively. There were 2 cases of liver abscesses with one culminating in a treatment-related mortality. An objective intention to treat tumor response of 67% was reported using the EASL (European Association for the Study of the Liver) and AASLD (American Association for the Study of Liver Diseases) guidelines. Malagari et al reported on 71 patients prospectively enrolled and treated segmentally with doxorubicin-loaded beads.85 All patients had underlying cirrhosis and compensated disease (Child A or B). According to the EASL guidelines the reported complete and partial responses of the cohort at 24 months were 16.1 and 66%, respectively. The overall survival at 30 months was 88.2%. All patients were observed to have varying degrees of self limiting PES. Severe adverse events with this therapy included liver abscess, cholecystitis and pleural effusion. The authors concluded that DEB therapy was a safe and effective treatment option in patients not eligible for curative treatments with high rates of response. Significant reductions in peak plasma concentrations have been observed with DEB when compared to conventional TACE suggesting that a greater amount of the anti-cancer agent is being sequestered by the tumor versus distributing in the systemic circulation.81 This may theoretically result in a more pronounced tumor response while concomitantly diminishing the systemic bioavailability of the drug. The early results of DEB appear promising. Further experience is necessary to fully elucidate the safety and efficacy of this new and evolving therapy.

Conclusion

As the incidence of hepatocellular carcinoma continues to rise there is an imminent need for superior surveillance, diagnosis and treatment. Therapy for HCC is a challenge given that most neoplastic transformations occur in the setting of underlying liver disease. Intra-arterial therapies are gaining widespread recognition as a promising therapeutic tool in treating this uniformly fatal disease. The unique aspects of all these therapies are the minimal toxicity profiles and highly effective tumor responses. These unique characteristics coupled with the minimally invasive nature provide an attractive therapeutic option in patients who may have previously had few alternatives. As the delivered agents becomes more potent (drugs, radiation, ischemia), it is anticipated that this will result in higher treatment efficacies and survival benefits. The advent and rapid adoption of cytostatic targeted therapies (Raf kinase inhibitors) represents a new and novel method of treating the unresectable patient. Clinical investigations into combining the effects of these

118

Recent Advances in Liver Surgery

cytostatic therapies with the cytotoxic effects of intra-arterial therapies are currently underway and the results from these studies may provide valuable clinical data that may translate into enhanced clinical outcomes and overall survivals.

References

1. Mulcahy MF. Management of hepatocellular cancer. Curr Treat Options Oncol 2005; 6:423-435. 2. Portolani N, Coniglio A, Ghidoni S et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg 2006; 243:229-235. 3. Ercolani G, Grazi GL, Ravaioli M et al. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg 2003; 237:536-543. 4. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30:1434-1440. 5. Okada S, Shimada K, Yamamoto J et al. Predictive factors for postoperative recurrence of hepatocellular carcinoma. Gastroenterology 1994; 106:1618-1624. 6. Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol 1954; 30:969-977. 7. Gyves JW, Ziessman HA, Ensminger WD et al. Definition of hepatic tumor microcirculation by single photon emission computerized tomography (SPECT). J Nucl Med 1984; 25:972-977. 8. Bierman HR, Byron RL Jr, Kelley KH et al. Studies on the blood supply of tumors in man. III. Vascular patterns of the liver by hepatic arteriography in vivo. J Natl Cancer Inst 1951; 12:107-131. 9. Covey AM, Brody LA, Maluccio MA et al. Variant hepatic arterial anatomy revisited: digital subtraction angiography performed in 600 patients. Radiology 2002; 224:542-547. 10. Lewandowski RJ, Sato KT, Atassi B et al. Radioembolization with (90)y microspheres: angiographic and technical considerations. Cardiovasc Intervent Radiol 2007; 30:571-592. 11. Allen PJ, Stojadinovic A, Ben-Porat L et al. The management of variant arterial anatomy during hepatic arterial infusion pump placement. Ann Surg Oncol 2002; 9:875-880. 12. Carr BI. Hepatic artery chemoembolization for advanced stage HCC: experience of 650 patients. Hepato-Gastroenterology 2002; 49:79-86. 13. Chun HJ, Byun JY, Yoo SS et al. Added benefit of thoracic aortography after transarterial embolization in patients with hemoptysis. AJR Am J Roentgenol 2003; 180:1577-1581. 14. Arora R, Soulen MC, Haskal ZJ. Cutaneous complications of hepatic chemoembolization via extrahepatic collaterals. J Vasc Interv Radiol 1999; 10:1351-1356. 15. Ueno K, Miyazono N, Inoue H et al. Embolization of the hepatic falciform artery to prevent supraumbilical skin rash during transcatheter arterial chemoembolization for hepatocellular carcinoma. Cardiovasc Intervent Radiol 1995; 18:183-185. 16. Inaba Y, Arai Y, Matsueda K et al. Right gastric artery embolization to prevent acute gastric mucosal lesions in patients undergoing repeat hepatic arterial infusion chemotherapy. J Vasc Interv Radiol 2001; 12:957-963. 17. Chung JW, Park JH, Han JK et al. Hepatic tumors: predisposing factors for complications of transcatheter oily chemoembolization. Radiology 1996; 198:33-40. 18. Markowitz J. The hepatic artery. Surg Gynecol Obstet 1952; 95:644-666. 19. Loewe C, Cejna M, Schoder M et al. Arterial embolization of unresectable hepatocellular carcinoma with use of cyanoacrylate and lipiodol. J Vasc Interv Radiol 2002; 13:61-69. 20. Rand T, Loewe C, Schoder M et al. Arterial embolization of unresectable hepatocellular carcinoma with use of microspheres, lipiodol and cyanoacrylate. Cardiovasc Intervent Radiol 2005; 28:313-318. 21. Marelli L, Stigliano R, Triantos C et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 2007; 30:6-25. 22. Llovet JM, Real MI, Montana X et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359:1734-1739. 23. Chang JM, Tzeng WS, Pan HB et al. Transcatheter arterial embolization with or without cisplatin treatment of hepatocellular carcinoma. A randomized controlled study. Cancer 1994; 74:2449-2453. 24. Kawai S, Okamura J, Ogawa M et al. Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma—a comparison of lipiodol-transcatheter arterial embolization with and without adriamycin (first cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan. Cancer Chemother Pharmacol 1992; 31(Suppl):S1-6. 25. Covey AM, Maluccio MA, Schubert J et al. Particle embolization of recurrent hepatocellular carcinoma after hepatectomy. Cancer 2006; 106:2181-2189. 26. Brown KT, Nevins AB, Getrajdman GI et al. Particle embolization for hepatocellular carcinoma. J Vasc Interv Radiol 1998; 9:822-828.

Vascular Embolotherapy in Hepatocellular Carcinoma

119

27. Bruix J, Llovet JM, Castells A et al. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology 1998; 27:1578-1583. 28. Maluccio M, Covey AM, Gandhi R et al. Comparison of survival rates after bland arterial embolization and ablation versus surgical resection for treating solitary hepatocellular carcinoma up to 7 cm. J Vasc Interv Radiol 2005; 16:955-961. 29. Yeo W, Mok TS, Zee B et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005; 97:1532-1538. 30. Johnson PJ. Hepatocellular carcinoma: is current therapy really altering outcome? Gut 2002; 51:459-462. 31. Okada S. Chemotherapy in hepatocellular carcinoma. Hepato-gastroenterology 1998; 45(Suppl 3):1259-1263. 32. Bhattacharya S, Dhillon AP, Winslet MC et al. Human liver cancer cells and endothelial cells incorporate iodised oil. Br J Cancer 1996; 73:877-881. 33. Bhattacharya S, Novell JR, Winslet MC et al. Iodized oil in the treatment of hepatocellular carcinoma. Br J Surg 1994; 81:1563-1571. 34. Terayama N, Matsui O, Gabata T et al. Accumulation of iodized oil within the nonneoplastic liver adjacent to hepatocellular carcinoma via the drainage routes of the tumor after transcatheter arterial embolization. Cardiovasc Intervent Radiol 2001; 24:383-387. 35. Coldwell DM, Stokes KR, Yakes WF. Embolotherapy: agents, clinical applications and techniques. Radiographics 1994; 14:623-43; quiz 45-46. 36. Gunji T, Kawauchi N, Akahane M et al. Long-term outcomes of transcatheter arterial chemoembolization with autologous blood clot for unresectable hepatocellular carcinoma. Int J Oncol 2002; 21:427-432. 37. Kwok PC, Lam TW, Chan SC et al. A randomized clinical trial comparing autologous blood clot and gelfoam in transarterial chemoembolization for inoperable hepatocellular carcinoma. J Hepatol 2000; 32:955-964. 38. Poon RT, Ngan H, Lo CM et al. Transarterial chemoembolization for inoperable hepatocellular carcinoma and postresection intrahepatic recurrence. J Surg Oncol 2000; 73:109-114. 39. Lau WY, Yu SC, Lai EC et al. Transarterial chemoembolization for hepatocellular carcinoma. J Am Coll Surg 2006; 202:155-168. 40. Madden MV, Krige JE, Bailey S et al. Randomised trial of targeted chemotherapy with lipiodol and 5-epidoxorubicin compared with symptomatic treatment for hepatoma. Gut 1993; 34:1598-1600. 41. Pelletier G, Roche A, Ink O et al. A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Hepatol 1990; 11:181-184. 42. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. N Engl J Med 1995; 332:1256-1261. 43. Lo CM, Ngan H, Tso WK et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35:1164-1171. 44. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003; 37:429-442. 45. Kim KW, Bae SK, Lee OH et al. Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer Res 1998; 58:348-351. 46. Wu XZ, Xie GR, Chen D. Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma. J Gastroenterol Hepatol 2007; 22:1178-1182. 47. Erler JT, Bennewith KL, Nicolau M et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006; 440:1222-1226. 48. Ingold JA, Reed GB, Kaplan HS et al. Radiation Hepatitis. Am J Roentgenol Radium Ther Nucl Med 1965; 93:200-208. 49. Lawrence TS, Robertson JM, Anscher MS et al. Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys 1995; 31:1237-1248. 50. Kennedy AS, Nutting C, Coldwell D et al. Pathologic response and microdosimetry of (90)Y microspheres in man: review of four explanted whole livers. Int J Radiat Oncol Biol Phys 2004; 60:1552-1563. 51. Yorke ED, Jackson A, Fox RA et al. Can current models explain the lack of liver complications in Y-90 microsphere therapy? Clin Cancer Res 1999; 5:3024s-3030s. 52. Dawson LA, McGinn CJ, Normolle D et al. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol 2000; 18:2210-2218. 53. Dawson LA, McGinn CJ, Lawrence TS. Conformal chemoradiation for primary and metastatic liver malignancies. Semin Surg Oncol 2003; 21:249-255.

120

Recent Advances in Liver Surgery

54. Ariel IM. Treatment of Inoperable Primary Pancreatic and Liver Cancer by the Intra-Arterial Administration of Radioactive Isotopes (Y90 Radiating Microspheres). Ann Surg 1965; 162:267-278. 55. Salem R, Thurston KG. Radioembolization with yttrium-90 microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies: part 3: comprehensive literature review and future direction. J Vasc Interv Radiol 2006; 17:1571-1593. 56. Andrews JC, Walker SC, Ackermann RJ et al. Hepatic radioembolization with yttrium-90 containing glass microspheres: preliminary results and clinical follow-up. J Nucl Med 1994; 35:1637-1644. 57. Sarfaraz M, Kennedy AS, Cao ZJ et al. Physical aspects of yttrium-90 microsphere therapy for nonresectable hepatic tumors. Med Phys 2003; 30:199-203. 58. Dancey JE, Shepherd FA, Paul K et al. Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres. J Nucl Med 2000; 41:1673-1681. 59. Salem R, Thurston KG, Carr BI et al. Yttrium-90 microspheres: radiation therapy for unresectable liver cancer. J Vasc Interv Radiol 2002; 13:S223-229. 60. Salem R, Thurston KG. Radioembolization with 90Yttrium Microspheres: A State-of-the-Art Brachytherapy Treatment for Primary and Secondary Liver Malignancies: Part 1: Technical and Methodologic Considerations. J Vasc Interv Radiol 2006; 17:1251-1278. 61. TheraSphere Yttrium-90 microspheres package insert, MDS Nordion, Kanata, Canada. 2004. 62. SIR-Spheres Yttrium-90 microspheres package insert, SIRTeX Medical, Lane Cove, Australia. 2004. 63. Salem R, Lewandowski RJ, Atassi B et al. Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response and survival. J Vasc Interv Radiol 2005; 16:1627-1639. 64. Kennedy AS, Coldwell D, Nutting C et al. Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience. Int J Radiat Oncol Biol Phys 2006; 65:412-425. 65. Murthy R, Xiong H, Nunez R et al. Yttrium 90 resin microspheres for the treatment of unresectable colorectal hepatic metastases after failure of multiple chemotherapy regimens: preliminary results. J Vasc Interv Radiol 2005; 16:937-945. 66. Murthy R, Nunez R, Szklaruk J et al. Yttrium-90 microsphere therapy for hepatic malignancy: devices, indications, technical considerations and potential complications. Radiographics 2005; 25(Suppl 1): S41-55. 67. Yip D, Allen R, Ashton C et al. Radiation-induced ulceration of the stomach secondary to hepatic embolization with radioactive yttrium microspheres in the treatment of metastatic colon cancer. J Gastroenterol Hepatol 2004; 19:347-349. 68. Liu DM, Salem R, Bui JT et al. Angiographic considerations in patients undergoing liver-directed therapy. J Vasc Interv Radiol 2005; 16:911-935. 69. Ho S, Lau WY, Leung TW et al. Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer. Eur J Nucl Med 1997; 24:293-298. 70. Lewandowski R, Salem R. Incidence of radiation cholecystitis in patients receiving Y-90 treatment for unresectable liver malignancies. J Vasc Interv Radiol 2004; 15:S162. 71. Carr BI. Hepatic arterial 90Yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients. Liver Transpl 2004; 10:S107-110. 72. Salem R, Lewandowski R, Roberts C et al. Use of Yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis. J Vasc Interv Radiol 2004; 15:335-345. 73. Geschwind JF, Salem R, Carr BI et al. Yttrium-90 microspheres for the treatment of hepatocellular carcinoma. Gastroenterology 2004; 127:S194-205. 74. Goin JE, Salem R, Carr BI et al. Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: a risk-stratification analysis. J Vasc Interv Radiol 2005; 16:195-203. 75. Sangro B, Bilbao JI, Boan J et al. Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2006; 66:792-800. 76. Kamel IR, Reyes DK, Liapi E et al. Functional MR imaging assessment of tumor response after 90Y microsphere treatment in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2007; 18:49-56. 77. Kulik LM, Atassi B, van Holsbeeck L et al. Yttrium-90 microspheres (TheraSphere(R)) treatment of unresectable hepatocellular carcinoma: Downstaging to resection, RFA and bridge to transplantation. J Surg Oncol 2006; 94:572-586. 78. Kulik LM, Mulcahy MF, Hunter RD et al. Use of yttrium-90 microspheres (TheraSphere) in a patient with unresectable hepatocellular carcinoma leading to liver transplantation: a case report. Liver Transpl 2005; 11:1127-1131. 79. Kulik LM, Carr BI, Mulcahy MF et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2008; 47:71-81.

Vascular Embolotherapy in Hepatocellular Carcinoma

121

80. Lewis AL, Gonzalez MV, Leppard SW et al. Doxorubicin eluting beads—1: effects of drug loading on bead characteristics and drug distribution. J Mater Sci Mater Med 2007; 18:1691-1699. 81. Hong K, Georgiades CS, Geschwind JF. Technology insight: Image-guided therapies for hepatocellular carcinoma—intra-arterial and ablative techniques. Nat Clin Pract Oncol 2006; 3:315-324. 82. Varela M, Real MI, Burrel M et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46:474-481. 83. Constantin M, Fundueanu G, Bortolotti F et al. Preparation and characterisation of poly(vinyl alcohol)/cyclodextrin microspheres as matrix for inclusion and separation of drugs. Int J Pharm 2004; 285:87-96. 84. Gonzalez MV, Tang Y, Phillips GJ et al. Doxorubicin eluting beads-2: methods for evaluating drug elution and in-vitro:in-vivo correlation. J Mater Sci 2008; 19:767-775. 85. Malagari K, Alexopoulou E, Chatzimichail K et al. Transcatheter chemoembolization in the treatment of HCC in patients not eligible for curative treatments: midterm results of doxorubicin-loaded DC bead. Abdom Imaging 2007; (Epub ahead of print).

Chapter 10

Sequential Arterial and Portal Vein Embolization before Right Hepatectomy in Patients with Cirrhosis and Hepatocellular Carcinoma Jacques Belghiti,* Béatrice Aussilhou and Valérie Vilgrain

Abstract

M

ajor hepatectomy for large HCC in patients remains a crucial procedure due to the possibility of a low regeneration of the future liver remnant (FLR). It has been demonstrated that preoperative portal vein embolization (PVE) increase the tolerance of right hepatectomy. Selective transcatheter arterial chemoembolization (TACE) before PVE could improve the rate of hypertrophy of the FLR in patients with chronic liver disease. In this chapter we show the efficacy and the long term effect of this double preparation before a major hepatectomy. TACE, 3-4 weeks before PVE is well tolerated and increased significantly the FLR as compared to PVE alone. Preoperative, sequential TACE and PVE increase the FLR and provide a high rate of complete tumor necrosis which was associated with good disease free survival. We advocate this double preoperative radiological procedure in cirrhotic patients with HCC requiring major hepatectomy.

Introduction

Therapeutic embolization of portal venous branches or of hepatic arteries has been developed and utilized during the past two decades.1 Portal vein embolization (PVE) is applied mainly preoperatively to induce contralateral hypertrophy and thus, used to increase the safety of major resection in patients with liver malignancy while transarterial chemoembolization (TACE) is one of the most widely used treatments for patients with unresectable hepatocellular carcinoma (HCC). This chapter presents an overview of a combined approach for patients with HCC considered marginal candidates for hepatic resection utilizing a strategy of sequential arterial and portal vein embolization based on our experience at the hospital Beaujon in France.

Rationale Portal Vein Embolization

Preoperative PVE has been used to induce contralateral compensatory hypertrophy of the future liver remnant before major liver resection and is usually indicated in patients with liver metastases or hilar bile duct cancer before extended resection. However, a great proportion of patients with chronic liver disease continue to present with advanced large tumors requiring *Corresponding Author: Jacques Belghiti— Department of HPB Surgery, University of Paris, 7 Denis Diderot, Hospital Beaujon, 92118 CLICHY Cédex, France. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Sequential Arterial and Portal Vein Embolization 123

Figure 1. Sequential arterial and portal vein embolization in a patient with HCC. A) Arterial phase CT showing a large hypervascular tumor in the right liver. B) Hepatic arteriogram shows that the tumor is hypervascular and supplied by the right hepatic artery. The lesion was treated with TACE (not shown). C) Arterial-phase CT after sequential arterial and portal vein embolization shows massive uptake of the Lipiodol by the tumor. D) Portal venous phase CT after sequential arterial and portal vein embolization shows a dramatic decrease in size of the tumor compared to A with marked hypertrophy of the contra-lateral lobe is seen (this patient had successful resection).

124

Recent Advances in Liver Surgery

major resection. Although some concern exists about the regenerative capacity of fibrotic or cirrhotic liver parenchyma after technically successful PVE, it has been shown that preoperative PVE induces significant hypertrophy of the future liver remnant (FLR) even in patients with chronic liver disease.2 Furthermore, it has been shown that preoperative PVE improves the safety and tolerance of major liver resection in patients with chronic liver disease.3,4 A direct antitumoral effect of PVE on HCC was initially suspected when used to control tumor thrombus spread within the portal vein but that has not been confirmed.5 Conversely, researchers have shown that there is a compensatory increase in arterial flow in the embolized lobe after PVE which could accelerate the growth of the HCC.6,7

Transcatheter Arterial Chemoembolization

Transcatheter arterial chemoembolization (TACE) involves the administration of a chemotherapeutic agent (usually doxorubicin, mitomycin C and/or cisplatin) into the hepatic artery followed by hepatic artery embolization. Because liver tumors preferentially receive their blood supply from the hepatic artery, occlusion of this artery induces selective ischemia of the tumor and enhances the cytotoxicity of the chemotherapeutic agent. Two prospective studies and two meta-analyses reported earlier this decade showed a significant survival benefit with TACE in unresectable HCCs.7-11 However, there has been no clear evidence that neoadjuvant TACE procedures prolong overall survival or disease-free survival after curative resection of HCC.12,13 It has been speculated that performing preoperative selective TACE and PVE in a standardized sequential manner could increase the rates of hypertrophy and resection, mainly by decreasing the arterial flow to the liver that will subsequently be treated with PVE, by suppressing arterioportal shunts that may negatively affect regeneration and by having a strong anticancer effect on the HCC.

History

During the last two decades, three groups of investigators performed combined TACE and PVE in a small number of patients.5,14-16 Interestingly, most of the patients that have been treated in this fashion were considered nonsurgical candidates. Procedures were different in terms of materials used and the timing of the TACE and PVE procedures. Material used for embolization by Nakao et al14 were Gelfoam sponge in both the hepatic artery and portal vein with, while Yamakado et al15 used TACE with injection of a mixture of iodized oil and doxorubicin followed by administration of Gelfoam and transportal ethanol injection. Simultaneous embolization of the hepatic artery and portal vein was performed by Nakao et al,14 while Kinoshita et al5 did the PVE two weeks after hepatic artery recanalization and Yamakado et al15 realized the portal vein occlusion one to four weeks after TACE. Results of these preliminary studies showed that complete necrosis of the tumor assessed by histologic examination was observed in most cases. Simultaneous arterial and portal vein embolization led to hepatic infarction in most cases with an infarction ratio ranging from 5 to 35% and a recovery time after the combined procedure longer that after TACE alone.14 Therefore, Nakao et al14 recommended “that combined embolization should be performed only in cases that involve relative small tumors and that are located in the subsegment region near the surface of the liver.” Some patients became resectable after the procedure14,15 and most of the nonresected patients (seven of the nine in the Yamakado study) showed no recurrence or intrahepatic metastasis during a follow-up of 7 to 42 months.15 At least, TACE could be repeated in patients with incomplete response with mild liver damage.15

Hospital Beaujon’s Experience

The purpose of our study was to investigate the tolerance and efficacy of preoperative sequential TACE and PVE before right hepatectomy in patients with chronic liver disease and HCC and to compare perioperative outcome with that of a matched group of patients undergoing PVE alone.17

Sequential Arterial and Portal Vein Embolization

125

Technique

TACE was performed before PVE. After arterial and portal venous flow assessment, the tip of the catheter (5-french or coaxially placed microcatheter according to the difficulty of catheterization) was placed selectively into the right hepatic artery. A mixture of 10 to15 mL iodized oil and 40 to 60 mg doxorubicin was injected under fluoroscopic control, followed by embolization with gelatin-sponge until complete stasis. All patients underwent volumetric helical computed tomographic estimation of liver volume before PVE and before surgery. The interval between preoperative CT volumetry and surgery was 6-8 days and the interval between PVE and preoperative CT volumetry was 4-6 weeks. Measurements were performed for the whole liver as well as for the right and left lobes, using the middle hepatic vein, identified by intravenous bolus injection of contrast and the gallbladder as landmarks. The FLR volume was defined as the volume of the left liver (segments I-IV). The estimated percentage FLR volume was calculated as (left liver volume 100)/total liver volume. PVE was carried out at least 3 weeks after TACE (mean interval 3-4 weeks). Right PVE was performed using the contralateral transhepatic approach. The left portal branch was punctured under general anaesthesia and ultrasonographic guidance. Following venous portography, the right anterior and posterior portal branches were embolized with a mixture of ethiodized oil and cyanoacrylate until complete stasis. Right hepatectomy was performed 4-8 weeks after PVE. All patients underwent liver resection by one of two senior liver surgeons, using a standardized technique for right hepatectomy. After right hepatectomy, the resected specimens were examined pathologically, paying attention to the extent of necrosis of HCC. Tumor necrosis was defined as complete if no viable cells were observed in any nodule.

Results of Sequential Arterial and Portal Vein Embolization

TACE and right PVE were feasible in all of our 18 patients and they were discharged between 2 and 7 days after each procedure with no major complications. Results of liver function tests after TACE and after PVE showed peak levels of AST and ALT that were significantly higher than baseline but returned to baseline before surgery. Mean peak levels of AST and ALT after PVE were significantly higher in the TACE + PVE group than in comparative group with HCC arising in chronic liver disease who underwent PVE alone (303 and 200 vs 95 and 100U/L, respectively). The mean increase in percentage FLR was 12% and this mean increase was significantly higher than that in the PVE group alone (8%). Two third of the patients had an increase of more than 10% of the FLR; however, 20% with F4 fibrosis had had an increase >10%. Seven of the 18 patients had no perioperative or postoperative complications, two died of liver failure during the hospital stay. The most common complications were significant ascites, liver failure and pulmonary complications. Examination of the resected specimens showed that complete necrosis of the tumor induced by TACE combined with PVE occurred in 83% of the cases. Overall survival rates were 83%, 54% and 43% at 1, 3 and 5 years respectively. Recurrence-free survival rates were 78%, 37% and 37% at 1, 3 and 5 years, respectively. Interestingly 5-years recurrence-free survival rate was higher in the group of patients who underwent sequential TACE and PVE as compared to a group with PVE alone.17 These results were similar to the series of Aoki et al18 who reported their experience in 17 patients with HCC in whom TACE and PVE were feasible in all patients without major complications. Similarly, the AST and ALT values increased within 3 days after PVE and returned to their prePVE values within two weeks. All patients but one (94%) ultimately had major hepatic resection and examination of the resected specimens showed that the extent of the tumor necrosis was 50% to 60% in 4 patients, 70% to 80% in 2 patients and 90% to 100% in 10 patients. The 5-year disease-free and overall survival rates after curative hepatic resections were 46.7% and 55.6%, respectively. However, there were discrepancies and other findings: the median interval between the TACE and PVE procedures was only 9 days and this shorter interval could explain the higher rate of complications in the Aoki’s paper (5/17, 29%) vs no complication in our series.

126

Recent Advances in Liver Surgery

The volumes of the non-embolized and embolized liver segments was evaluated by enhanced CT approximately 2 weeks after the PVE and showed that sufficient hypertrophy of the future remnant segments was achieved. Serum alphafoetoprotein levels between the TACE and PVE procedures and between the PVE and the hepatectomy procedures were significantly lower than the alphafoetoprotein levels before TACE.

Comparison with PVE Alone in Patients with HCC

In our experience, the FLR and the mean increase in percentage FLR were significantly higher in the patients who had sequential arterial and portal venous embolization than that in patients with PVE alone (12% versus 8%).17 Examination of the resected specimens showed that complete necrosis of the tumor induced by TACE combined with PVE occurred in 83%, compared with 5% following PVE alone.17 There was a clear relationship between the increase in percentage FLR volume and postoperative risk. The overall postoperative morbidity rate was 18%, 67% and 100% if the increase in percentage FLR volume was >10%, between 5 and 10% and <5%, respectively. The overall postoperative mortality rate was 0%, 13% and 50% if the increase in percentage FLR volume was >10%, between 5 and 10% and <5%, respectively. The overall survival rates were not significantly different but 1-, 3- and 5-year recurrence-free survival rates were higher in the TACE + PVE patients than in the PVE patients (83, 54 and 43 per cent vs 72, 31 and 31 per cent, respectively). However, 1-, 3- and 5-year recurrence-free survival rates were higher in the TACE + PVE group than in the PVE group (93, 37 and 37 per cent vs 63, 19 and 19 per cent).17 Our study concluded that sequential TACE and PVE before hepatic resection increases the rate of hypertrophy of the FLR and leads to a higher rate of complete tumor necrosis associated with longer recurrence-free survival than PVE alone. Our results confirm Yamakado’s results16 which demonstrated that hypertrophy of the nonembolized liver parenchyma was greater with combined use of TACE and PVE than in the patients without TACE (57% vs 36%).

Complications

Although complications after sequential arterial and portal vein embolization were minor in the published series, one should remember that PVE in patients with chronic liver disease has a higher morbidity than in patients with normal underlying liver. The two most frequent complications are liver failure (6%) and portal vein thrombosis (5%); conversely to patients with normal liver where they are observed in less than 1% of the cases.2,19 Transient ascites may also be seen. The rate of complications is higher in patients with cirrhosis than with fibrosis.20

PVE Alone Versus Sequential Arterial Embolization and PVE for HCC

PVE alone is used in patients with HCC to extend the indications for and the safety of major hepatectomy and is indicated in patients with a F3 fibrosis score or Child-Pugh A cirrhosis without severe portal hypertension with an anticipated inadequate FLR volume. According to different authors, this last criterion may be either a FLR volume less than 40%, a future liver volume less than 285mL/m2 or when a major resection is planned.2,12,21 In this indication, sequential arterial and portal vein embolizations seem even more adequate than PVE alone because they permit a tumor control and increase more the rate of hypertrophy of FLR. Therefore, at our institution, when a PVE is indicated in HCC patients with chronic liver diseases, we systematically perform sequential arterial and portal vein embolization. HCC may also develop in patients with non alcoholic fatty liver disease. In these patients, HCC may be observed before cirrhosis is seen.22 The size of the tumor at diagnosis is often large because these patients are not enrolled in a screening program and major resections are often required. Although not been extensively studied, patients with non alcoholic fatty liver disease may have a limited regeneration capacity and present with at least some liver fibrosis on preoperative biopsy that could indicate the need for sequential arterial and portal vein embolization.

Sequential Arterial and Portal Vein Embolization

127

Another indication of PVE with or without TACE is to determine preoperatively the patients who are at higher risk for postoperative liver failure. Two studies have shown that those who do not exhibit significant left hypertrophy after PVE are at higher risk.21,23 We have also demonstrated that minimal or absence of hypertrophy after PVE alone or sequential arterial and portal vein embolization could be a prognostic factor. The overall mortality rate was 0% when the percentage FLR/total liver volume increased more than 10% and was 50% if percentage FLR/total liver volume did not exceed 5%.17 Finally, in the future, sequential TACE and PVE is indicated in unresectable patients with Evidence Medicine Level 1 showing an improvement in survival.13 Because complete necrosis of the tumor induced by TACE combined with PVE is achieved in the vast majority of the cases, there may be a role for sequential arterial and portal vein embolizations in unresectable patients.

Conclusion

Our experience confirms other studies in showing that sequential arterial embolization and PVE effectively increase the FLR and induce a high rate of complete tumor necrosis. This combined procedure should replace the indication of PVE alone for major resection in chronic liver disease. Further studies need to be done to evaluate the role of sequential arterial embolization and PVE in other indications such as non alcoholic fatty liver disease.

References

1. De Baere T, Roche A, Vavasseur D et al. Portal vein embolization—Utility for inducing left hepatic lobe hypertrophy before surgery. Radiology 1993; 188:73-77. 2. Denys A, Lacombe C, Schneider F et al. Portal vein embolization with n-butyl cyanoacrylate before partial hepatectomy in patients with hepatocellular carcinoma and underlying cirrhosis or advanced fibrosis. J Vasc Interv Radiol 2005; 16:1667-1674. 3. Tanaka H, Hirohashi K, Kubo S et al. Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma in patients with impaired hepatic function. Br J Surg 2000; 87:879-882. 4. Azoulay D, Castaing D, Krissat J et al. Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver. Ann Surg 2000; 232:665-672. 5. Kinoshita H, Sakai K, Hirohashi K et al. Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg 1986; 10:803-808. 6. Nagino M, Nimura Y, Kamiiya J et al. Immediate increase in arterial blood flow in embolized hepatic segments after portal vein embolization: CT demonstration. AJR Am J Roentgenol 1998; 171:1037-1039. 7. Wakabayashi H, Ishimura K, Okano K et al. Is preoperative portal vein embolization effective in improving prognosis after major hepatic resection in patients with advanced-stage hepatocellular carcinoma? Cancer 2001; 92:2384-2390. 8. Llovet JM, Real MI, Montana X et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled study. Lancet 2002; 359:1734-1739. 9. Lo CM, Nghan H, Tso WK et al. Randomized controlled trial of transarterial Lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35:1164-1171. 10. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003; 37:429-442. 11. Cammà C, Schepis F, Orlando A et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002; 224:47-54. 12. Kokudo N, Makuuchi M. Current role of portal vein embolization/hepatic artery chemoembolization. Surg Clin N Am 2004; 84:643-657. 13. Lau WY, Yu SC, Lai EC et al. Transarterial chemoembolization for hepatocellular carcinoma. J Am Coll Surg 2006; 202:155-168. 14. Nakao N, Miura K, Takahashi H et al. Hepatocellular carcinoma: combined hepatic, arterial and portal venous embolization. Radiology 1986; 161:303-307. 15. Yamakado K, Hirano T, Kato N et al. Hepatocellular carcinoma: treatment with a combination of transcatheter arterial chemoembolization and transportal ethanol injection. Radiology 1994; 193:75-80.

128

Recent Advances in Liver Surgery

16. Yamakado K, Nakatsuka A, Tanaka N et al. Long-term follow-up arterial chemoembolization combined with transportal ethanol injection used to treat hepatocellular carcinoma. J Vasc Interv Radiol 1999; 10:641-647. 17. Ogata S, Belghiti J, Farges O et al. Sequential arterial and portal vein embolizations before right hepatectomy in patients with cirrhosis and hepatocellular carcinoma. Br J Surg 2006; 93:1091-1098. 18. Aoki T, Imamura H, Hasegawa K et al. Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma. Arch Surg 2004; 139:766-774. 19. Di Stefano DR, de Baere T, Denys A et al. Preoperative percutaneous portal vein embolization: Evaluation of adverse events in 188 patients. Radiology 2005; 234:625-630. 20. Madoff DC, Abdalla EK, Vauthey JN. Portal vein embolization in preparation for major hepatic resection: evolution of a new standard of care. J Vasc Interv Radiol 2005; 16:779-790. 21. Farges O, Belghiti J, Kianmanesh R et al. Portal vein embolization before right hepatectomy: Prospective clinical trial. Ann Surg 2003; 237:208-217. 22. Iannaccone R, Piacentini F, Murakami T et al. Hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: helical CT and MR imaging findings with clinical-pathologic comparison. Radiology 2007; 243:422-430. 23. Wakabayashi H, Ishimura K, Okano K et al. Application of preoperative portal vein embolization before major hepatic resection in patients with normal or abnormal liver parenchyma. Surgery 2002; 131:26-33.

Chapter 11

Intraoperative Ultrasonic Examination in Liver Surgery Junichi Arita,* Norihiro Kokudo, Keiji Sano and Masatoshi Makuuchi

Abstract

T

he safety of liver surgery has improved dramatically over the course of a few decades through the development of intraoperative ultrasonography, an imaging modality that is currently indispensable for hepatic resection. Although intraoperative ultrasonography is necessary at all stages and for a variety of purposes during hepatic resection, it has two major roles. One is surveying the liver just before parenchymal transection. Intraoperative ultrasonography’s high spatial resolution and ability to demonstrate, in real time, vessels and tumors in the liver while directly scanning the liver’s surface makes it one of the most useful imaging modalities to be used during liver surgery. The second role is to guide the direction of the transection plane during hepatic resection. Current advances in this modality are focused on the development of contrast-enhanced ultrasonography and the rapid evolution of contrast materials and related detection systems. The progress of three-dimensional ultrasonography is also anticipated.

Introduction

The safety of liver surgery has substantially improved over the last few decades, with the consequence that its indications have been expanded. The invention and widespread use of intraoperative ultrasonography (IOUS) have contributed greatly to the advancement of liver surgery,1 and IOUS is currently indispensable for hepatic resection. In some aspects, IOUS is superior to extracorporeal ultrasound (US). First, higher frequency probes (5-7.5 MHz) can be used, since no energy is lost during the passage of the US signal through the abdominal wall.2 This enables superior definition, compared with that obtained using the lower frequency probes required for extracorporeal US (2.5-3.5 MHz); thus, smaller hepatic lesions, vessels and ducts can be identified. Second, the liver can be mobilized during laparotomy, enabling surgeons to obtain multiple images without interference from the ribs or gas-filled loops of bowel. Third, interference arising from breathing and heartbeats can be easily eliminated through the controlled ventilation and manual fixation of the liver, respectively. Finally, IOUS enables the biopsy of tiny abnormal tissue and the cannulation of thin intrahepatic vessels and duct.3 Despite the advantages provided by the unlimited choice of imaging planes, novice examiners might feel strange to the US images obtained during surgery. In such instances, conventional imaging planes (intercostal oblique, subcostal oblique, epigastric transverse and epigastric sagital views) should be obtained first; then, the direction or contact point of the US probe should be gradually altered. Intensive learning and a considerable accumulation of experience are mandatory for maximizing the benefits of IOUS. In this chapter, the IOUS technique and important points regarding the use of IOUS during liver surgery are described. *Corresponding Author: Junichi Arita—Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

130

Recent Advances in Liver Surgery

History

In the 1970s, IOUS with epicardial M-mode imaging was attempted during cardiac surgery; the need for more comprehensive imaging subsequently led to the invention of real-time two-dimensional B-mode imaging systems. Clinical applications and evaluations of B-mode IOUS systems started in the late 1970s and early 1980s. IOUS with real-time B-mode imaging was first applied to liver surgery by Makuuchi and colleagues.4 A small side-viewing probe, consisting of electronic linear-array transducers and dedicated for IOUS scanning of the liver, was invented4 and quickly became popular in Japan. Through the 1980s, the clinical use of IOUS gradually increased and the benefits of IOUS were defined.3 Using IOUS, the stage and resectability of tumors could be determined more accurately than with preoperative studies. Intraoperative localization of nonpalpable tumors and precise screening for liver metastasis also became possible using IOUS.5 New surgical techniques were even developed as a result of the introduction of IOUS. For example, IOUS-guided systematic segmentectomy6,7 and a hepatectomy procedure that preserved the inferior right hepatic vein8 provided new perspectives for the surgical treatment of cirrhotic patients with primary tumors. In 1990s, two new US modalities were incorporated into IOUS: color or power Doppler imaging that enhanced the value of IOUS and laparoscopic US (LUS) that extended the utility of IOUS. Intraoperative color Doppler imaging mostly benefited cardiovascular surgery. It also facilitated IOUS image interpretation during general surgical procedures and transplantations by delineating the blood vessels in color. Although the construction of prototype B-mode LUS instruments was attempted in the 1980s, rigid and flexible probes specifically made for LUS and that can be inserted through the currently used 10-mm trocars were developed in the early to mid-1990s.9,10 These probes rapidly became popular among laparoscopic surgeons because this IOUS method was able to compensate for the limitations of laparoscopy, mainly the limited tactile feedback from tissues and the inability to examine underlying structures. The most recent advances in ultrasound imaging are harmonic contrast-specific imaging and three-dimensional (3-D) imaging. Harmonic imaging, represented by the coded harmonic and pulse-inversion technique, has enabled otherwise undetectable blood flow in vessels and produces effects in real-time that are similar to or even better than those produced using digital subtraction angiography. This technique has developed in parallel to the development of contrast material. Carbon-dioxide gas was initially used as the contrast material;11,12 subsequently, first-generation ultrasonic contrast materials that enabled systemic circulation through pulmonary capillary vessels but that were fragile to ultrasonic pressure were developed.13,14 Presently, second-generation contrast materials that are more sensitive but less fragile to ultrasonic pressure and that enable real-time continuous enhanced ultrasonic imaging have been developed.15,16 Recently invented 3-D imaging is now being used in clinical fields like gynecology, neurology and hepatology. Although this technique has not been widely applied for practical IOUS,17-19 3-D images could help novice liver surgeons to simplify the planning and guiding of hepatic resections and might be a useful educational tool for instruction on liver anatomy.

Transducer

The ultrasonic probe has been miniaturized and the spatial resolution of the B-mode image has been improved, compared with those used in the 1970s when IOUS was first introduced.4,20 The size of the hand piece is very important because it must be placed between the diaphragm and the liver dome, where the free space is only several centimeters wide. The authors use a micro-convex probe (UST-9132; Aloka, Tokyo, Japan; Fig. 1), which is small enough to hold with only two fingers and enables the whole liver to be viewed from every point and in every direction (Fig. 2). This probe also has a wide view range, enabling the surgeon to visualize the entire vasculature within a short time period. The current transducer for IOUS has a frequency range of between 5 and 10 MHz and its frequency can be adjusted according to the examination settings. Other types of ultrasonic probes are also available, such as a stick-shaped probe dedicated for laparoscopic surgery

Intraoperative Ultrasonic Examination in Liver Surgery

131

Figure 1. A micro-convex probe dedicated for intraoperative ultrasonography (UST-9132; Aloka, Tokyo, Japan).

and a T-shaped probe. Both the stick-shaped and T-shaped probes are conventionally used and have linear transducers, providing a narrow field but a high spatial resolution.

Intraoperative Surveillance

IOUS is a highly useful imaging study that is performed just before liver parenchymal transection, providing real-time images with high spatial resolution and fewer blind corners. Liver transection should be commenced after the following information has been obtained. 1. Re-evaluation of the tumor: The location, size and relationship to adjacent vasculatures should be reconfirmed by comparing the IOUS images with the preoperative imaging studies. Also, the preoperative diagnosis should be reconfirmed after evaluating the ultrasonic characteristics of the tumor. The characteristic ultrasonic findings of hepatocellular carcinoma include a mosaic pattern of internal echoes, posterior echo enhancement, a thin halo and a lateral shadow; these features are important for intraoperative diagnosis. Because of its high spatial resolution, IOUS sometimes shows tiny peripheral intrahepatic

Figure 2. View of intraoperative ultrasonography showing the phrenic dome of the right liver.

132

Recent Advances in Liver Surgery

2.

3.

4.

5.

vasculatures that cannot be visualized using preoperative US; the border and/or internal structure of the tumor may also be clearer. IOUS examinations should be done with meticulous attention because they provide the final and most useful information for liver transection, otherwise safety of hepatic resection may be compromised and the tumor staging may be misunderstood. Vascular anatomy: The surgeon’s understanding of the patient’s vascular anatomy, as visualized using preoperative imaging, must be reconfirmed using IOUS. Any intrahepatic vasculature can be imaged longitudinally and followed from its origin to periphery utilizing unlimited imaging planes. Additionally, hepatic veins are sometimes obscured because of the phase of contrast enhancement on preoperative CT, while IOUS can demonstrate the branching pattern of venous tributaries. In other cases, the inferior and middle right hepatic veins21 may be demonstrated for the first time using IOUS. The dissection of the hepatoduodenal ligament can be safely done using anatomical surveillance by IOUS. For example, identifying branching type of portal vein, including bifurcation type, trifurcation type and independent posterior segmental branching type22,23 and determining whether the right hepatic artery runs behind or in front of the common hepatic duct or is an aberrant type (running behind or on the right side of the portal vein) are important steps. Additionally, IOUS is the most sensitive imaging modality for detecting and localizing intrahepatic biliary strictures after liver surgery, especially after liver transplantation.24,25 Tumor detection: IOUS is the most sensitive technique for detecting liver tumors. This technique is particularly useful for tumors located on the subphrenic dome or in the caudate lobe, where ultrasonic demonstrations are often difficult using extracorporeal US. The sensitivity of IOUS for detecting colorectal liver metastases is reported to be between 95% and 99% and lesions with diameters as small as 2 mm can also be visualized.26,27 The sensitivity of IOUS for detecting small HCC was 98-99%, which was superior to the sensitivities of preoperative ultrasound, angiography and computed tomography.2,28,29 Also, IOUS is superior to other preoperative imaging modalities for detecting intrahepatic metastases and tumor thrombi.2IOUS demonstrates new nodules in 14-30% of all patients with hepatocellular carcinoma.30-32 IOUS has been shown to yield significant new information, including the detection of new tumors, vascular invasion and the denial of preoperatively suggested tumors. Thus, IOUS findings result in the operative plan being changed in 10-50% of patients.27,33-36 To insure that occult lesions are not missed, systematic ultrasonic observation is necessary. For example, the pursuit of the portal pedicles according to the numerical order of Couinaud segments37 is one effective approach for surveying the entire liver. In particular, screening of the caudate lobe should be carefully performed because of this lobe’s deep location and the possible presence of artifacts created by the adjacent round ligament and hilar connective tissue. In most clinical settings, small colorectal liver metastases are more difficult to detect using IOUS than small hepatocellular carcinomas; thus, the late phase of contrast-enhanced IOUS might be effective for the detection of colorectal metastases.38-40 Detection of tumor vascular invasion: Hepatocellular carcinomas occasionally form tumor thrombi in the portal vein, hepatic vein or intrahepatic bile duct. On the other hand, metastatic liver tumors from adenocarcinoma tend to invade the portal pedicle, rather than form tumor thrombi.41Such vascular invasions are sometimes difficult to reveal using preoperative imaging modalities and may be seen for the first time using IOUS, possibly because of its high spatial resolution.4 Careless surveillance could result in tumor invasion being missed; thus, surgeons should always bear in mind the possibility of tumor invasion to the vasculature. Tumor biopsy under IOUS guidance: A more accurate biopsy of liver tumors is possible under IOUS guidance, compared with extracorporeal US guidance, because of the superior spatial resolution and the absence of an intervening abdominal wall. Thus, the biopsy of small tumors, which would be difficult using extracorporeal US guidance, is possible using IOUS guidance. Furthermore, intraoperative biopsies are safer because the needle

Intraoperative Ultrasonic Examination in Liver Surgery

133

route is unrestricted. Nonetheless, the indications for tumor biopsy should be considered carefully, since tumor dissemination through seeding is always possible.42

Guidance for Hepatic Resection

In patients with hepatocellular carcinoma, anatomical resection is superior to non-anatomical limited resection in terms of patient prognosis.43,44 Anatomical resection means the resection of hepatic parenchyma that is fed by the portal vein bearing the tumor. Parenchyma-sparing anatomical resection for cirrhotic patients was first reported by Makuuchi et al7 as a subsegmentectomy procedure. In patients with colorectal liver metastases, anatomical resection is indicated in cases where the tumor invades a major intrahepatic vasculature. IOUS is necessary for most segmentectomy and subsegmentectomy procedures. First, the tumor-bearing portal vein must be investigated and longitudinally demonstrated using IOUS. Subsequently, the portal vein must be punctured using a long 22-gauge needle under IOUS guidance and a dye is slowly injected into the portal vein after the proper hepatic artery has been clamped. If the injection is performed too quickly, the injected dye will regurgitate in portal vein; this regurgitation can be ultrasonically visualized. The proper hepatic artery is temporarily and selectively clamped on the hepatoduodenal ligament before the dye injection to prevent the washing out of the dye as a result of arterioportal shunting arising from hepatocellular carcinoma and/or liver cirrhosis. This selective arterial clamp is usually confirmed by color Doppler US. The puncture route should be carefully decided, referring to the IOUS images, to avoid injuring the intrahepatic vasculature. The tip of the needle must be completely followed by IOUS until it reaches the portal vein, so the US probe must be kept still and patient ventilation should be temporarily suspended. The flow of the dye can be seen using IOUS as an echogenic stream. The stained area that appears on the liver surface soon after is then marked using electrocautery (Fig. 3). Parenchymal transection is commenced from the marked line toward the trunk of the portal pedicle. IOUS is also used to confirm and modify the transection plane. IOUS should be frequently performed to enable the relations among the transection plane, tumor and vasculature to be recognized (Fig. 4). If the transection plane is difficult to see, a sheet of gauze may be placed between the transection planes and a hyperechoic line corresponding to the transection plane will appear. To recognize ultrasonically vessels appearing on the transection plane, the tip of the forceps may be placed on the vessel or a thread encircling the vessel may be retracted.45 The liver transection line should be followed using IOUS to maintain the surgical margin, especially when a limited (partial) resection is performed; surgeons should proceed with the parenchymal transection under IOUS guidance bearing in mind that the surgical margin tends to be insufficient, possibly exposing the tumor, after the transection line reaches the deepest point of the tumor.

Figure 3. Dyed surface of the liver after segmental staining through a puncture in the portal branch.

134

Recent Advances in Liver Surgery

Figure 4. Intraoperative sonogram during liver transection. A deep hyperechoic tumor (arrow) is visible. The transection planes are shown as hyperechoic lines (arrowhead).

Although percutaneous transhepatic biliary drainage46 has become a safe and reliable technique, minimally dilated bile ducts are yet difficult to puncture and it can also be difficult to drain all the dilated bile ducts if a hilar bile duct cancer has invaded several intrahepatic bile ducts. Intraoperative US-guided biliary drainage is safer in such cases because it enables finer cannulation and provides an unlimited choice of puncture routes. Doppler ultrasonography is one advance that has generally utilized IOUS. During hilar dissection, intrahepatic arterial flow can be examined using Doppler ultrasonography when a branch of hepatic artery to be divided is clamped and released (Fig. 5). Sano et al47 proposed that congestion induced by the occlusion of a hepatic venous tributary can be demonstrated using Doppler ultrasonography as the absence of hepatic venous flow and the regurgitation of the corresponding portal vein. A clamp test of the hepatic venous tributary demonstrates the presence or absence of a collateral vein; regurgitation of the clamped hepatic vein definitely suggests the presence of a collateral vein. The recently developed e-flow system (Aloka, Tokyo, Japan) can clearly show very small peripheral communications between hepatic veins (Fig. 6). Other techniques utilizing IOUS have also been developed. Kokudo et al48 performed Belghiti’s liver hanging maneuver49 using IOUS; in this technique, the forceps can be safely advanced along the retrohepatic plane under IOUS guidance. Also, the surgical margin can be confirmed using US examination of the resected specimen soaked in water (Fig. 7). And after or during liver transection, thrombus formation is occasionally found in the portal or hepatic vein exposed at the transection plane50 (Fig. 8).

Contrast-Enhanced IOUS

Microbubble contrast agents for US have gained increasing interest in recent years and contrast-enhanced US (CEUS) is a rapidly evolving field. Specialized contrast-specific US modes that enable one to overcome the limitations of baseline gray-scale and color Doppler US have been

Intraoperative Ultrasonic Examination in Liver Surgery

135

Figure 5. Doppler sonograms of the middle hepatic artery before (a) and after (b) the left hepatic artery has been clamped.

introduced and have been shown to lead to improved imaging performance after the injection of microbubbles.51,52 This has been done as a result of the safe profile and the increased stability of the second-generation contrast materials, which persist in the bloodstream for a period of minutes. Second-generation microbubbles include SonoVue (Bracco, Milan, Italy), Definity (Bristol-Myers Squibb, New York, USA) and Sonazoid (GE Healthcare, Oslo, Norway). The former two can be well visualized when they are insonated at a very low mechanical index (below 0.1)53,54 and thus are highly tolerable to ultrasonic power. On the other hand, Sonazoid should be insonated at a higher mechanical index, from 0.2 to 0.4, to be appropriately visualized.55,56 However, it has the unique characteristic of accumulating in Kupffer cells in the liver, enabling a lengthened contrast effect between tumor cells and liver parenchyma.57,58 The development of specialized contrast-specific US techniques, represented by the pulse-inversion technique,56 is also important. Such techniques allow a definite improvement in the contrast resolution and suppression of signals from stationary tissues. CEUS with a low transmit power allows real-time scanning with the possibility of prolonged organ insonation. CEUS allows the assessment of tumor vascularity and improves the diagnostic accuracy of liver tumors.16,59,60 The application of contrast-enhanced IOUS (CE-IOUS) has not yet become widespread; however, several reports concerning its use during surgery for colorectal hepatic metastases and hepatocellular carcinoma have been made. Torzilli et al38 reported that CE-IOUS found new lesions in 4 out of 24 consecutive patients with colorectal liver metastases, with a significant impact on surgical strategy and radicality. Leen et al39 performed CE-IOUS in 57 patients with colorectal liver metastases and also found that it had a significantly higher sensitivity than CT/MR and IOUS (96.1%) and that it altered the surgical management in 29.8% of the cases. On the other hand, Fioole et al40 also studied 39 consecutive patients with colorectal metastases and insisted that the addition of CE-IOUS did not improve diagnostic accuracy when compared to the combination

136

Recent Advances in Liver Surgery

Figure 6. Sonogram in e-flow mode, demonstrating the peripheral communication of the hepatic veins. Note the minimal blooming effect with the fine delineation of small communications.

Figure 7. Sonogram of resected specimen soaked in water. A negative surgical margin is confirmed between the tumor (arrow) and transection surface (arrowhead).

Intraoperative Ultrasonic Examination in Liver Surgery

137

Figure 8. A clot (arrow) that formed in the middle hepatic vein during liver transection. The transection plane is also visible as a hyperechoic line (arrowhead).

of contrast-enhanced CT and IOUS (P = 0.617). One important problem concerning the use of IOUS in surgery for hepatocellular carcinoma is that although new nodules are found using IOUS in a substantial percentage of patients with cirrhosis, only one-third of these nodules turn out to actually be hepatocellular carcinoma.30,31 Contrast-enhanced studies might resolve this problem, since such studies can be used to assess the vascularity of nodules. If a new nodule found by IOUS shown an early enhancement during CE-IOUS or presents as a defect in the late phase, the possibility of hepatocellular carcinoma should be considered. Torzilli et al61 reported a prospective study validating CE-IOUS in surgery for hepatocellular carcinoma. In a total of 87 patients, 59 new nodules were found using plain IOUS and were assessed using CE-IOUS. The sensitivity for hepatocellular carcinoma was 100% and the positive predictive value was 63%, guaranteeing the efficacy of CE-IOUS. Because of the insufficient prevalence and experience using CE-IOUS at present, however, conclusive statements cannot be made and the accumulation of further experience and observations is needed.

Conclusions

IOUS is now an essential technique for liver surgery, playing two major roles: as a final diagnostic tool before liver transection and as an essential guide for hepatic resection. The remarkable advancement of IOUS instrumentation and techniques seems to have reached its limit; however, not all aspects of IOUS in the future can be readily predicted because of the rapid advances that are being made in US and other medical or surgical technologies. Future applications of IOUS will likely appear through a combination of surgeons’ experience with US and technological advances. Preoperative imaging modalities may improve, which is expected to decrease the incidence of the diagnosis of so-called “occult” lesions using IOUS. However, IOUS will likely remain as the best real-time imaging method for the localization and evaluation of lesions during surgery because it

138

Recent Advances in Liver Surgery

will also continue to improve. Virtual reality technology is persistently advancing, enabling a more realistic simulation of IOUS examinations and surgical procedures. Computer-based US simulators will greatly assist future education and training in IOUS, particularly for novice surgeons. Telemonitoring via IOUS is also promising, although its role remains to be established. IOUS, even a few decades from now, may not mean the same thing as it does today.

References

1. Tachimori Y, Makuuchi M, Asamura H et al. A case of hepatocellular carcinoma with tumor thrombi in the epiploic vein. Jpn J Clin Oncol 1988; 18(3):269-273. 2. Makuuchi M, Hasegawa H, Yamazaki S et al. The use of operative ultrasound as an aid to liver resection in patients with hepatocellular carcinoma. World J Surg 1987; 11(5):615-621. 3. Makuuchi M. Abdominal Intraoperative Ultrasonography. 1st ed. Tokyo, New York: Igaku-Shoin, 1987. 4. Makuuchi M, Hasegawa H, Yamazaki S. Intraoperative ultrasonic examination for hepatectomy. Ultrasound Med Biol 1983; (Suppl 2):493-497. 5. Machi J, Isomoto H, Yamashita Y et al. Intraoperative ultrasonography in screening for liver metastases from colorectal cancer: comparative accuracy with traditional procedures. Surgery 1987; 101(6):678-684. 6. Makuuchi M, Hasegawa H, Yamazaki S. Development on segmentectomy and subsegmentectomy of the liver due to introduction of ultrasonography. Nippon Geka Gakkai Zasshi 1983; 84(9):913-917. 7. Makuuchi M, Hasegawa H, Yamazaki S. Ultrasonically guided subsegmentectomy. Surg Gynecol Obstet 1985; 161(4):346-350. 8. Makuuchi M, Hasegawa H, Yamazaki S et al. Four new hepatectomy procedures for resection of the right hepatic vein and preservation of the inferior right hepatic vein. Surg Gynecol Obstet 1987; 164(1):68-72. 9. Fornari F, Civardi G, Cavanna L et al. Laparoscopic ultrasonography in the study of liver diseases. Preliminary results. Surg Endosc 1989; 3(1):33-37. 10. Kubota K, Bandai Y, Sano K et al. Appraisal of intraoperative ultrasonography during laparoscopic cholecystectomy. Surgery 1995; 118(3):555-561. 11. Matsuda Y, Yabuuchi I. Hepatic tumors: US contrast enhancement with CO2 microbubbles. Radiology 1986; 161(3):701-705. 12. Kudo M, Tomita S, Tochio H et al. Small hepatocellular carcinoma: diagnosis with US angiography with intraarterial CO2 microbubbles. Radiology 1992; 182(1):155-160. 13. Blomley MJ, Albrecht T, Cosgrove DO et al. Improved imaging of liver metastases with stimulated acoustic emission in the late phase of enhancement with the US contrast agent SH U 508A: early experience. Radiology 1999; 210(2):409-416. 14. Heckemann RA, Cosgrove DO, Blomley MJ et al. Liver lesions: intermittent second-harmonic gray-scale US can increase conspicuity with microbubble contrast material-early experience. Radiology 2000; 216(2):592-596. 15. Leen E, Angerson WJ, Yarmenitis S et al. Multi-centre clinical study evaluating the efficacy of SonoVue (BR1), a new ultrasound contrast agent in Doppler investigation of focal hepatic lesions. Eur J Radiol 2002; 41(3):200-206. 16. Q uaia E, Calliada F, Bertolotto M et al. Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence. Radiology 2004; 232(2):420-430. 17. Harms J, Feussner H, Baumgartner M et al. Three-dimensional navigated laparoscopic ultrasonography: first experiences with a new minimally invasive diagnostic device. Surg Endosc 2001; 15(12):1459-1462. 18. Beller S, Hunerbein M, Eulenstein S et al. Feasibility of navigated resection of liver tumors using multiplanar visualization of intraoperative 3-dimensional ultrasound data. Ann Surg 2007; 246(2):288-294. 19. Chopra SS, Hunerbein M, Eulenstein S et al. Development and validation of a three dimensional ultrasound based navigation system for tumor resection. Eur J Surg Oncol 2007; 20. Rifkin MD, Mack LA, Lennard ES et al. Intraoperative abdominal ultrasonography: initial experience with a dedicated high-resolution operative transducer. J Ultrasound Med 1986; 5(8):429-433. 21. Makuuchi M, Hasegawa H, Yamazaki S et al. The inferior right hepatic vein: ultrasonic demonstration. Radiology 1983; 148(1):213-217. 22. Lee SG, Hwang S, Kim KH et al. Approach to anatomic variations of the graft portal vein in right lobe living-donor liver transplantation. Transplantation 2003; 75(3 Suppl):S28-32. 23. Kishi Y, Sugawara Y, Kaneko J et al. Classification of portal vein anatomy for partial liver transplantation. Transplant Proc 2004; 36(10):3075-3076.

Intraoperative Ultrasonic Examination in Liver Surgery

139

24. Pariente D, Bihet MH, Tammam S et al. Biliary complications after transplantation in children: role of imaging modalities. Pediatr Radiol 1991; 21(3):175-178. 25. Caiado AH, Blasbalg R, Marcelino AS et al. Complications of liver transplantation: multimodality imaging approach. Radiographics 2007; 27(5):1401-1417. 26. Schmidt J, Strotzer M, Fraunhofer S et al. Intraoperative ultrasonography versus helical computed tomography and computed tomography with arterioportography in diagnosing colorectal liver metastases: lesion-by-lesion analysis. World J Surg 2000; 24(1):43-47; discussion 48. 27. Zacherl J, Scheuba C, Imhof M et al. Current value of intraoperative sonography during surgery for hepatic neoplasms. World J Surg 2002; 26(5):550-554. 28. Nagasue N, Kohno H, Chang YC et al. Intraoperative ultrasonography in resection of small hepatocellular carcinoma associated with cirrhosis. Am J Surg 1989; 158(1):40-42. 29. Choi BI, Han JK, Song IS et al. Intraoperative sonography of hepatocellular carcinoma: detection of lesions and validity in surgical resection. Gastrointest Radiol 1991; 16(4):329-333. 30. Kokudo N, Bandai Y, Imanishi H et al. Management of new hepatic nodules detected by intraoperative ultrasonography during hepatic resection for hepatocellular carcinoma. Surgery 1996; 119(6):634-640. 31. Takigawa Y, Sugawara Y, Yamamoto J et al. New lesions detected by intraoperative ultrasound during liver resection for hepatocellular carcinoma. Ultrasound Med Biol 2001; 27(2):151-156. 32. Eguchi A, Furuta T, Haraguchi M et al. Early stage hepatocellular carcinoma detected during intraoperative ultrasonography. Am J Gastroenterol 1994; 89(4):595-598. 33. Gunven P, Makuuchi M, Takayasu K et al. Preoperative imaging of liver metastases. Comparison of angiography, CT scan and ultrasonography. Ann Surg 1985; 202(5):573-579. 34. Conlon R, Jacobs M, Dasgupta D et al. The value of intraoperative ultrasound during hepatic resection compared with improved preoperative magnetic resonance imaging. Eur J Ultrasound 2003; 16(3):211-216. 35. Charnley RM, Morris DL, Dennison AR et al. Detection of colorectal liver metastases using intraoperative ultrasonography. Br J Surg 1991; 78(1):45-48. 36. Paul MA, Mulder LS, Cuesta MA et al. Impact of intraoperative ultrasonography on treatment strategy for colorectal cancer. Br J Surg 1994; 81(11):1660-1663. 37. Couinaud C. Les hepatectomies elargies. In: Cuinaud C, ed. LeFoie: Etudes Anatomiques et Chirurgicales. Paris: Masson, 1957. 38. Torzilli G, Del Fabbro D, Palmisano A et al. Contrast-enhanced intraoperative ultrasonography during hepatectomies for colorectal cancer liver metastases. Journal of Gastrointestinal Surgery 2005; 9(8):1148. 39. Leen E, Ceccotti P, Moug SJ et al. Potential value of contrast-enhanced intraoperative ultrasonography during partial hepatectomy for metastases: an essential investigation before resection? Ann Surg 2006; 243(2):236-240. 40. Fioole B, de Haas RJ, Wicherts DA et al. Additional value of contrast enhanced intraoperative ultrasound for colorectal liver metastases. Eur J Radiol 2007; In Press. 41. Kokudo N, Miki Y, Sugai S et al. Genetic and histological assessment of surgical margins in resected liver metastases from colorectal carcinoma: minimum surgical margins for successful resection. Arch Surg 2002; 137(7):833-840. 42. Torzilli G, Minagawa M, Takayama T et al. Accurate preoperative evaluation of liver mass lesions without fine-needle biopsy. Hepatology 1999; 30(4):889-893. 43. Imamura H, Matsuyama Y, Miyagawa Y et al. Prognostic significance of anatomical resection and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma. Br J Surg 1999; 86(8):1032-1038. 44. Hasegawa K, Kokudo N, Imamura H et al. Prognostic impact of anatomic resection for hepatocellular carcinoma. Ann Surg 2005; 242(2):252-259. 45. Torzilli G, Takayama T, Hui A-M et al. A new technical aspect of ultrasound-guided liver surgery. Am J Surg 1999; 178(4):341-343. 46. Makuuchi M, Bandai Y, Ito T et al. Ultrasonically guided percutaneous transhepatic cholangiography and percutaneous pancreatography. Radiology 1980; 134(3):767-770. 47. Sano K, Makuuchi M, Miki K et al. Evaluation of hepatic venous congestion: proposed indication criteria for hepatic vein reconstruction. Ann Surg 2002; 236(2):241-247. 48. Kokudo N, Imamura H, Sano K et al. Ultrasonically assisted retrohepatic dissection for a liver hanging maneuver. Ann Surg 2005; 242(5):651-654. 49. Belghiti J, Guevara OA, Noun R et al. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 2001; 193(1):109-111. 50. Arita J, Kokudo N, Hasegawa K et al. Hepatic venous thrombus formation during liver transection exposing major hepatic vein. Surgery 2007; 141(2):283-284.

140

Recent Advances in Liver Surgery

51. Wilson SR, Burns PN, Muradali D et al. Harmonic hepatic US with microbubble contrast agent: initial experience showing improved characterization of hemangioma, hepatocellular carcinoma and metastasis. Radiology 2000; 215(1):153-161. 52. Bertolotto M, Dalla Palma L, Quaia E et al. Characterization of unifocal liver lesions with pulse inversion harmonic imaging after Levovist injection: preliminary results. Eur Radiol 2000; 10(9):1369-76. 53. Schneider M, Arditi M, Barrau MB et al. BR1: a new ultrasonographic contrast agent based on sulfur hexafluoride-filled microbubbles. Invest Radiol 1995; 30(8):451-457. 54. Krix M, Kiessling F, Essig M et al. Low mechanical index contrast-enhanced ultrasound better reflects high arterial perfusion of liver metastases than arterial phase computed tomography. Invest Radiol 2004; 39(4):216-222. 55. Marelli C. Preliminary experience with NC100100, a new ultrasound contrast agent for intravenous injection. Eur Radiol 1999; 9(Suppl 3):S343-346. 56. Forsberg F, Piccoli CW, Liu JB et al. Hepatic tumor detection: MR imaging and conventional US versus pulse-inversion harmonic US of NC100100 during its reticuloendothelial system-specifi c phase. Radiology 2002; 222(3):824-829. 57. Watanabe R, Matsumura M, Munemasa T et al. Mechanism of hepatic parenchyma-specific contrast of microbubble-based contrast agent for ultrasonography: microscopic studies in rat liver. Invest Radiol 2007; 42(9):643-651. 58. Yanagisawa K, Moriyasu F, Miyahara T et al. Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells. Ultrasound Med Biol 2007; 33(2):318-325. 59. Giorgio A, Ferraioli G, Tarantino L et al. Contrast-enhanced sonographic appearance of hepatocellular carcinoma in patients with cirrhosis: comparison with contrast-enhanced helical CT appearance. AJR Am J Roentgenol 2004; 183(5):1319-1326. 60. Jang HJ, Kim TK, Burns PN et al. Enhancement patterns of hepatocellular carcinoma at contrast-enhanced US: comparison with histologic differentiation. Radiology 2007; 244(3):898-906. 61. Torzilli G, Palmisano A, Del Fabbro D et al. Contrast-enhanced intraoperative ultrasonography during surgery for hepatocellular carcinoma in liver cirrhosis: Is it useful or useless? A prospective cohort study of our experience. Ann Surg Oncol 2007; 14(4):1347-1355.

Chapter 12

Perioperative Blood Transfusion in Hepatocellular Carcinomas Gianlorenzo Dionigi*, Salvatore Cuffari, Giovanni Cantone, Alessandro Bacuzzi and Renzo Dionigi

Abstract

A

llogeneic blood transfusion during liver resection for malignancies has been associated with an increased incidence of different types of complications: infectious complications, tumor recurrence, decreased survival. Even if there is clear evidence of transfusion-induced immunosuppression, it is difficult to demonstrate that transfusion is the only determinant factor that decisively affects the outcome. In any case there are several motivations to reduce the practice of blood transfusion. Advantages and drawbacks of different transfusion alternatives are reviewed, emphasizing that surgeons and anesthetists who practice in Centers with high volume of liver resections should be familiar with all the possible alternatives.

Introduction

Development in surgical techniques, improvements in preoperative and postoperative care and increased experience have markedly raised the safety of liver resections for hepatocellular carcinoma (HCC), and these procedures frequently can be carried out without blood perfusions.1-5 In contrast, complicated and riskier hepatectomies, including posterior resections with reconstruction of vena cava or resection of caudate lobe represent complex and invasive procedures which could require perioperative blood transfusion. Transfusion of allogenic blood has been reported to be associated with risks of human immunodeficiency virus and hepatitis transmission, transfusion reactions, increased postoperative infection rate and increased incidence of tumor recurrences for certain cancers.6 Transfusion of allogenic whole blood products has been shown to induce variations in certain immune functions,7,8 such as reduced NK cell activity and T-lymphocyte blastogenesis and increased suppressor T-lymphocyte activity, which may be of great relevance for host resistance to infection and spread of neoplastic cells. But, the adverse effect of allogeneic whole blood transfusion on cancer recurrence and survival rates,9-12 regardless of innumerable published studies, continues to be debatable, since virtually as many studies can be found that invalidate13-18 as studies that substantiate,19-27 this hypothesis. The latest advances in surgical techniques to control blood loss and transfusion need28-32 and the growing vast experience with hepatic resections, have been responsible of a remarkable reduction in the use of blood and blood products during surgery. Despite these efforts, allogeneic blood transfusion rates during hepatic resections have been reported at 40% to 80% depending upon the magnitude of the resection.3 Furthermore, even if the introduction of the hepatic inflow occlusion technique introduced by Pringle33 and the selective and/or intermittent inflow occlusion have been very effective for reducing blood loss during hepatic resection, still during Pringle *Corresponding Author: Gianlorenzo Dionigi—Department of Surgical Sciences, Azienda Ospedaliera-Polo Universitario, Via Guicciardini, 21100, Varese, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

142

Recent Advances in Liver Surgery

manoeuvre back bleeding from the hepatic veins and their tributaries could be unpredictable, severe and unexpected.34 The present review outlines the current perspectives about blood transfusion in hepatic resection, focusing on allogeneic blood transfusion, intraoperative autotransfusion, preoperative autologous blood donation and intraoperative isovolemic hemodilution.

Allogeneic Blood Transfusion

Recently there has been more and more concern about blood transfusion safety. Besides the previously mentioned risk of transmission of viral and bacterial infections, avoidable transfusion errors remain an important if uncommon cause of death and injury. New measures to reduce transfusion errors have been recently defined by Regan and Taylor.35 The incidence of allogeneic blood transfusion is high in patients with cirrhotic livers undergoing liver resections for HCC and for that reason it is consequential to indicate whether these transfusions stimulate tumor recurrence. The postoperative recurrence of HCC associated with perioperative blood transfusion has been supported36 and disputed,37 furthermore it has been investigated the relation between perioperative allogeneic blood transfusions, the recurrence free survival and the immunologic profiles of patients with HCC who had undergone curative liver resections.38 These studies have shown that in the transfused patients, the CD4 levels are decreased by 90 postoperative days, whereas the CD8 levels are elevated during 14-90 days after surgery, as compared with nontransfused patients. And postoperative levels of the CD57 (NK-cell subset) and PHA in the transfused group are elevated as compared with the nontransfused group and the PHA response of the transfused patients is significantly increased at 7 postoperative days. The recurrence free survival seems not to be affected by perioperative blood transfusions. All these studies suggest the suspicion of the significance of perioperative blood transfusion as an independent prognostic variable in terms of recurrence, survival, complications and death. In fact, patients who need preoperative, intraoperative, or postoperative transfusions are generally those with large lesions that either require a tri-segmentectomy, or are too close to the vena cava. On the other side, patients who do not need blood transfusions tend to have smaller, more peripheral lesions that can be resected under close hemostatic control. This suggests that patients with large HCC (and poor prognosis) are more likely to receive blood and possible other factors should be taken into consideration for a more accurate evaluation. In regard to survival, for instance, margin of resection, evidence of metastatic disease, liver failure or some other perioperative complications should always be reviewed. There are many complexities in this area, the only certainty being that there are conflicting factors that go into determining the success of a liver resection.

Intraoperative Autotransfusion

Intraoperative autotransfusion, also known as autologous blood salvage or intraoperative blood salvage (IBS) is a medical procedure involving recovering blood lost during surgery and re-infusing it into the patient. Several medical devices have been developed to assist in salvaging the patient’s own blood in the perioperative setting. It is widely used in a variety of surgical procedures, including cardiovascular, orthopedic and gynecologic procedures and emergency medical situations.39-41 IBS in oncologic patients has not been widely studied. It has been cited as a contraindication42 because of the potential risk of disseminating metastasis. This concept was introduced firstly by Yaw et al43 who demonstrated tumor cells in processed blood that passed through filters in the Bentley autotransfusion device. Other studies support that IBS can be safely used in patients with cancer.44-46 Because the Haemonetics cell saver processes blood by centrifuge-based washing after filtration, the risk of reinfusion of malignant cells seems to be lower than by the Bentley system. Clinical evidence of dissemination of cancer cells caused by IBS has not been reported and several studies show no correlation between the presence of malignant cells and their subsequent dissemination.47,48 The Haemonetics cell saver was employed by Fujimoto et al49 as an intraoperative scavenger of blood also in patients undergoing hepatectomy for HCC. In this study autotransfusion has been shown to be safe and effective and the pattern and frequency of recurrence suggest that autotransfusion is

Perioperative Blood Transfusion in Hepatocellular Carcinomas

143

not responsible for recurrence or metastasis. Recently Hashimoto et al have been able to show that intraoperative blood salvage in living liver donors undergoing liver resection for graft procurement offered the advantage of reduced blood loss during parenchymal transaction.50 At the present time the processes used to assist in salvaging the patient’s own whole blood in the perioperative setting can be categorized into three general types: (1) Cell processors and salvage devices that wash and save red blood cells, i.e., “cell washers” or RBC-savers; (2) Direct transfusion; (3) Ultrafiltration of whole blood. Cell processors are red cell washing devices that collect anticoagulated shed or recovered blood, wash and separate the red blood cells (RBCs) by centrifugation and reinfuse the RBCs. RBC washing devices can help remove byproducts in salvaged blood such as activated cytokines, anaphylatoxins and other waste substances that may have been collected in the reservoir suctioned from the surgical field. However, they also remove viable platelets, clotting factors and other [plasma proteins] essential to whole blood and homeostasis. Direct transfusion is a blood salvaging method associated with cardiopulmonary bypass (CPB) circuits or other extracorporeal circuits (ECC) that are used in surgery such as coronary artery bypass grafts (CABG), valve replacement, or surgical repair of the great vessels. Hemofiltration or ultrafiltration devices constitute the third major type of blood salvage appearing in operating rooms. In general, ultrafiltration devices filter the patient’s anticoagulated whole blood. The filter process removes unwanted excess noncellular plasma water, low molecular weight solutes, platelet inhibitors and some particulate matter through hemoconcentration, including activated cytokines, anaphylatoxins and other waste substances making concentrated whole blood available for reinfusion. Hemofilter devices return the patient’s whole blood with all the blood elements and fractions including platelets, clotting factors and plasma proteins with a substantial Hb level. Presently, the only whole blood ultrafiltration device in clinical use is the Hemobag.

Figure 1. Algorithm showing the overall criteria followed by our Group for perioperative blood transfusions during liver resections for HCC. Abbreviations: CAD: Coronary Artery Disease; CHF: Congestive Heart Failure; COPD: Chronic Obstructive Pulmonary Disease; SvO2: Saturated Venous Oxygen.

144

Recent Advances in Liver Surgery

The concern for possible contamination of autologous RBC with cancer cells responsible for metastasis still continues to limit the use of IBS in cancer patients, regardless of the fact that no evidence has been reported showing an increase in metastasis or a decrease in patient survival, in spite of the obvious demonstration that salvaged blood is contaminated with viable tumor cells which are not washed out of the RBC layer during IBS. Total elimination of the risk of reinfusion of cancer cells such as irradiation has been proposed by Hansen,51 who has been able to show that IBS with blood irradiation is safe as it provides efficient elimination of contaminating cancer cells, it does not compromise the quality of RBC and is very effective in saving blood resources. The effectiveness of this procedure has been shown on a large number of oncologic patients patients.52

Preoperative Autologous Blood Donation

Evidence that allogeneic transfusion may lead to a potential risk of postoperative infections and the increased demand for blood with a declining population of qualified, willing and healthy donors, give reason for the current encouragement for the use of preoperative autologous transfusion (PAD).53,54 The overall benefits of PAD have been assessed in both randomized trials and cohort studies.55 Assuming that the donor is not bacteremic at the time of donation and/or there are no clerical errors resulting in the accidental transfusion of the wrong unit of blood, the patient is also protected against hemolytic, febrile or allergic transfusion reactions; alloimmunization to erythrocyte, leukocyte, platelet or protein antigens; and graft-versus-host disease (GVHD). An additional benefit is that erythropoiesis may be stimulated by repeated phlebotomies, thereby enabling the patient to regenerate hemoglobin at an accelerated rate after surgery. PAD programs are not without some disadvantages. Perhaps the most important is that autologous blood is considerably more expensive than allogeneic blood. This problem is compounded by

Figure 2. The use of different techniques of blood transfusion during liver resection for HCC.

Perioperative Blood Transfusion in Hepatocellular Carcinomas

145

the fact that current reimbursement programs of most of the National Health systems around the world either deny the medical necessity of PAD or ignore the well-documented increase in cost.56 Moreover, the blood that is not transfused to the intended recipient (approximately 50 percent of donated blood) is generally wasted rather than transfused to other patients.57 This wastage of blood and the costs of administering autologous programmes result in collection expenses that are higher than those for allogeneic transfusion. Patients undergoing PAD may donate a unit (450 ± 45 ml) of blood as often as twice weekly, until 72 hours before surgery. Under normal conditions, patients conventionally donate once weekly. Oral iron supplements are routinely prescribed. This iatrogenic blood loss is accompanied by a response in endogenous erythropoietin (EPO) levels that, although increased significantly over basal levels, remain within the normal range. The erythropoietic response that occurs under these conditions is therefore modest.58 With routine PAD, erythropoiesis of 220-351 ml (11-19% RBC expansion)59,60 or the equivalent of 1-1.75 blood units, occurs in excess of basal erythropoiesis, which indicates the efficacy of this blood conservation practice. The use of autologous blood deposit for cancer patients undergoing elective surgical procedures has been studied by Lichtiger,61 who was able to show that the majority of his patients—132/182(tumors of head and neck, neurosurgical, gastrointestinal and colorectal, adrenal, gynecologic, soft tissue and bone, breast and genitourinary) underwent surgery using only autologous transfusions. Kajikawa et al evaluated the benefit of autologous blood transfusion and the effect of recombinant human erythropoietin (rh-EPO) on preoperative autologous blood donation for hepatectomy in patients with cirrhosis. Their study shows that autologous blood transfusion yields clinically superior results for hepatectomy in patients with cirrhosis when compared with homologous transfusion. In addition preoperative rh-EPO administration minimizes presurgical decreases in hematocrit caused by autologous blood donation.62 Likewise preoperative autologous blood donation in combination with rh-EPO therapy markedly reduces the requirements for homologous blood transfusion during hepatic resections.63 Other studies on patients undergoing hepatic resection have shown that the predeposit of autologous blood decreased the need for homologous transfusions from 56% to 38%. A further reduction in the transfusion rate of 25% could have been possible if all patients had donated 2 U of autologous blood.64 To determine if predonation of autologous blood impacts upon transfusion practice and clinical outcome following liver resection, clinical records of 379 consecutive patients undergoing hepatic resection for metastases of colorectal cancer were identified from the prospective hepatobiliary database and reviewed by Chan et al.65 No conclusion could be drawn from their data concerning the influence of allogeneic transfusion on tumor recurrence, since their study was not a randomized trial comparing allogeneic blood transfusion with autologous transfusion. Data from their study however demonstrated that PAD alone is insufficient to alter the rate of tumor recurrence or disease-specific survival. Furthermore major hepatic resections using current surgical techniques can be performed safely with low blood loss so that transfusion is required for only a minority of patients. PAD may further reduce the need for allogeneic blood. Autologous blood transfusion is safe after storage and it has advantages if compared with homologous blood transfusion with regard to postoperative liver function and survival rate after hepatectomy for HCC.66 In a recent study Hirano et al67 have shown that their autologous blood program, with intraoperative blood salvage and preoperative blood donation, reduces the volume of banked blood needed and improves the prognosis of patients undergoing hepatectomy for HCC.

Intraoperative Isovolemic Hemodilution

Acute isovolemic hemodilution (ANH) is another possible alternative to allogeneic blood transfusions, which has been introduced in the early 1970s.68 The procedure implies the removal of blood from the patient immediately before operation and the simultaneous replacement with appropriate volume of crystalloid or colloid fluids. ANH will reduce the hematocrit (HCT) so that blood shed during the operative procedure will result in less red blood cell mass loss. The

146

Recent Advances in Liver Surgery

amount of blood removed varies between one and three units (450 to 500 mL constitutes one unit), although larger volumes may be withdrawn safely in certain circumstances The removed blood is then reinfused as autologous whole blood after the major blood loss portion of the procedure is completed. The blood withdrawn is anticoagulated and maintained at room temperature, in the operating room, for up to eight hours. It is reinfused into the patient as needed during, or after, the surgical procedure. ANH can be used as the only blood preservation technique, or it can be combined with preoperative autologous donation, blood salvage, or both. Hemodilution could be classified according to the target hematocrit (Ht) as mild (hematocrit > 30%), moderate (30 < hematocrit > 20%), or severe (hematocrit < 20%).16 The target hematocrit with ANH is variable but is often around 25% to 30%. Severe hemodilution (e.g., 20%) is likely to be more efficacious with regards to blood conservation, but the risks are greater, particularly for patients with preexisting medical conditions such as coronary heart disease.69 ANH should be taken into consideration for patients with good initial hematocrits who are assumed to be deprived of more than two units of blood (900 to 1000 mL) during surgery. This technique works better in healthy, young adults, but it has been successfully employed in children and the elderly patients. ANH has been used in vascular, orthopedic and in some general surgical procedures. In addition, Jehovah’s Witnesses patients accept this technique with the modification that we keep the blood moving and in direct contact with the patient’s vascular system. Some Jehovah’s Witnesses will agree to ANH if the blood is maintained in a closed circuit continuous flow system.70 ANH is contraindicated in cardiac disease, since the main compensatory mechanism for the induced anemia is an increase in the cardiac output, when renal function is impaired, since large amounts of infused fluids need to be excreted and when baseline hemoglobin is below 110 gm/L (11 g/dL). Furthermore low concentrations of coagulation proteins, inadequate vascular access and the absence of appropriate monitoring capability indicate that ANH should not be used.71 In the last twenty years several groups reported the use of ANH during major hepatic resections72-76 and the overall conclusion is that ANH, in selected patients, is a safe and effective technique that appears to reduce the number of patients requiring homologous blood transfusion as well as the number of units transfused per patient. Furthermore, Jehova’s Witnesses with hepatic tumors represent a major problem for liver surgeons to achieve good outcome, in fact these patients, because of their religious beliefs, refuse transfusion of blood and blood products. In order to avoid transfusion Barakat et al75 have recently described the use of ANH in a Jehova’s Witness who underwent a combined left trisegmentectomy and caudate lobectomy to treat a large intrahepatic cholangiocarcinoma. ANH is considered a simple and inexpensive procedure and has the advantage that fresh autologous blood is readily available. Numerous studies of its efficacy, however, have produced conflicting results, perhaps because of the heterogeneity of the surgeries in which it was used, differences in study protocol and differences in the definition of outcome variables.77,78

Discussion

Liver resection is still the mainstay of treatment for patient with hepatocellular carcinoma. Even if improved surgical techniques and anesthesia have remarkably decreased the mortality rates of liver resections, morbidity rates, remain high. One of the major risk of hepatectomy is large-volume blood loss, which necessitates perioperative blood transfusion (Figs. 1 and 2). The possible consequences of homologous blood transfusion are well known and include noninfectious risks such as transfusion reactions, transient immunodeficiency, transfusion-associated graft-versus-host disease and transfusion-related acute lung injury.79-84 Thus there are conclusive motivations to reduce blood loss during surgery and, as a consequence to lessen blood transfusion. It has been clearly shown that transfusion has a significant negative effect on perioperative mortality, complications and length of hospital stay, even if it is difficult to demonstrate that transfusion is the only factor that decisively affects the outcome. The magnitude of the surgical procedure has always to be considered the most critical factor, being intuitive that anterior, small, marginal

Perioperative Blood Transfusion in Hepatocellular Carcinomas

147

atypical resections are quite different than complicated posterior large resections which include reconstruction of resected vena cava. An association between transfusion and postoperative complications has been shown in preclinical models85,86 and in clinical studies.87-91 The review of 378 consecutive elective liver resections performed in our institution shows that 62% of the patients were not transfused and the remaining 38% received blood products delivered with different procedures (Fig. 3). Infectious complications (wound infections, pneumonia, urinary tract infections, central venous catheter infections, abscesses and undiagnosed postoperative fever) have been more frequent in the transfused group of patients (33 vs 7). Most of the infections complications (18) have been recorded in the patients receiving autologous blood transfusions, the most frequent being wound infections (7) and pneumonia (5). Our results confirm the observation of Alfieri et al who in a series of 254 liver resections found a significant association between blood transfusions and development of complications.92 More recently Kooby et al have been able to show that perioperative blood transfusion is a prognostic factor for the development of complications in univariate and multivariate analysis. Transfusion predicted development of both minor and major complications. Transfused patients had twice as high a chance of developing major complications and four

Figure 3. Transfusion procedures in 378 patients undergoing liver resection. Abbreviations: No TR: Not Transfused (62%); ABT: Autologous Blood Transfusion (21%); IBS: Intraoperative Blood Salvage (3%); PAD: Preoperative Autologous Blood Donation (12%); ANH: Acute Normovolemic Hemodilution (2%, 7 of the 8 pts were Jehowa’s Witnesses). Data from the Department of Surgical Sciences, University of Insubria, Varese, Italy.

148

Recent Advances in Liver Surgery

Figure 4. Details of postoperative infectious complications (44 pts, 11,6%) occurred in 378 patients undergoing liver resections and correlated to transfusion procedures. Abbreviations: UTV: Urinary Tract Infection; CVC: Central Venous Catheter; UPF: Undiagnosed Post-operative Fever. Data from the Department of Surgical Sciences, University of Insubria, Varese, Italy.

times the risk of perioperative death. Transfused patients also had a higher incidence of infectious complications (17% vs 13%, P = 0.03).93 Despite these results and studies, it is still debatable to state that transfusion is the only and independent factor related to short term outcome and specifically the only determinant of postoperative infectious complications. Is the transfusion itself and not the reason for the transfusion the cause of postoperative morbidity? Intraoperative hypotension, complexity of operation (extended hepatectomies vs lesser resections), duration of anesthesia, age, stage of the neoplastic lesion, degree of liver disfunction, nutritional status, possible neoadjuvant treatment, they are all factors which could interfere with some aspects of the complex immunologic response. Furthermore, timing of the transfusion and the circumstances necessitating transfusions have been proposed as the real determinants of prognosis.94 Today we are not able to conclude that transfusion is the factor producing the infectious complication and the correlation we found of transfusion with complications should not be interpreted as a direct cause and effect relationship. The infectious complications are different in the transfused patients and not transfused, but we cannot say for sure that immunologic irregularities are what produces the difference. In the last years we had the occasion to carry out seven major liver resections on Jehova’s Witnesses with large tumors. The management of Jehova’s Witnesses with HCC, or any other type of liver tumors, entails a multidisciplinary, adapted plan in harmony with their religious beliefs to achieve good outcome.95 This approach enabled us to perform the surgical procedure respecting their religious conviction and authorize us to anticipate that ANH could be considered a safe alternative for use in selected cases in which allogeneic blood transfusion is considered of high risk. This approach, in our series, has been associated with a relative high incidence of infectious complications, if compared with other autologous blood transfusion procedures (Fig. 4).

Conclusions

A substantial discrepancy is apparent in transfusion practice for elective surgery and even more for liver resections.96 Reducing unneeded exposure to blood components by blood saving measures is essential in patients undergoing elective surgery. A publication for anesthesists reviews good transfusion practices in surgical patients.97 Perioperative blood transfusion has been described as one of the risk factors for poor outcome after liver resection. This seems particularly verifiable for infectious complications. The postoperative recurrence of HCC associated with perioperative blood transfusion has been the

Perioperative Blood Transfusion in Hepatocellular Carcinomas

149

subject of controversy due to conflicting results. Although allogeneic blood transfusion may have immunosuppressive effects, perioperative blood transfusions seem not influence the cancer free survival rate in patients with hepatocellular carcinoma. Even if there is no evidence of transfusion procedure which prevails over the others, surgeons who practice in Centers with high volume of liver resections should be familiar with all the possible alternatives (ABT, IBS, PAD, ANH), since each of them, when blood products are needed, have a place depending upon the different clinical pattern.

References

1. Tsao JI, Loftus JP, Nagorney DM et al. Trends in morbidity and mortality of hepatic resection for malignancy. A matched comparative analysis. Ann Surg 1994; 220(2):199-205. 2. Rees M, Plant G, Wells J et al. One hundred and fifty hepatic resections: evolution of technique towards bloodless surgery. Br J Surg 1996; 83(11):1526-1529. 3. Gozzetti G, Mazziotti A, Grazi GL et al. Liver resection without blood transfusion. Br J Surg 1995; 82(8):1105-1110. 4. Torzilli G, Gambetti A, Del Fabbro D. Techniques for hepatectomies without blood transfusion, focusing on interpretation of postoperative anemia. Arch Surg 2004; 139(10):1061-1065. 5. Torzilli G, Makuuchi M, Inoue K et al. No-mortality liver resection for hepatocellular carcinoma in cirrhotic and noncirrhotic patients: is there a way? A prospective analysis of our approach. Arch Surg 1999; 134(9):984-992. 6. Nielsen HJ. Detrimental effects of perioperative blood transfusion. Br J Surg 1995; 82(5):582-587. 7. Kaplan J, Sarnaik S, Gitlin J et al. Diminished helper/suppressor lymphocyte ratios and natural killer activity in recipients of repeated blood transfusions. Blood 1984; 64(1):308-310. 8. Gafter U, Kalechman Y, Sredni B. Induction of a subpopulation of suppressor cells by a single blood transfusion. Kidney Int 1992; 41(1):143-148. 9. Chung M, Steinmetz OK, Gordon PH. Perioperative blood transfusion and outcome after resection for colorectal carcinoma. Br J Surg 1993; 80(4):427-432. 10. Tartter PI. The association of perioperative blood transfusion with colorectal cancer recurrence. Ann Surg 1992; 216(6):633-638. 11. Rosen CB, Nagorney DM, Taswell HF et al. Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 1992; 216(4):493-504; discussion 504-505. 12. Tang R, Wang JY, Chien CR et al. The association between perioperative blood transfusion and survival of patients with colorectal cancer. Cancer 1993; 72(2):341-348. 13. Weiden PL, Bean MA, Schultz P. Perioperative blood transfusion does not increase the risk of colorectal cancer recurrence. Cancer 1987; 60(4):870-874. 14. Keller SM, Groshen S, Martini N et al. Blood transfusion and lung cancer recurrence. Cancer 1988; 62(3):606-610. 15. Foster RS Jr, Foster JC, Costanza MC. Blood transfusions and survival after surgery for breast cancer. Arch Surg 1984; 119(10):1138-1140. 16. Voogt PJ, van de Velde CJ, Brand A et al. Perioperative blood transfusion and cancer prognosis. Different effects of blood transfusion on prognosis of colon and breast cancer patients. Cancer 1987; 59(4):836-843. 17. Kampschöer GH, Maruyama K, Sasako M et al. The effects of blood transfusion on the prognosis of patients with gastric cancer. World J Surg 1989; 13(5):637-643. 18. Moriguchi S, Maehara Y, Akazawa K et al. Lack of relationship between perioperative blood transfusion and survival time after curative resection for gastric cancer. Cancer 1990; 66(11):2331-2335. 19. Foster RS Jr, Costanza MC, Foster JC et al. Adverse relationship between blood transfusions and survival after colectomy for colon cancer. Cancer 1985; 55(6):1195-1201. 20. Parrott NR, Lennard TW, Taylor RM et al. Effect of perioperative blood transfusion on recurrence of colorectal cancer. Br J Surg 1986; 73(12):970-973. 21. Tartter PI. The association of perioperative blood transfusion with colorectal cancer recurrence. Ann Surg 1992; 216(6):633-638. 22. Hyman NH, Foster RS Jr, DeMeules JE et al. Blood transfusions and survival after lung cancer resection. Am J Surg 1985; 149(4):502-507. 23. Moores DW, Piantadosi S, McKneally MF. Effect of perioperative blood transfusion on outcome in patients with surgically resected lung cancer. Ann Thorac Surg 1989; 47(3):346-51. Comment in: Ann Thorac Surg 1989; 48(5):746-747. 24. Little AG, Wu HS, Ferguson MK et al. Perioperative blood transfusion adversely affects prognosis of patients with stage I nonsmall-cell lung cancer. Am J Surg 1990; 160(6):630-632; discussion 633.

150

Recent Advances in Liver Surgery

25. Nowak MM, Ponsky JL. Blood transfusion and disease-free survival in carcinoma of the breast. J Surg Oncol 1984; 27(2):124-130. 26. Manyonda IT, Shaw DE, Foulkes A et al. Renal cell carcinoma: blood transfusion and survival. Br Med J (Clin Res Ed) 1986; 293(6546):537-538. 27. Rosenberg SA, Seipp CA, White DE. Perioperative blood transfusions are associated with increased rates of recurrence and decreased survival in patients with high-grade soft-tissue sarcomas of the extremities. J Clin Oncol 1985; 3(5):698-709. 28. Belghiti J, Noun R, Zante E et al. Portal triad clamping or hepatic vascular exclusion for major liver resection. A controlled study. Ann Surg 1996; 224(2):155-161. 29. Man K, Fan ST, Ng IO et al. Prospective evaluation of pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg 1997; 226(6):704-11; discussion 711-713. 30. Melendez JA, Arslan V, Fischer ME et al. Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion and the risk of postoperative renal dysfunction. J Am Coll Surg 1998; 187(6):620-625. Comment in Curr Surg 2005; 62(4):374-382. 31. Chan AC, Blumgart LH, Wuest DL et al. Use of preoperative autologous blood donation in liver resections for colorectal metastases. Am J Surg 1998; 175(6):461-465. 32. Johnson LB, Plotkin JS, Kuo PC. Reduced transfusion requirements during major hepatic resection with use of intraoperative isovolemic hemodilution. Am J Surg 1998; 176(6):608-611. 33. Pringle JH. Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg 1908; 48(4):541-549. 34. Hashimoto T, Kokudo N, Orii R et al. Intraoperative blood salvage during liver resection: a randomized controlled trial. Ann Surg 2007; 245(5):686-691. 35. Regan F, Taylor C. Blood transfusion medicine. BMJ 2002; 325(7372):1116. 36. Yamamoto J, Kosuge T, Takayama T et al. Perioperative blood transfusion promotes recurrence of hepatocellular carcinoma after hepatectomy. Surgery 1994; 115(3):303-309. 37. Matsumata T, Ikeda Y, Hayashi H et al. The association between transfusion and cancer-free survival after curative resection for hepatocellular carcinoma. Cancer 1993; 72(6):1866-1871. 38. Kwon AH, Matsui Y, Kamiyama Y. Perioperative blood transfusion in hepatocellular carcinomas: influence of immunologic profile and recurrence free survival. Cancer 2001; 91(4):771-778. 39. Hallett JW Jr, Popovsky M, Ilstrup D. Minimizing blood transfusions during abdominal aortic surgery: recent advances in rapid autotransfusion. J Vasc Surg 1987; 5(4):601-606. 40. Dzik WH, Jenkins R. Use of intraoperative blood salvage during orthotopic liver transplantation. Arch Surg 1985; 120(8):946-948. 41. Williamson KR, Taswell HF. Intraoperative blood salvage: a review transfusion 1991; 31(7):662-675. 42. Council on scientific affairs autologous blood transfusions. JAMA 1986; 256(17):2378-2380. 43. Yaw PB, Sentany M, Link WJ et al. Tumor cells carried through autotransfusion. Contraindication to intraoperative blood recovery? JAMA 1975; 231(5):490-491. 44. Klimberg I, Sirois R, Wajsman Z et al. Intraoperative autotransfusion in urologic oncology. Arch Surg 1986; 121(11):1326-1329. 45. Muscari F, Suc B, Vigouroux D et al. Blood salvage autotransfusion during transplantation for hepatocarcinoma: does it increase the risk of neoplastic recurrence? Transpl Int 2005; 18(11):1236-1239. 46. Valbonesi M, Bruni R, Lercari G et al. Autoapheresis and intraoperative blood salvage in oncologic surgery. Transfus Sci 1999; 21(2):129-139. 47. Salsbury AJ The significance of the circulating cancer cell. Cancer Treat Rev 1975; 2(1):55-72. 48. Griffiths JD, McKinna JA, Rowbotham HD et al. Carcinoma of the colon and rectum: circulating malignant cells and five-year survival. Cancer 1973; 31(1):226-236. 49. Fujimoto J, Okamoto E, Yamanaka N et al. Efficacy of autotransfusion in hepatectomy for hepatocellular carcinoma. Arch Surg 1993; 128(9):1065-1069. 50. Hashimoto T, Kokudo N, Orii R. Intraoperative blood salvage during liver resection: a randomized controlled trial. Ann Surg 2007; 245(5):686-691. 51. Ernil H, Bechmann V, Altmeppen J. Intraoperative blood salvage in cancer surgery: safe and effective? Transfusion and Apheresis Science 2002; 27(2):153-157. 52. Valbonesi M, Bruni R, Lercari G et al. Autoapheresis and intraoperative blood salvage in oncologic surgery. Transfus Sci 1999; 21(2):129-39. 53. Toy PT, Strauss RG, Stehling LC et al. Predeposited autologous blood for elective surgery. A national multicenter study. N Engl J Med 1987; 316(9):517-520. 54. Lichtiger B, Huh YO, Armintor M et al. Autologous transfusions for cancer patients undergoing elective ablative surgery. J Surg Oncol 1990; 43(1):19-23. 55. Vanderlinde ES, Heal JM, Blumberg N. Autologous transfusion. BMJ 2002; 324(7340):772-775. 56. Yomtovian R, Kruskall MS, Barber JP. Autologous-blood transfusion: the reimbursement dilemma. J Bone Joint Surg Am 1992; 74(8):1265-1272.

Perioperative Blood Transfusion in Hepatocellular Carcinomas

151

57. Fontaine MJ, Winters JL, Moore SB et al. Frozen preoperative autologous blood donation for heart transplantation at the mayo clinic from 1988 to 1999. Transfusion 2003; 43(4):476-480. 58. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron and erythropoiesis. Blood 2000; 96:823-833. 59. Kasper SM, Gerlich W, Buzello W. Preoperative red cell production in patients undergoing weekly autologous blood donation. Transfusion 1997; 37:1058-1062. 60. Kasper SM, Lazansky H, Stark C et al. Efficacy of oral iron supplementation is not enhanced by additional intravenous iron during autologous blood donation. Transfusion 1998; 38:764-770. 61. Lichtiger B, Huh YO, Armintor M et al. Autologous transfusions for cancer patients undergoing elective ablative surgery. J Surg Oncol 1990; 43(1):19-23. 62. Kajikawa M, Nonami T, Kurokawa T et al. Autologous blood transfusion for hepatectomy in patients with cirrhosis and hepatocellular carcinoma: use of recombinant human erythropoietin. Surgery 1994; 115(6):727-734. 63. Shinozuka N, Koyama I, Arai T et al. Autologous blood transfusion in patients with hepatocellular carcinoma undergoing hepatectomy. Am J Surg 2000; 179(1):42-45. 64. Cunningham JD, Fong Y, Shriver C et al. One hundred consecutive hepatic resections. Blood loss, transfusion and operative technique. Arch Surg 1994; (10):1050-1056. 65. Chan AC, Blumgart LH, Wuest DL et al. Use of preoperative autologous blood donation in liver resections for colorectal metastases. Am J Surg 1998; 175(6):461-465. 66. Kitagawa K, Taniguchi H, Mugitani T et al. Safety and advantage of perioperative autologous blood transfusion in hepatic resection for hepatocellular carcinoma. Anticancer Res 2001; 21(5):3663-3667. 67. Hirano T, Yamanaka J, Iimuro Y et al. Long-term safety of autotransfusion during hepatectomy for hepatocellular carcinoma. Surg Today 2005; 35(12):1042-1046. 68. Messmer K. Hemodilution. Surg Clin North Am 1975; 55(3):659-678. 69. Napier JA, Bruce M, Chapman J et al. Guidelines for autologous transfusion: II. Perioperative haemodilution and cell salvage. Br J Anaesth 1997; 78:768-771. 70. Schaller RT Jr, Schaller J, Morgan A et al. Hemodilution anesthesia: a valuable aid to major cancer surgery in children. Am J Surg 1983; 146(1):79-84. 71. Kreimeier U, Messmer K. Hemodilution in clinical surgery: state of the art 1996. World J Surg 1996; 20:1208-1217. 72. Chen H, Sitzmann JV, Marcucci C et al. Acute isovolemic hemodilution during major hepatic resection— an initial report: does it safely reduce the blood transfusion requirement? J Gastrointest Surg 1997; 1(5):461-466. 73. Johnson LB, Plotkin JS, Kuo PC. Reduced transfusion requirements during major hepatic resection with use of intraoperative isovolemic hemodilution. Am J Surg 1998; 176(6):608-611. 74. Rhim CH, Johnson LB, Kitisin K et al. Intra-operative acute isovolemic hemodilution is safe and effective in eliminating allogeneic blood transfusions during right hepatic lobectomy: Comparison of living donor versus nondonors. HPB 2005; 7(3):201-203. 75. Barakat O, Cooper JR Jr, Riggs SA et al. Complex liver resection for a large intrahepatic cholangiocarcinoma in a jehovah’s witness: a strategy to avoid transfusion. J Surg Oncol 2007; 96(3):249-253. 76. Balci ST, Pirat A, Torgay A et al. Effect of restrictive fluid management and acute normovolemic intraoperative hemodilution on transfusion requirements during living donor hepatectomy. Transplant Proc 2008; 40(1):224-227. 77. Segal JB, Blasco-Colmenares E et al. Preoperative acute normovolemic hemodilution: a meta-analysis. Transfusion 2004; 44:632-644. 78. Bryson GL, Laupacis A, Wells GA. Does acute normovolemic hemodilution reduce perioperative allogeneic transfusion? A meta-analysis. The international study of perioperative transfusion. Anesth Analg 1998; 86:9-15. 79. Doyle JD. Blood transfusions and the Jehovah’s Witness patient. Am J Ther 2002; 9:417-424. 80. America’s Blood Centers. West nile virus and the blood supply. ABC Bulletin 2003; 6(1):1-2. 81. Marcucci C, Madjdpour C, Spahn DR. Allogeneic blood transfusions: benefi t, risks and clinical indications in countries with low or high development index. Br Med Bull 2004; 70:15-28. 82. Leal-Noval SR, Rincon-Ferrari MD, Garcia-Curiel A et al. Transfusion of blood components and postoperative infections in patients undergoing cardiac surgery. Chest 2001; 119:1461-1468. 83. Domen RE, Hoeltge GA. Allergic transfusion reactions: an evaluation of 273 consecutive reactions. Arch Pathol Lab Med 2003; 127:316-320. 84. Roth VR, Kuehnert MJ, Haley NR et al. Evaluation of a reporting system for bacterial contamination of blood components in the United States. Transfusion 2001; 41:1486-1493. 85. Tadros T, Wobbes T, Hendriks T. Blood transfusion impairs the healing of experimental intestinal anastomoses. Ann Surg 1992; 215(3):276-281.

152

Recent Advances in Liver Surgery

86. Tadros T, Wobbes T, Hendriks T. Opposite effects of interleukin-2 on normal and transfusion-suppressed healing of experimental intestinal anastomoses. Ann Surg 1993; 218(6):800-808. 87. van de Watering LM, Hermans J, Houbiers JG et al. Beneficial effects of leukocyte depletion of transfused blood on postoperative complications in patients undergoing cardiac surgery: a randomized clinical trial. Circulation 1998; 97(6):562-568. 88. Vamvakas EC, Carven JH. Allogeneic blood transfusion, hospital charges and length of hospitalization: a study of 487 consecutive patients undergoing colorectal cancer resection Arch Pathol Lab Med 1998; 122(2):145-51. Comment in: Arch Pathol Lab Med 1998; 122(2):117-119. 89. Bellantone R, Sitges Serra A, Bossola M et al. Transfusion timing and postoperative septic complications after gastric cancer surgery: a retrospective study of 179 consecutive patients. Arch Surg 1998; 133(9):988-992. 90. Kinoshita Y, Udagawa H, Tsutsumi K et al. Usefulness of autologous blood transfusion for avoiding allogenic transfusion and infectious complications after esophageal cancer resection. Surgery 2000; 127(2):185-192. 91. Mynster T, Christensen IJ, Moesgaard F et al. Effects of the combination of blood transfusion and postoperative infectious complications on prognosis after surgery for colorectal cancer. Danish RANX05 Colorectal Cancer Study Group Br J Surg 2000; 87(11):1553-1562. 92. Alfieri S, Carriero C, Caprino P et al. Avoiding early postoperative complications in liver surgery. A multivariate analysis of 254 patients consecutively observed. Dig Liver Dis 2001; 33(4):341-346. 93. Kooby DA, Stockman J, Ben Porat L et al. Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg 2003; 237(6):860-9; discussion 869-870. 94. Bossola M, Pacelli F, Bellantone R et al. Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg 2005; 241(2):381. 95. Barakat O, Cooper JR Jr, Riggs SA et al. Complex liver resection for a large intrahepatic cholangiocarcinoma in a Jehovah’s witness: a strategy to avoid transfusion. J Surg Oncol 2007; 96(3):249-253. 96. The sanguis study group use of blood products for elective surgery in 43 European hospitals. Transfus Med 1994; 4(4):251-268. 97. Association of anaesthetists of great britain and ireland blood transfusion and the anaesthetist: red cell transfusion. London: Association of Anaesthetists of Great Britain and Ireland 2001.

Chapter 13

Inferior Vena Cava Resection for Infiltrating Hepatic Malignancy

Gabriele Piffaretti, Gianlorenzo Dionigi, Matteo Tozzi, Patrizio Castelli and Renzo Dionigi*

Abstract

L

iver tumors with involvement of the inferior vena cava (IVC) may demand the combined resection of the liver and IVC. This approach, even if it has become common for hepatic malignancies involving the IVC, still represents a high risk surgical procedure with a poor long-term prognosis. The objective of this article is to review distinct approaches used in different centers and evaluate the results in order to determine the effectiveness of this aggressive approach.

Introduction

It would appear that tumoral invasion of the inferior vena cava (IVC) was noticed more than 300 years ago. Jacob Bontius ( Jakob de Bondt, 1592-1631) should be considered the first physician to report tumoral involvement of the inferior vena cava. He was a Dutch physician who spent the last four years of his life in Djackarta, Java. His writings were preserved and published posthumously by his brother. This important and rare work is divided into four sections: (1) criticisms of the third book of Garcia de Orta’s treatise on Asian materia medica; (2) the maintenance of a healthy diet; (3) Indian methods of treatment; and ( 4) observations from autopsies. In the fourth section he describes an autopsy performed “me praesente” on September 7, 1629 in which the vena cava was invaded by “medullosa substantia” from a peritoneal tumor—vena cava loco sanguinis, repleta erat adiposa ac medullosa substantia quadam-.1 Stephanus Blancardus (Steven Blankaart, 1650-1702), physician at Amsterdam, who may be regarded as one of the most important Dutch physicians, was a prolific writer of popular medical treatises, books on anatomy, surgery, etc, including an herbal and a large work on insects. He was the first to introduce Cartesianism into medical science and in his Anatomica Practica Rationalis, at Obs. XVI, he also describes a postmortem finding in which the inferior cava was filled with neoplastic “steatomatus matter”—vena cava descendens materia adiposa and medullæ instar repleta erat-.2 During the latter part of the 19th century until the early 80s of the 20th, removal of a neoplastic thrombus occupying the IVC lumen or the vein resection for mural involvement by tumor invasion entailed formidable technical difficulties that submerged surgical abilities of those eras. Starzl and coworkers have been the first to report complete excision of the retrohepatic cava and its replacement with a vena cava homograft during liver resection.3 For many years lateral excision of IVC with or without patch angioplasty has been preferred over graft replacement when possible, mainly because this procedure is safer and easier to perform. Subsequently, it has been only in the last twenty-five years that autologous and prosthetic grafts have been frequently *Corresponding Author: Renzo Dionigi—Department of Surgical Sciences, Azienda Ospedaliera-Polo Universitario, Via Guicciardini, 21100, Varese, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

154

Recent Advances in Liver Surgery

and successfully used to replace the vena cava.4-7 Liver resections, due to the adoption of several advanced techniques, such as vascular exclusion,8-10 veno-venous bypass, hypothermic perfusion of the liver (in situ, ante situm, or ex situ11), have become more common and, when IVC is involved, resection of the vein is not considered a contraindication anymore. Recent technical improvements indicate that aggressive surgical resection for liver carcinomas is justified and it could improve the prospects for long-term survival of patients who otherwise have a poor prognosis.12-21 The majority of these studies are case reports based mainly on small numbers and do not contribute to outline a definitive consensus on different aspects of such an aggressive procedure. Purpose of this review is to review different groups experiences with liver resection and IVC resection and reconstruction, taking into account the anatomy, diagnosis and treatment of IVC invasion of hepatic liver tumors.

Surgical Anatomy

Accurate knowledge of the surgical anatomy of the hepatic veins and inferior vena cava is necessary for hepatic surgery. Details and accurate measurements of its retrohepatic segment and its tributaries have been reported by different groups.22,23 From a clinical and surgical point of view, the IVC may be considered as having three segments (Fig. 1).24 The lower segment (segment 1) is the infrarenal vena cava, from the confluence of the common iliac veins to the renal veins. The middle segment (segment 2) includes the origins of the renal veins and the retrohepatic portion of the IVC. Segment 2 is composed by an infrahepatic sub-segment, between the inferior edge of the liver and the confluence of the renal veins and a retrohepatic sub-segment, behind the liver. The upper segment (segment 3) includes the origins of the hepatic veins and the suprahepatic portion of the IVC, up to the right atrium. Segment 2 is the segment most frequently involved by liver tumors infiltrating the IVC.

Anomalies

Anomalies of the IVC and its tributaries have been known since 1793, when the English surgeon John Abernethy (1764-1831) described a congenital mesocaval shunt and azygos continuation of the IVC in a 10-month-old infant with polysplenia and dextrocardia.24 Since the development of cross-sectional imaging, congenital anomalies of the IVC and its tributaries have become more frequently encountered in asymptomatic patients.25 For the interested reader, to better understand the embryogenesis of the IVC, a comprehensive review has been published by Phillips.26 During embryogenesis, the IVC is shaped by the development, regression and anastomosis of three sets of paired veins: the posterior cardinal, subcardinal and supracardinal veins.27 The normal IVC turns to an unilateral right-sided system which is composed, from cauda to cranium, of the postrenal, renal, prerenal and hepatic segments. If the originally structures do not fuse, anomalies of the IVC may be the consequence. Such anomalies have an estimated prevalence of 0.07% to 8.7% in the general population.28 Anomalies become manifest in infants when combined with heart failure or visceral malformations,29 whereas in adults, they are commonly seen incidentally in abdominal surgery or in radiologic work-up.28,30 Dealing with IVC resection during hepatectomy, lack of appreciation of these anomalies can cause serious clinical problems and technical challenges; therefore, as several reports in the literature31-37 have now confirmed, computed-tomography-angiography (CT-A) or contrast-enhanced magnetic-resonance (MR) can often diagnose these anomalies and should be performed preoperatively in order to assess the morphology of the IVC, especially of the segment to be replaced. Fifteen types of anomalies have been reported so far, many of these are minor variations and some have been reported only in animals. Of clinical relevance are the nine reported by Bass et al:37 Left IVC, Double IVC, Azygos Continuation of the IVC, Circumaortic Left Renal Vein, Retroaortic Renal Vein, Double IVC with Retroaortic Right Renal Vein and Hemiazygos Continuation of the IVC, Double IVC with Retroaortic Left Renal Vein and Azygos Continuation of the IVC, Circumcaval Ureter, Absent Infrarenal IVC with Preservation of the Suprarenal Segment.

Inferior Vena Cava Resection for Infiltrating Hepatic Malignancy

155

Figure 1. Schematic representation of the IVC and its division in three segments: segment 1—infrarenal; segment 2—composed by the infrahepatic sub-segment and the retrohepatic sub-segment; segment 3—suprahepatic. HVs: hepatic veins; RV: renal vein.

Diagnosis

Hepatocarcinoma (HCC) for its magnitude or location may invade the wall of the retrohepatic suprarenal IVC up to and including the hepatic veins. It may obstruct its lumen by extrinsic compression, invasion of the caval wall, or intraluminal growth of tumor thrombus. Diagnosis sometimes remains difficult and not always the lesion is recognized preoperatively. The most crucial point in clinical practice is to clearly discriminate between external compression and direct parietal infiltration. It is also critical for the surgeon to distinctly diagnose not only the infiltration by the thrombus, but the level of its extension and adherence to the vessel wall. The four most useful modalities for visualizing the possible involvement of the vena cava are: ultrasonography, computed tomography (CT) (Figs. 2 and 3), magnetic resonance imaging (MRI) and vena-cavography. A combination of these studies is recommended to define a correct diagnosis and have the necessary information to determine resectability and to plan the type of vena cava reconstruction. More recently a new technology, intracaval endovascular ultrasonography (ICEUS), also called percutaneous endocaval sonography (PECS) has been proposed in the assessment of IVC infiltration.38,39

156

Recent Advances in Liver Surgery

Figure 2. Contrast enhanced abdominal CT scan (coronal plane) showing a neoplastic thrombus in the intra-hepatic inferior vena cava.

Ultrasonography may represent an important step in diagnosis. It provides imaging of the whole IVC, including the retrohepatic segment; however, distorsion of the major venous structures by tumor and the presence of bowel gas impair evaluation of the vena cava and are the major limitations with this technique. Nevertheless, ultrasonography has the same sensitivity of MRI and vena-cavography for detecting the patency of the vein and the possible presence and extension of a neoplastic thrombus in the lumen.40 CT-A and MRI should be considered the two most frequently used tests in the evaluation of patients with the suspicion of IVC invasion.41 Both techniques detect the primary tumor and the neoplastic invasion of IVC. MRI has evolved into a particularly flexible technique because it allows imaging of the tumor and vena cava in axial, coronal and sagittal planes. Additionally, both CT and MRI are useful for postoperative oncologic follow-up and for monitoring graft patency when venous reconstruction is performed.42 Cava-venography has long been the “gold standard” for the evaluation of patients with suspected neoplastic invasion by the liver tumor. The most recent developments in software and

Inferior Vena Cava Resection for Infiltrating Hepatic Malignancy

157

Figure 3. Contrast enhanced abdominal CT scan (sagittal plane) showing a neoplastic thrombus in the intra-hepatic inferior vena cava.

instrumentation have replaced this technique, which has very rare indications, although still useful in selected cases. With the recent progress of ultrasound technology, an intravascular ultrasound catheter has been developed. ICEUS is a new evolving modality which provides high resolution, cross-sectional and real-time images of the vessel wall. Kaneko et al38 applied this technology to the diagnois of vena caval involvement by hepatic tumor and came to the final conclusion that ICEUS is a useful technique to evaluate the IVC for possible hepatic tumor invasion.38,39 The indications for ICEUS to evaluate the intracaval tumor thrombus by hepatic cancer, according to Kaneko, are the following: 1) when the draining portion of the hepatic vein to the IVC is not visualized well because of hepatic tumor and invasion of the hepatic vein is suspected by conventional imaging techniques and 2) when an intracaval tumor thrombus does not occlude the IVC lumen with equivocal cephalad extension, ICEUS is indicated. ICEUS can detect small tumor thrombus, diagnose its extent and evaluate the degree of adherence to the IVC wall. Okada et al43 have been more cautious about ICEUS and they consider that one drawback of ICEUS is the near-field artifact: the single-crystal

158

Recent Advances in Liver Surgery

transducer has a dead space immediately in front of the crystal face because it is unable to detect echoes from extremely close reflecting interfaces.44,45 This limitation may result in false-negative examinations in the presence of severe IVC stenosis. Technologic improvements, such as an endoluminal probe that has a movable tip,44 should overcome this drawback. In conclusion the diagnostic program when IVC invasion by liver tumor is suspected should be the following: conventional ultrasound should be used first because it is a noninvasive, low-cost, real-time procedure. CT scan including dynamic study and MRI should follow, since they are non-invasive. Based on the results of these examinations, patients should be selected for ICEUS, with cavography only in selected cases.

Treatment

In the past years, surgery was rarely performed in patients with HCC invading the vena cava for reasons related mainly to advanced age, poor prognosis and high operative risk. More recently, advances in preoperative imaging studies for staging, surgical techniques, post-operative care and development of new materials for prosthetic grafts, persuaded liver surgeons to be more aggressive in selected groups of patients.46-61

Inferior Vena Cava Resection Without Replacement

Complete resection of the IVC without venous replacement has been performed, but has been reported to show more risk of renal insufficiency and lower extremity edema if compared with resection of the infrarenal segment.19,62 When the retrohepatic IVC is occluded circulation is assured by collaterals represented by lumbar, epigastric, renal, adrenals, gonadal and paravertebral veins.63 However, it is impossible to predict late venous sequelae on the basis of preoperative signs, symptoms, or imaging.19,62 Unfeasibility to reconstruct the resected segment of IVC may induce a transient or irreversible renal insufficiency in about 50% of patients.64 At present, most of the liver surgeons advise to replace the retrohepatic segment of the IVC for the majority of the patients.

Inferior Vena Cava Partial Resection

If less than 30% of the circumference of the IVC wall is involved or infiltrated for a short segment, (<2 cm), partial resection can be chosen and the vein is sutured longitudinally (Fig. 4). The direct suture should be performed very carefully not to narrow the IVC considerably. If the wall involvement is between 30% and 50%, the IVC should be sutured transversely (as for pyloroplasty) to prevent stenosis of the vein; a patch of autologous saphenous vein, fascial peritoneum, or heterologous materials can be used in the presence of extended infiltration of the wall (>2 cm), to prevent lumen stenosis (Fig. 5). Since the resection should always be carried out at a safe distance from the tumor, partial resection of the IVC followed by direct suture or prosthetic patch angioplasty is rarely adequate to be considered curative.

Inferior Vena Cava Complete Segmental Resection

If half or more of the circumference of the wall is damaged, or in the presence of a longitudinal infiltration, or, less frequently, in the presence of an intracaval thrombus, or any situation in which the retroperitoneal dissection or resection has removed the pre-existing collaterals, in all these situations the circumferential resection of IVC under total hepatic vascular esclusion (THVE) is the only alternative (Fig. 6). Different materials have been used as patches to substitute segments of IVC, including xenografts,65,66 allografts,3 autologous grafts67,68 and Dacron.69 At present there is a general consensus for using reinforced polytetrafluoroethylene (PTFE), based on experimental70-72 and clinical studies.17,19,46,48,49,56,57,59 The rationale for the use of ring-reinforced PTFE grafts is that they would resist respiratory compression and graft collapse, which may promote thrombosis.56,59,73 The common practice for resection of IVC retrohepatic segment is to divide the parenchima first down to the cava and thereafter replace the IVC with a graft while at the same time restore the portal inflow. Madariaga et al58,46 described a novel technique for IVC excision and replacement before parenchymal transection. This approach has the benefit of a short warm ischemia time

Inferior Vena Cava Resection for Infiltrating Hepatic Malignancy

Figure 4. Partial IVC resection and longitudinal suture.

Figure 5. Partial IVC resection with a patch of heterologous material.

159

160

Recent Advances in Liver Surgery

Figure 6. IVC complete segmental resection and replacement with ring-reinforced PTFE graft.

because it eliminates cross clamping of the hilum. According to these Authors it provides also a better control resection and is well tolerated by the patient.

Discussion

Inferior vena cava involvement by HCC for a long time has been in general considered a contraindication for surgery59 and it might result, if untreated, to death within 3 months after recognition.15 Aggressive resections have been reported in only a few studies.3,9-11,14,17-20,46-49,51-58,61 Results and experiences around the world indicate that these patients with such an advanced tumor should be treated in centers with high volume of liver surgery and with an interdisciplinary approach, which involves oncologic, radiologic, vascular and general surgery proficiencies. The approach to the retrohepatic IVC resection in patients with HCC depends on the general conditions and the extent and location of tumor involvement. The risks of IVC and hepatic outflow reconstructions are real, not all patients can tolerate the physiologic aggression and the

161

Inferior Vena Cava Resection for Infiltrating Hepatic Malignancy

surgeon should find the right compromise and sometimes carry out a smaller resection or discard a plan for vascular reconstruction. At our institution there were 11 hepatectomies combined with IVC reconstruction. (Table 1). All the patients were investigated to exclude extrahepatic malignant disease. Furthermore, the patient’s performance status has been evaluated using the method outlined by Zubrod74 which provides an assessment of the patient’s physical fitness and has been a useful measure of functional quality of life for patients with malignant disease. A scoring system from 0 to 4 is used: a score of 0 indicates the patient is fully active, a score of 4 indicates that the patient is confined to bed and scores from 1 through 3 indicate varying degrees of physical limitation between these extremes. No options for curative treatment other than resection were considered available for these patients. Jaundice and poor synthetic liver function have been considered unfavorable signs expanding the morbidity of a combined approach. Cirrhosis and renal function insufficiency have been regarded as contraindication for the procedure, due to a possible irreversible deterioration of liver and renal function after in-flow vascular exclusion and even a transient vena cava exclusion. Portal vein embolization as an effective method for inducing selective hepatic hypertrophy of the nondiseased portion of the liver was performed in one case, as described by Makuuchi et al.75 In most of the cases (8 cases) vascular control was achieved by total vascular exclusion. The infrahepatic vena cava, hilum and suprahepatic vena cava were serially clamped following ligation and division of the adrenal vein.9,10 In situ hypothermic perfusion of the liver was applied in one case when we assumed that the total vascular exclusion could have lasted beyond 1 hour. In one case we followed the two-step vascular exclusion as described by Azoulay et al.13

Table 1. Results of 11 patients undergoing combined resection of the liver and IVC for HCC Vascular Cava Duration of Blood Follow-up Patient Operation Exclusion Resection Replacement Surgery (min) Loss (mL) (Months) 1

RL-wCR

HTVE

Partial

Direct suture 507

2820

43: dead

2

RL-wCR

HTVE

Partial

Patch

470

3100

46: alive

3

RL-sCR

HTVE

Segmental

Graft

386

2180

13: dead

4

LTS-wCR

Partial Hypothermic perfusion

Patch

670

1820

14: dead

5

RL-wCR

HTVE

Partial

Direct suture 350

2450

22: dead

6

RL-sCR

HTVE

Segmental

Graft

412

4150

16: dead

7

RL-wCR

HTVE

Partial

Patch

280

1940

14: alive

8

LTS-sCR

HTVE

Segmental

Graft

358

3245

12: dead

9

LTS-wCR

HTVE

Partial

Direct suture 310

1750

12: alive

10

LTS-sCR

Two step VE

Segmental

Graft

474

3875

10: alive

11

RL-sCR

HTVE

Segmental

Graft

330

2960

8: alive

RL: Right Liver; LTS: Left Trisegmentectomy; wCR: Wedge Resection of Vena Cava; sCR: Segmental Resection of Vena Cava; HTVE: Hepatic Total Vascular Exclusion.

162

Recent Advances in Liver Surgery

IVC replacement is usually performed using PTFE graft. It has been observed that in case of patients undergoing simultaneous liver resection with biliary reconstruction and prosthetic IVC replacement, postoperative graft infection should be taken into consideration. In these circumstances in order to reduce infection it has been suggested to use omental interposition between graft and the resected viscera. Use of anticoagulation drugs after caval replacement is variable in the literature. There are reports which are not in favor of routine administration of long-term anticoagulation or antiplatelet agents,49, 56, 76,77 others recommend indefinite application of oral anticoagulation.15,78 In our series long-term anticoagulation therapy was not employed and grafts have been found to be patent during systemic follow-up.19,76

Conclusion

Inferior vena cava involvement by HCC does not inevitably exclude resection of the vein. Replacement of the IVC can be performed in highly selected cases and applying different reconstruction techniques depending upon the location and extension of the lesion. This aggressive approach seems to be justified also by the scarcity of alternatives. If surgery is carried out by specialized surgical teams in centers with a high volume of liver surgery and an interdisciplinary perspective, the procedure has a low morbidity and mortality and acceptable survival rates.

References

1. Alpini, Prosper. De medicina Aegyptiorvm, libri qvatvor and Iacobi Bontii in Indiis archiatri, De medicina Indorvm. Editio vltima. Parisiis, Apud Nicolavm Redelichvysen, M.DC.XLV; 4:36. 2. Blankaart, Steven Steph. Blancardi Anatomia practica rationalis, sive rariorum cadaverum morbis denatorum anatomica inspectio. Accedit item tractatus novus de circulatione sanguinis per tubulos, deque eorum valvulis and c. Amstelodami, Ex officina Corn: Blancardi in Platea Vulgo de Warmoes Straat, 1688:38. 3. Starzl TE, Koep LJ, Weil R III et al. Right trisegmentectomy for hepatic neoplasma. Surg Gynecol Obstet 1980; 150(2):208-14. 4. Doty DB, Baker WH. Bypass of superior vena cava with spiral vein graft. Ann Thorac Surg 1976; 22(5):490-493. 5. Doty DB. Bypass of superior vena cava: Six years’ experience with spiral vein graft for obstruction of superior vena cava due to benign and malignant disease. J Thorac Cardiovasc Surg 1982; 83(3):326-338. 6. Dale WA, Harris J, Terry RB. Polytetrafluoroethylene reconstruction of the inferior vena cava. Surgery 1984; 95(5):625-630. 7. Gloviczki P, Pairolero PC, Cherry KJ et al. Reconstruction of the vena cava and of its primary tributaries: a preliminary report. J Vasc Surg 1990; 11(3):373-381. 8. Heaney JP, Stanton WK, Halbert DS. An improved technic for vascular isolation of the liver: experimental study and case reports. Ann Surg 1966; 163(2):237-241. 9. Huguet C, Nordlinger B, Galopin JJ et al. Normothermic hepatic vascular exclusion for extensive hepatectomy. Surg Gynecol Obstet 1978; 147(5):689-693. 10. Bismuth H, Castaing D, Garden OJ. Major hepatic resection under total vascular exclusion. Ann Surg 1989; 210(1):13-19. 11. Azoulay D, Eshkenazy R, Andreani P et al. In situ hypothermic perfusion of the liver versus standard total vascular exclusion for complex liver resection. Ann Surg 2005; 241(2):277-285. 12. Beck SD, Lalka SG. Long-term results after inferior vena caval resection during retroperitoneal lymphadenectomy for metastatic germ cell cancer. J Vasc Surg 1998; 28(5):808-814. 13. Miyazaki M, Ito H, Nakagawa K et al. Aggressive surgical resection for hepatic metastases involving the inferior vena cava. Am J Surg 1999; 177(4):294-298, Comment in: Am J Surg 2000; 179(1):77-78. 14. Takayama T, Makuuchi M, Kosuge T et al. A hepatoblastoma originating in the caudate lobe radically resected with the inferior vena cava. Surgery 1991; 109(2):208-213. 15. Bower TC, Nagorney DM, Cherry KJ Jr et al. Replacement of the inferior vena cava for malignancy: an update. J Vasc Surg 2000; 31(2):270-281. 16. Lodge JP, Ammori BJ, Prasad KR et al. Ex vivo and in situ resection of inferior vena cava with hepatectomy for colorectal metastases. Ann Surg 2000; 231(4):471-479. 17. Hemming AW, Reed AI, Langham MR Jr et al. Combined resection of the liver and inferior vena cava for hepatic malignancy. Ann Surg 2004; 239(5):712-9; discussion 719-721. 18. Ohwada S, Watanuki F, Nakamura S et al. Glutaraldehyde-fixed heterologous pericardium for vena cava grafting following hepatectomy. Hepatogastroenterology 1999; 46(26):855-858.

Inferior Vena Cava Resection for Infiltrating Hepatic Malignancy

163

19. Huguet C, Ferri M, Gavelli A. Resection of the suprarenal inferior vena cava. The role of prosthetic replacement. Arch Surg 1995; 130(7):793-797. 20. Kubota K, Makuuchi M, Kobayashi T et al. Reconstruction of the inferior vena cava using a hepatic venous patch obtained from resected liver. Hepatogastroenterology 1997; 44(14):378-379. 21. Yamamoto H, Hayakawa N, Ogawa A et al. Segmental resection and reconstruction of the inferior vena cava with an autogenous vein graft. Br J Surg 1997; 84(1):51. 22. Nakamura S, Tsuzuki T. Surgical anatomy of the hepatic veins and the inferior vena cava. Surg Gynecol Obstet 1981; 152(1):43-50. 23. Sharma D, Deshmukh A, Raina VK. Surgical anatomy of retrohepatic inferior vena cava and hepatic veins: a quantitative assessment. Indian J Gastroenterol 2001; 20(4):136-139. 24. Abernethy J. Account of two instances of uncommon formation in the viscera of the human body Philos Trans R Soc 1793; 83:59-66 cited by Bass JE, Redwine MD, Kramer LA et al. Spectrum of congenital anomalies of the inferior vena cava: cross-sectional imaging findings. Radiographics 2000; 20(3):639-652. 25. Schultz CL, Morrison S, Bryan PJ. Azygos continuation of the inferior vena cava: demonstration by NMR imaging. J Comput Assist Tomogr 1984; 8(4):774-776. 26. Phillips E. Embriology, normal anatomy and anomalies. In: Ferris EJ, Hipona FA, Kahn PC et al. eds. Venography of the Inferior Vena Cava and Its Branches. Baltimored: Williams and Wilkins 1969: 1-32. 27. Kieffer E, Berrod JL, Chomette G. Primary tumors of the inferior vena cava In: Bergan JJ, Yao ST, eds. Surgery of the Veins. New York: Grune and Stratton, 1985:423-443. 28. Chuang VP, Mena CE, Hoskins PA. Congenital anomalies of the inferior vena cava. Review of embryogenesis and presentation of a simplified classification. Br J Radiol 1974; 47(556):206-213. 29. Kellman GM, Alpern MB, Sandler MA et al. Computed tomography of vena caval anomalies with embryologic correlation. Radiographics 1988; 8(3):533-556. 30. Muelheims GH, Mudd JG. Anomalous inferior vena cava. Am J Cardiol 1962; 9:945-952. 31. Baldridge ED Jr, Canos AJ. Venous anomalies encountered in aortoiliac surgery. Arch Surg 1987; 122(10):1184-1188. 32. Yilmaz E, Gulcu A, Sal S et al. Interruption of the inferior vena cava with azygos/hemiazygos continuation accompanied by distinct renal vein anomalies: MRA and CT assessment. Abdom Imaging 2003; 28(3):392-394. 33. Munechika H, Cohan RH, Baker ME et al. Hemiazygos continuation of a left inferior vena cava: CT appearance. J Comput Assist Tomogr 1988; 12(2):328-330. 34. Arakawa A, Nagata Y, Miyagi S et al. Interruption of inferior vena cava with anomalous continuations. J Comput Tomogr 1987; 11(4):341-345. 35. Obernosterer A, Aschauer M, Mitterhammer H et al. Congenital familial vascular anomalies: a study of patients with an anomalous inferior vena cava and of their first-degree relatives. Angiology 2004; 55(1):73-77. 36. Xue HG, Yang CY, Asakawa M et al. Duplication of the inferior vena cava associated with other variations. Anat Sci Int 2007; 82(2):121-125. 37. Bass JE, Redwine MD, Kramer LA et al. Spectrum of congenital anomalies of the inferior vena cava: cross-sectional imaging findings. Radiographics 2000; 20(3):639-652. 38. Kaneko T, Nakao A, Nomoto S et al. Intracaval endovascular ultrasonography for preoperative assessment of retrohepatic inferior vena cava infiltration by malignant hepatic tumors. Hepatology 1996; 24(5):1121-1127. 39. Kaneko T, Nakao A, Endo T et al. Intracaval endovascular ultrasonography for malignant hepatic tumor: new diagnostic technique for vascular invasion. Semin Surg Oncol 1996; 12(3):170-178. 40. Bower TC, Stanson A. Diagnosis and Management of Tumors of the Inferior Vena Cava, In Rutherford RB, Vascular Surgery, Philadelphia, WB Saunders 2000:2083. 41. Stanson AW, Breen JF. Computed tomography and magnetic resonance imaging. In: Gloviczki P, Yao JST, eds. Handbook of Venous Disorders: Guidelines of the American Venou Forum. 2001; 2nd Ed.:529-550. 42. Bower TC, Nagorney DM, Toomey BJ et al. Vena cava replacement for malignant disease: is there a role? Ann Vasc Surg 1993; 7(1):51-62. 43. Okada Y, Nagino M, Kamiya J et al. Diagnosis and treatment of inferior vena caval invasion by hepatic cancer. World J Surg 2003; 27(6):689-694. 44. Kume A, Nimura Y, Nakahara R. Ultrasound imaging of the retrohepatic vena caval wall by percutaneous endocaval sonography (PECS). Hepatogastroenterology 1994; 41(3):225-229. 45. Cavaye DM, White RA. The principles of diagnostic ultrasound imaging. In Intravascular ultrasound imging, New York Raven 1993:13-30.

164

Recent Advances in Liver Surgery

46. Delis SG, Madariaga J, Ciancio G. Combined liver and inferior vena cava resection for hepatic malignancy. J Surg Oncol 2007; 96(3):258-264. 47. Kuehnl A, Schmidt M, Hornung HM et al. Resection of malignant tumors invading the vena cava: perioperative complications and long-term follow-up. J Vasc Surg 2007; 46(3):533-540. 48. Castelli P, Caronno R, Piffaretti G et al. Surgical treatment of malignant involvement of the inferior vena cava. Int Semin Surg Oncol 2006; 3:19. 49. Azoulay D, Andreani P, Maggi U et al. Combined liver resection and reconstruction of the supra-renal vena cava: the Paul Brousse experience. Ann Surg 2006; 244(1):80-88. 50. Yoshidome H, Takeuchi D, Ito H et al. Should the inferior vena cava be reconstructed after resection for malignant tumors? Am J Surg 2005; 189(4):419-424. 51. Nardo B, Ercolani G, Montalti R et al. Hepatic resection for primary or secondary malignancies with involvement of the inferior vena cava: is this operation safe or hazardous? J Am Coll Surg 2005; 201(5):671-679. 52. Ai-jun L, Meng-chao W, Guang-shun Y et al. Management of retrohepatic inferior vena cava injury during hepatectomy for neoplasms. World J Surg 2004; 28(1):19-22. 53. Aoki T, Sugawara Y, Imamura H et al. Hepatic resection with reconstruction of the inferior vena cava or hepatic venous confluence for metastatic liver tumor from colorectal cancer. J Am Coll Surg 2004; 198(3):366-372. 54. Hemming AW, Reed AI, Langham MR Jr et al. Combined resection of the liver and inferior vena cava for hepatic malignancy. Ann Surg 2004; 239(5):712-9; discussion 719-721. 55. Okada Y, Nagino M, Kamiya J et al. Diagnosis and treatment of inferior vena caval invasion by hepatic cancer. World J Surg 2003; 27(6):689-694. 56. Arii S, Teramoto K, Kawamura T et al. Significance of hepatic resection combined with inferior vena cava resection and its reconstruction with expanded polytetrafluoroethylene for treatment of liver tumors. J Am Coll Surg 2003; 196(2):243-249. 57. Sarmiento JM, Bower TC, Cherry KJ et al. Is combined partial hepatectomy with segmental resection of inferior vena cava justified for malignancy? Arch Surg 2003; 138(6):624-630; discussion 630-631. 58. Madariaga JR, Fung J, Gutierrez J et al. Liver resection combined with excision of vena cava. J Am Coll Surg 2000; 191(3):244-250. 59. Hardwigsen J, Baqué P, Crespy B et al. Resection of the inferior vena cava for neoplasms with or without prosthetic replacement: a 14-patient series. Ann Surg 2001; 233(2):242-249. 60. Bower TC, Nagorney DM, Cherry KJ Jr et al. Replacement of the inferior vena cava for malignancy: an update. J Vasc Surg 2000; 31(2):270-281. 61. Dionigi R, Madariaga JR. New Technologies for Liver Resections Basel; New York: Karger Landes Systems, 1997; 46-51. 62. Duckett JW Jr, Lifland JH, Peters PC. Resection of the inferior vena cava for adjacent malignant diseases. Surg Gynecol Obstet 1973; 136(5):711-716. 63. Perhoniemi V, Salmenkivi K, Vorne M. Venous haemodynamics in the legs after ligation of the inferior vena cava. Acta Chir Scand 1986; 152:23-27. 64. McCullough DL, Gittes RF. Ligation of the renal vein in the solitary kidney: effects on renal function. J Urol 1975; 113(3):295-298. 65. Del Campo C, Konok GP. Use of a pericardial xenograft patch in repair of resected retrohepatic vena cava. Can J Surg 1994; 37(1):59-61. 66. Ohwada S, Watanuki F, Nakamura S. Glutaraldehyde-fixed heterologous pericardium for vena cava grafting following hepatectomy. Hepatogastroenterology 1999; 46(26):855-858. 67. Miller CM, Schwartz ME, Nishizaki T. Combined hepatic and vena caval resection with autogenous caval graft replacement. Arch Surg 1991; 126(1):106-108. 68. Togo S, Tanaka K, Endo I. Caudate lobectomy combined with resection of the inferior vena cava and its reconstruction by a pericardial autograft patch. Dig Surg 2002; 19(5):340-343. 69. Iwatsuki S, Todo S, Starzl TE. Right trisegmentectomy with a synthetic vena cava graft. Arch Surg 1988; 123(8):1021-1022. 70. Herring M, Gardner A, Peigh P. Patency in canine inferior vena cava grafting: effects of graft material, size and endothelial seeding. J Vasc Surg 1984; 1(6):877-887. 71. Graham LM, Burkel WE, Ford JW. Expanded polytetrafluoroethylene vascular prostheses seeded with enzymatically derived and cultured canine endothelial cells. Surgery 1982; 91(5):550-559. 72. Li JM, Menconi MJ, Wheeler HB et al. Experimental femoral vein reconstruction with expanded polytetrafluoroethylene grafts seeded with endothelial cells. Cardiovasc Surg 1993; 1(4):362-368. 73. Illuminati G, Calio’ FG, D’Urso A et al. Prosthetic replacement of the infrahepatic inferior vena cava for leiomyosarcoma. Arch Surg 2006; 141(9):919-924; discussion 924. 74. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6):649-655.

Inferior Vena Cava Resection for Infiltrating Hepatic Malignancy

165

75. Makuuchi M, Thai BL, Takayasu K et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990; 107(5):521-527. 76. Sarkar R, Eilber FR, Gelabert HA et al. Prosthetic replacement of the inferior vena cava for malignancy. J Vasc Surg 1998; 28(1):75-81; discussion 82-83. 77. Kieffer E, Alaoui M, Piette JC et al. Leiomyosarcoma of the inferior vena cava: experience in 22 cases. Ann Surg 2006; 244(2):289-295. 78. Fueglistaler P, Gurke L, Stierli P. Major vascular resection and prosthetic replacement for retroperitoneal tumors. World J Surg 2006; 30(7):1344-1349.

Chapter 14

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement Tsuyoshi Sano* and Yuji Nimura

Abstract

I

n patients with advanced hepatocellular carcinoma (HCC) presenting with vascular and/or biliary invasion, major hepatectomy is often indicated for curative resection. In HCC patients with portal vein tumor thrombus, limited anatomical resection such as sectionectomy is a possible alternative for a case of small size HCC with localized portal thrombus in the affected section of the cirrhotic liver. Invasion of the caudate lobe branch of the portal vein and hepatic functional reserve affect the selection of the operative procedure. In HCC patients with hepatic vein or IVC tumor thrombus, hepatectomy with hepatic venous thrombectomy or concomitant resection of the involved hepatic vein and/or IVC is indicated. Depending on the extent of tumor thrombus, we must discuss about the necessity of the active veno-veno bypass during total hepatic vascular exclusion. HCC patients with biliary invasion extending over the hepatic confluence often develop obstructive jaundice, accelerating deterioration in the functional reserve of the future remnant liver, especially in the cirrhotic patients. Thus, radical hepatectomy for patients with biliary tumor thrombi is rarely indicated due to the poor hepatic functional reserve. Immediate percutaneous transhepatic biliary drainage plays a key role in recovery of the impaired liver function. As most of a biliary tumor thrombus can be removed through choledochotomy, extrahepatic bile duct resection with bilioenterostomy is not required in many cases. Therefore, hepatobiliary resection with bilioenterosotmy should be avoided even for patients with HCC presenting with biliary tumor thrombus. In conclusion, the design of resectional procedure according to the precise preoperative diagnosis of tumor extent and performance of rational surgery using advanced surgical techniques can offer the chance of prolonged survival even in advanced HCC patients with vascular and/or biliary involvement.

Introduction

Recent advances in diagnostic and therapeutic techniques have meant markedly better outcomes in patients with hepatocellular carcinoma (HCC).1-4 Most patients with HCC have underlying chronic liver damage and hepatectomy in the case of cirrhotic liver still remains a difficult operation because of the increased operative risk of intraoperative bleeding, postoperative liver failure and intractable ascites, compared with normal liver resection. This clinical setting restricts extended hepatectomy, leaving limited hepatectomy in the treatment of choice for HCC patients.5-7 *Corresponding Author: Tsuyoshi Sano—Gastroenterological Surgery Division, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

167

However, advanced HCC associated with vascular and/or biliary invasion necessitates an extended hepatectomy for complete removal of the tumor and the role of hepatectomy in such difficult conditions is controversial. Many liver surgeons consider the presence of a tumor thrombus in the inferior vena cava (IVC), main portal trunk, or common hepatic duct with obstructive jaundice as contraindications for hepatectomy because of high operative risk and poor prognosis even after an aggressive surgery. In this chapter, an aggressive preoperative management and advanced surgical techniques for HCC patients with vascular and/or biliary invasion are presented.

General Preoperative Examination for Liver Functional Reserve

Our standard preoperative assessment of liver function includes serum total bilirubin, albumin, cholesterol, choline esterase and the total bile acid level. Coagulopathy is also examined and the indocyanine green (ICG) retention rate at 15 minutes is crucial for evaluation of liver functional reserve.8 Estimation of the resection rate for hepatic parenchyma using CT-volumetry is essential in case of anatomical sectionectomy or more extended resection. Gastroesophageal fiberscopy is routinely performed to determine the presence of varices formation and/or peptic ulcer.

HCC with Tumor Thrombus in the Main Portal Trunk or Major Portal Vein Branches9-12

Many hepatic surgeons consider anatomical hepatic resection superior to non-anatomical hepatectomy for patients with portal vein tumor thrombus (PVTT) because of the high risk of intrahepatic metastasis via the portal venous system. For patients with poor functional reserve and PVTT localized in the second order branch of the portal vein, limited anatomical hepatic resection such as sectionectomy is an alternative to major hepatectomy.13 For example, in a case of small size HCC with PVTT localized in the anterior branch of the right portal vein in the marked cirrhotic liver, right anterior sectionectomy should be selected.

Right Anterior Sectionectomy (Figs. 1-3)

At first, an evaluation of extension of the PVTT using intraoperative ultrasonography (IOUS) is mandatory.14 After cholecystectomy, the right hepatic artery (RHA) is encircled and the anterior branch of the RHA is identified. Test clamp of the putative anterior branch of the RHA under Doppler IOUS is useful to confirm the identification of the affected arterial branch. It is advisable to minimize dissection of the hepatic hilum because of the potential risk of postoperative lymphorrea or intractable ascites. After ligation and division of the right anterior branch of the RHA, the right portal vein (RPV), the posterior branch of the RPV and the anterior branch of the RPV are carefully skeletonized and encircled. If ligation of the right anterior branch of the RPV is impossible because the tumor extension hangs over the main RPV and right hemihepatectomy is contraindicated in terms of functional liver reserve or operative risk, the posterior branch and main RPV are occluded with vascular clamps and the root of the anterior branch of the PRV is incised. Thrombectomy in the RPV10 followed by transverse suture of the origin of the anterior branch of the RPV should be completed prior to mobilization of the liver. Demarcations corresponding to the main and right portal fissures are marked with an electronic cautery on the liver surface. After mobilization of the right liver, liver transection is started along the demarcation on the main portal fissure. The middle hepatic vein is exposed on the raw surface. Then the second liver transection is progressed along the demarcation on the right portal fissure and the right hepatic vein is exposed on the transection plane. Finally, the right anterior biliary branch is isolated and divided and the right anterior section is removed.

168

Recent Advances in Liver Surgery

Figure 1. Conventional computed tomography (CT) shows a vague and ill-defined hyper-attenuated tumor (arrow) in the early phase (A). The tumor turns into a hypo-attenuated area (arrow) in the late phase (B). CT during portography through superior mesenteric arteriography demonstrates a segmental perfusion defect corresponding to the right anterior section including the tumor, suggesting the presence of a portal vein tumor thrombus.

Figure 2. Intraoperative photography after the right anterior sectionectomy shows the clearly exposed right hepatic vein (RHV) on the raw surface of the liver. The stump of the right anterior portal pedicle (arrow) is noted.

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

169

Figure 3. Cut surface of the resected specimen shows a tiny tumor, 18 mm in diameter, associated with tumor thrombus in the right anterior branch of the portal vein (arrows).

Hemihepatectomy (Figs. 4-10)

HCC originating in the left liver with tumor thrombus in the portal vein is usually resected by left hemihepatectomy with or without left caudate lobectomy. It largely depends on the extet of the tumor thrombus. Tumor extension down to the portal bifurcation or the main portal vein is an indication for left hemihepatectomy with left caudate lobectomy and portal thrombectomy. If a tumor thrombus is localized in the umbilical portion of the left portal vein, left hemihepatectomy without caudate lobectomy is indicated. When the tumor thrombus is progressed into the left portal vein, anatomical variation of the caudate lobe branches and possible tumor extension into those branches must carefully be investigated by IOUS. If the portal tumor extension is documented in the caudate branches in patients with sufficient liver functional reserve, caudate lobectomy should concomitantly be carried out.

Figure 4. CT after transcatheter arterial chemoembolization demonstrates a tumor with lipiodol accumulation (arrows) and the left portal vein is not enhanced with contrast medium (arrowheads) suggesting the presence of a portal vein tumor thrombus.

170

Recent Advances in Liver Surgery

Figure 5. Intraoperative photography just after removal of the portal vein tumor thrombus (arrow) shows a backflow from the right portal vein (arrowheads) by releasing the vascular clump of the right portal vein.

Figure 6. Intraoperative photography after the left hemihepatectomy with caudate lobe resection shows the clearly exposed middle hepatic vein on the raw surface of the liver and IVC.

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

171

Figure 7. A protruding tumor thrombus from the stump of the left portal vein (arrow) is noted on the resected specimen.

Figure 8. CT shows diffuse-type hepatocellular carcinoma with portal vein tumor thrombus extending into the main portal vein (arrowheads: A) early phase; C) late phase). The right posterior portal vein is filled with cast-like tumor thrombus (arrows, B) early phase; D) late phase).

172

Recent Advances in Liver Surgery

Figure 9. The left portal vein, main portal vein and common hepatic duct are taped (A). After thrombectomy, the orifice of the right portal vein is closed with sutures (B). The right liver is transected and the tumor thrombus protruding from the stump of the right portal vein is noted (C).

Figure 10. Even after transverse suture of the orifice of the right portal vein, the portal flow of the umbilical portion of the left portal vein was markedly decreased by intraoperative Doppler ultrasonography because of formation of blood thrombi. After 2 sessions of thrombectomy, portal flow did not recover possibly due to deformity or stricture of the sutured portion. Thus, portal vein resection and reconstruction was performed in an end-to-end fashion to restore the portal flow (A, B).

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

173

HCC with Tumor Thrombus in the Biliary Tree15-19 (Figs. 11-14)

HCC patients with biliary invasion extending over the hepatic confluence often develop obstructive jaundice, which accelerates deterioration in the functional reserve of the future remnant liver. Thus, radical hepatectomy for patients with intrabiliary tumor thrombi is rarely indicated. Incidentally, most reports on HCC with biliary invasion have reviewed autopsy cases20 or patients who had undergone palliative treatment due to the poor hepatic functional reserve. Early percutaneous transhepatic biliary drainage (PTBD)21 should be performed because cirrhotic patients are seriously affected by obstructive jaundice. Appropriate and immediate biliary drainage plays a key role in the recovery of liver function and potentially leads to the possibility of radical hepatectomy. Cholangiography through PTBD shows a smooth, oval intraluminal filling defect in the bile duct that is a typical cholangiographic finding (Fig. 11A). Percutaneous transhepatic cholangioscopy (PTCS)22 shows a yellowish tumor thrombus that does not adherent to the bile duct wall which is another characteristic finding of cholangioscopy that facilitates histologic diagnosis of intraluminal tumor thrombi (Fig. 12). A cholangioscope can be passed through the bile duct lumen beside the tumor thrombus (Fig. 11B). Most of the bile duct tumor thrombus can be removed through choledochotomy, thereby eliminating the need for extrahepatic bile duct resection with bilioenterostomy in many cases (Fig. 13). Considering the high tumor recurrence rate23 or neocarcinogenesis of HCC in the remnant liver, transcatheter arterial chemoembolization (TACE)24 after hepatectomy is often indicated in patients with recurrent HCCs. TACE for patients with bilioenterostomy produces the potential risk of liver abscess complicated with damage to the Glissonean capsule.25 Therefore, we think hepatobiliary resection with bilioenterosotmy should be avoided even for patients with HCC presenting bile duct tumor thrombus. On the other hand,

Figure 11. Cholangiography through percutaneous transhepatic biliary drainage catheter shows a smooth and oval filling defect in the common hepatic duct (arrowheads). The right anteroinferior sectional bile duct branch is not visualized (A). A cholangioscope (arrow) can be passed through the bile duct lumen beside the tumor thrombus (B). Cholangioscopic cholangiography can not demonstrate a biliary branch of the anteroinferior segment (B5), B6: a right posteroinferior bile duct branch; B7: a right posterosuperior bile duct branch; B8: a right anterosperior bile duct branch; P: a right posterior sectional bile duct branch; L: left hepatic duct.

174

Recent Advances in Liver Surgery

Figure 12. Percutaneous transhepatic cholangioscopy shows a yellowish tumor thrombus that does not adhere to the bile duct wall (arrow).

Figure 13. A bile duct tumor thrombus (arrows) can be removed through choledochotomy.

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

175

Figure 14. Anatomical resection of the anteroinferior segment (S5) with tumor thrombectomy was performed. Cut surface of the resected specimens depicts a small tumor (arrow) with intrabiliary extension into the extrahepatic bile duct (arrowheads).

thrombectomy through choledochotomy has a potential risk of peritoneal seeding. There is no evidence that combined resection of the extrahepatic bile duct assures better survival in patients with HCC presenting macroscopic biliary invasion. Further investigation in a large series is warranted to elucidate the clinical significance of this controversial issue. A case of HCC with biliary invasion mimicking an intrahepatic cholangiocarcinoma dominantly presenting intraductal tumor growth is presented (Figs. 15-17). Preoperative examination revealed HBs antigen-negative and HC antibody-negative and biliary cytology was suggestive of adenocarcinoma. The preoperative diagnosis was therefore perihilar cholangiocarcinoma. Such HCC with a tiny primary tumor and marked extension into the biliary tree may be potentially misdiagnosed as cholangiocellular carcinoma.26 Tumor thrombus of HCC in the biliary tree that is often fragile and readily bleeds reflects the nature of the primary tumor. This may mean bile flow obstruction caused by fragmented tumor thrombus at the distal end of the common bile duct or hemobilia. This pathophysiological condition is clinically manifested as an epigastric pain, fever and liver function disorder including fluctuating jaundice similar to impacted choledocholithiasis.27 A careful intake of the clinical history is also important when HCC with biliary invasion is suppected before presenting with obstructive jaundice.

176

Recent Advances in Liver Surgery

Figure 15. Cholangiography through percutaneous transhepatic biliary drainage catheter demonstrates a clear round defect at the hepatic confluence (arrows) and a small filling defect (arrowhead) suggestive of floating tumor debris.

HCC with biliary invasion often may coexist with microscopic PVTT,28 and the first recurrence site is the remnant liver. On the other hand, patients with macroscopic bile duct invasion show significantly better survival than those with microscopic bile duct invasion.19

HCC with Tumor Thrombus in the Hepatic Vein and/or Inferior Vena Cava (IVC)29,30

Design of the operative procedure in terms of spread of the tumor thrombus as well as the evaluation of liver functional reserve must be the prime concern in HCC patients with tumor thrombus in the hepatic vein and/or inferior vena cava (IVC). Chest CT should be performed considering the relatively high possibility of lung metastasis or pulmonary tumor thrombus compared with HCC showing other types of spread. Hepatic parenchymal resection with hepatic venous thrombectomy and concomitant resection of the involved hepatic vein and/or IVC are indicated. There have been several discussions about indication of the active veno-veno bypass during total hepatic vascular exclusion (THVE)30-33 in terms of the extent of the tumor thrombus.

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

177

Figure 16. CT shows a mass with slightly attenuation at the hepatic hilum (arrows) and the proximal biliary dilatation in the right liver. Ill-defined slightly hyper attenuated area (arrowheads) is connected to the tumor in the hepatic hilum.

Actual surgical techniques of combined liver and IVC resection and reconstruction using the THVE technique without employing an active veno-veno bypass are described below. The right posterior sectionectomy and combined resection of the IVC at the confluence of the right hepatic vein (RHV) were performed with curative intent (Figs. 18-21). After dividing the right posterior branches of the hepatic artery and the portal vein, longitudinal venotomy was made around the confluence of the RHV to remove the tumor thrombi in the IVC and the defect of the IVC was

178

Recent Advances in Liver Surgery

Figure 17. Extrahepatic bile duct is longitudinally opened and a polypoid tumor protruding from the right hepatic duct (arrow) is noted (A). Resected specimen shows a small tumor in the liver parenchyma (arrowhead) and the cast-like tumor thrombus filling with the bile duct (arrows) (B).

longitudinally closed under THVE in 12 minutes. Then posterior sectionectomy with involved RHV resection was carried out. The patient survived more than 5 years despite developing recurrent lesions in the remnant liver. For a patient with HCC in the right liver associated with tumor thrombi in the RHV up to the right atrium through the IVC, the surgery was carried out (Figs. 22-25). Skin incision was made with median sternotomy and bilateral subcostal incision and the pericardium was opened. Then, taping of the ascending aorta, pulmonary artery, superior vena cava and supradiaphragmatic IVC was done to prepare for artificial cardio-pulmonary circulation (ACPC).29 The tip of the tumor thrombus could be moved from the right atrium into the IVC by pulling down the right liver in the caudal direction under IOUS guidance. Then surgical strategy was changed not to use ACPC but THVE. After cholecystectomy, the right hepatic artery and the right portal vein were ligated and divided. Liver transection along the demarcation line corresponding to the main portal fissure was started during intermittent inflow occlusion. The middle hepatic vein was exposed on the raw

Figure 18. CT depicts a round tumor (arrow) and belt-like low-density shadow corresponding to the right hepatic vein (arrowheads).

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

179

Figure 19. Cavography depicts a filling defect showing smooth border extended into the IVC through the right hepatic vein (arrowheads). This finding is suggestive of tumor thrombus into the hepatic vein and IVC.

Figure 20. Resected specimen depicts tumor thrombus protruding from the confluence of the right hepatic vein.

180

Recent Advances in Liver Surgery

Figure 21. A cut surface of the resected specimen shows main tumor (arrow) and tumor thrombus extending from the right hepatic vein to the IVC (arrowheads).

surface of the liver and the transection plane reached to the ventral plane of the IVC. The separated right liver was pulled down and the proximal IVC was clamped above the renal vein confluence and the distal clamp was placed on the right atrium under IOUS. Sometimes blood pressure drops with THVE. Preconditioning by several test clamping can be done so that the THVE can be started in terms of the decrease in systemic pressure. Longitudinal venotomy of the IVC and en bloc resection of the right liver together with the confluence of the RHV and tumor thrombus were done. During this procedure, control of the back flow bleeding from the confluence of the inferior phrenic vein was problematic, but the assistant surgeon closed the orifice of the vein by putting his finger. The IVC defect was longitudinally oversewn using 4-0 prolene, with the suture line extended to the right atrium. Postoperative recovery was uneventful and the patient died 5 years and 6 months after the surgery due to another cause of the HCC. Another large HCC patient had a tiny tumor thrombus into the IVC through the short hepatic vein (Figs. 26-29). Preoperative CT images showed a large tumor, 14 cm in size, compressing the IVC and a suspicious small filling defect in the IVC. After laparotomy, immediate IOUS clearly demonstrated a tiny tumor thrombus in the IVC. In this case, right liver mobilization would cause compression of the tumor leading to a risk of ingrowth or fragmentation of the tumor thrombus in the IVC. Thus, an anterior approach was used to carry out right hemihepatectomy.34 At first, cholecystectomy was performed and the right hepatic artery was then identified at the Calot’s triangle and ligated, transfixed and divided. Next, the right portal vein was encircled, ligated, transfixed and divided. The demarcation line corresponding to the Cantlie line was appeared. Liver parenchymal transection was started using the forceps clamp crushing method under intermittent inflow occlusion (Pringle’s maneuver). Special attention should be paid to the status of the tumor thrombus through periodical check using IOUS. After parenchymal transection, the right hepatic vein was divided and closed. The location of the tumor thrombus was identified by IOUS and a vascular clamp was placed longitudinally on the IVC to remove the tumor thrombus. Finally, the

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

181

Figure 22. MRI demonstrated a hepatocellular carcinoma (T) with tumor thrombus extending into the right atrium through the IVC (TT).

182

Recent Advances in Liver Surgery

Figure 23. An oblique sagittal scan of MRI clearly demonstrates a tumor thrombus (TT) in the IVC extending into the right atrium.

Figure 24. After resection, the longitudinal suture of the IVC is extending to the right atrium (arrowheads) and the middle hepatic vein is exposed on the raw surface of the liver (arrow).

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

183

Figure 25. Resected specimen shows a tumor thrombus protruding from the confluence of the right hepatic vein (arrows).

right liver together with the IVC wall including tumor thrombus was resected en bloc. The defect of the IVC wall was sutured longitudinally.

Conclusions

Design of the resectional procedure according to the precise preoperative diagnosis of tumor extent and performance of rational surgery using advanced surgical techniques can offer the chance of prolonged survival even in advanced HCC patients with vascular and/or biliary involvement.

Figure 26. CT shows a huge, typical hepatocellular carcinoma in the right liver. A tiny filling defect in the IVC (arrows) is documented and suggested a tumor thrombus.

184

Recent Advances in Liver Surgery

Figure 27. Intraoperative ultrasonography clearly depicts an echogenic nodule in the IVC (arrow).

Figure 28. After liver transection through an anterior approach, the IVC wall is longitudinally clamped and incised and a small tumor thrombus is exposed (arrow).

Aggressive Surgery for Hepatocellular Carcinoma with Vascular and/or Biliary Involvement

185

Figure 29. Resected specimen shows a tiny tumor thrombus (arrow) protruding through a short hepatic vein.

References

1. Jarnagin WR, Gonen M, Fong Y et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002; 236:397-406. 2. Poon RT, Fan ST, Lo CM et al. Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: Analysis of 1222 consecutive patients from a prospective database. Ann Surg 2004; 240:698-708. 3. Imamura H, Seyama Y, Kokudo N et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg 2003; 138:1198-1206. 4. Belghiti J, Hiramatsu K, Benoist S et al. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 2000; 191:38-46. 5. Kanematsu T, Takenaka K, Matsumata T et al. Limited hepatic resection effective for selected cirrhotic patients with primary liver cancer. Ann Surg 1984; 199:51-56. 6. Paquet KJ, Koussouris P, Mercado MA et al. Limited hepatic resection for selected cirrhotic patients with hepatocellular or cholangiocellular carcinoma: A prospective study. Br J Surg 1991; 78:459-462. 7. Yamashita Y, Taketomi A, Itoh S et al. Longterm favorable results of limited hepatic resections for patients with hepatocellular carcinoma: 20 years experience. J Am Coll Surg 2007; 205:27-36. 8. Miyagawa S, Makuuchi M, Kawasaki S et al. Criteria for safe hepatic resection. Am J Surg 1995; 169:589-594. 9. Kumada K, Ozawa K, Okamoto R et al. Hepatic resection for advanced hepatocellular carcinoma with removal of portal vein tumor thrombi. Surgery 1990; 108:821-827. 10. Yamaoka Y, Kumada, Ino K et al. Liver resection for hepatocellular carcinoma (HCC) with direct removal of tumor thrombi in the main portal vein. World J Surg 1992; 16:1172-1176. 11. Ikai I, Yamaoka Y, Yamamoto Y et al. Surgical intervention for patients with stage IV-A hepatocellular carcinoma without lymph node metastasis. Proposal as a standard therapy. Ann Surg 1998; 227:433-439. 12. Ohkubo T, Yamamoto J, Sugawara Y et al. Surgical results for hepatocellular carcinoma with macroscopic portal vein tumor thrombosis. J Am Coll Surg 2000; 191:657-660. 13. Chen XP, Qiu FZ, Wu ZD et al. Effects of location and extension of portal vein tumor thrombus on long-term outcomes of surgical treatment for hepatocellular carcinoma. Ann Surg Oncol 2006; 13:940-946. 14. Makuuchi M, Hasegawa H, Yamasaki S et al. The use of operative ultrasound as an aid to liver resection in patients with hepatocellular carcinoma. World J Surg 1987; 11:615-621.

186

Recent Advances in Liver Surgery

15. Chen MF, Jan YY, Jeng LB et al. Obstructive jaundice secondary to ruptured hepatocellular carcinoma into the common bile duct. Cancer 1994; 73:1335-1340. 16. Law W, Leung K, Leung TW et al. A logical approach to hepatocellular carcinoma presenting with jaundice. Ann Surg 1997; 225:281-285. 17. Satoh S, Ikai I, Honda G et al. Clinicopathologic evaluation of hepatocellular carcinoma with bile duct thrombi. Surgery 2000; 127:779-783. 18. Shiomi M, Kamiya J, Nagino M et al. Hepatocellular carcinoma with biliary tumor thrombi: Aggressive operative approach after appropriate preoperative management. Surgery 2001; 129:692-698. 19. Esaki M, Shimada K, Sano T et al. Surgical results for hepatocellular carcinoma with bile duct invasion: a clinicopathologic comparison between macroscopic and microscopic tumor thrombus. J Surg Oncol 2005; 90:226-232. 20. Nakashima T, Okuda K, Kojiro M et al. Pathology of hepatocellular carcinoma in Japan. 232 Consecutive cases autopsied in ten years. Cancer 1983; 51:863-877. 21. Nimura Y, Kamiya J, Kondo S et al. Technique of inserting multiple biliary drains and management. Hepatogastroenterology 1995; 42:323-331. 22. Nimura Y, Kamiya J, Hayakawa N et al. Cholangioscopic differentiation of biliary strictures and polyps. Endoscopy 1989; 21:351-356. 23. Yamamoto J, Kosuge T, Takayama T et al. Recurrence of hepatocellular carcinoma after surgery. Br J Surg 1996; 83:1219-1222. 24. Poon RT, Ngan H, Lo CM et al. Transarterial chemoembolization for inoperable hepatocellular carcinoma and postresectional intrahepatic recurrence. J Surg Oncol 2000; 73:109-114. 25. Chen C, Chen PJ, Yang PM et al. Clinical and microbiological features of liver abscess after transarterial embolization for hepatocellular carcinoma. Am J Gastroenterol 1997; 92:2257-2259. 26. Sakamoto Y, Takayama, T, Sano T et al. Curative resection of hepatocellular carcinoma with intrabile duct tumor growth mimicking hilar bile duct carcinoma. J Hepatobiliary Pancreat Surg 1995; 2:435-439. 27. Roslyn JJ, Kuchenbecker S, Longmire WP et al. Floating tumor debris. A cause of intermittent biliary obstruction. Arch Surg 1984; 119:1312-1315. 28. Adachi E, Maeda T, Kajiyama K et al. Factors correlated with portal venous invasion by hepatocellular carcinoma. Univariate and multivariate analysis of 232 resected cases without preoperative treatments. Cancer 1996; 77:2022-2031. 29. Fujisaki M, Kurihara E, Kikuchi K et al. Hepatocellular carcinoma with tumor thrombus extending into the right atrium: report of a successful resection with the use of cardiopulmonary bypass. Surgery 1991; 109:214-219. 30. Yamaoka Y, Ozawa K, Kumada K et al. Total vascular exclusion for hepatic resection in cirrhotic patients. Application of venoveno bypass. Arch Surg 1992; 127:276-280. 31. Huguet C, Nordlinger B, Galopin et al. Normothermic hepatic vascular exclusion for extensive hepatectomy. Surg Gynecol Obstet 1978; 147:689-693. 32. Bismuth H, Castaing D, Garden J. Major hepatic resection under total vascular exclusion. Ann Surg 1989; 210:13-19. 33. Emre S, Schwartz ME, Katz E et al. Liver resection under total vascular isolation: variations on a theme. Ann Surg 1993; 217:15-19. 34. Liu CL, Fan ST, Lo CM et al. Anterior approach for major right hepatic resection for large hepatocellular carcinoma. Ann Surg 2000; 232:25-31.

Chapter 15

Surgical Strategies and Technique for Hilar Cholangiocarcinoma Tsuyoshi Sano* and Yuji Nimura

Abstract

H

epatobiliary resection for hilar cholangiocarcinoma (HC) remains a technically demanding procedure, calling for a high level of expertise in biliary and hepatic surgery. Treatment strategy for HC includes preoperative staging, perioperative managements and radical surgery. Multidetector row computed tomography (MDCT) and direct cholangiography are mainstays for the precise preoperative staging. Preoperative bile replacement for patients with percutaneous transhepatic biliary drainage (PTBD) and postoperative early enteral feeding are important to reduce postoperative septic complications that potentially lead to postoperative liver failure. We have established an aggressive surgical approach for cases of HC, using PTBD, preoperative portal vein embolization (PVE) and major hepatobiliary resection. Radical surgery includes hemihepatectomy or hepatic segmentectomy, lymphadenectomy, vascular resection and reconstruction, combined pancreaticoduodenectomy in selected situations and concomitant caudate lobe resection. PVE for the liver segment to be resected, has been advocated as a useful option to induce compensatory hypertrophy of the future remnant liver. Resectional surgery for HC should be designed in terms of the tumor extent, anatomy of the hilar structure and hepatic functional reserve in each case. Not only surgical technique but also refinements of perioperative managements contributed to the improvement in the treatment of HC. In this chapter a surgical strategy and techniques for various types of hepatobiliary resection including right and left hemihepatectomy, right and left trisectionectomy are described.

Introduction

Hilar cholangiocarcinoma (HC) is a difficult disease for which to make an accurate diagnosis of tumor extension and curative resection. Although the use of hepatectomy1 has increased the resection rate of HC, hepatobiliary resection remains a technically demanding procedure, calling for a high level of expertise in biliary and hepatic surgery. Hepatobiliary resection for HC is a complex procedure involving lymphadenectomy, vascular resection and reconstruction and pancreaticoduodenectomy (HPD)2,3 in selected situations and concomitant caudate lobe resection1 is crucial for the clearance of periductal connective tissues of the caudate lobe potentially involved by the tumor. On the other hand, since the majority of patients with HC have cholestatic liver damage due to bile duct obstruction, major hepatobiliary resection carries a considerable risk of serious postoperative morbidity and mortality.4 Although curative surgical resection offers the only chance for long-term survival in patients with HC, the gold standard for its treatment strategy has not yet been determined. We have established hepatic segmentectomy and emphasized the importance of caudate lobe resection for HC.1 Currently we have implemented a management *Corresponding Author: Tsuyoshi Sano—Hepato-Biliary and Pancreatic Surgery Division, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

188

Recent Advances in Liver Surgery

Figure 1. Schematic illustration of the biliary anatomy of the liver. Numerals indicate Couinauld’s segment of the liver.

Figure 2. A typical case of hilar cholangiocarcinoma. Magnetic resonance cholangiopancreatography (MRCP) shows a stricture at the hepatic confluence (arrow) (A). Coronal images of multidetector row computed tomography (MDCT) clearly depict a tiny nodule in the hepatic hilum (B, C).

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

189

strategy for patients with HC, consisting of preoperative biliary drainage, portal vein embolization (PVE)5-8 and major hepatobiliary resection.9,10 In this chapter, current standard approach and surgical techniques in hepatobiliary resection for HC are described.

Preoperative Staging of Hilar Cholangiocarcinoma (Figs. 1-4)

First of all, the location and extent of the disease are diagnosed by ultrasonography, multidetector row computed tomography (MDCT) and/or magnetic resonance imaging (MRI). Percutaneous transhepatic biliary drainage (PTBD) for the future remnant liver is preferably used for icteric patients to increase safety of major hepatectomy and to prevent unexpected cholangitis after biliary drainage.9 Magnetic resonance cholangiopancreatography (MRCP) is insufficient to diagnose the difficult local anatomy of the separated intrahepatic segmental ducts and to design an appropriate operative procedure in patients with Bismuth type III or IV tumor.11 Selective cholangiography through PTBD catheter is more useful to decide which side of the liver should be resected and to determine the resection line of the separated intrahepatic segmental ducts in the future remnant liver. For suspicious cases of superficial spreading, mapping biopsy using percutaneous transhepatic cholangioscopy or peroral cholangioscopy is indispensable to design the expected resection line of the proximal or distal bile duct12 (Figs. 5-8). In summary, both proximal and distal cancer extension

Figure 3. Percutaneous transhepatic biliary drainage was performed and bilobar biliary drainage was achieved through a single catheter from the right anterior sectional duct to the left lateral sectional duct (A). A cholangiogram at the right anterior and caudal anterior oblique posture is advisable to delineate the left intrahepatic segmental ducts and to determine the expected resection line (arrow) (B). A three-dimensional CT angiography shows no abnormality in either the arterial phase (C) or the portal phase (D). Ant: right anterior sectional duct; Post: right posterior sectional duct; L: left intrahepatic segmental duct; B2: left lateral inferior segmental duct; B3: left lateral superior segmental duct; B4a1: a branch of the left medial inferior subsegmental duct; B4a2: a branch of the left medial inferior subsegmental duct; B4b: left medial superior subsegmental duct.

190

Recent Advances in Liver Surgery

Figure 4. Intraoperative photograph shows completed skeletonization of the hepatoduodenal ligament prior to the right hemihepatectomy. The right, left and main portal veins are taped (A). A right hemihepatectomy with caudate lobe resection was completed (B). Resected specimen after longitudinal incision of the extrahepatic bile duct has a tiny nodular tumor at the hepatic confluence (arrow) (C). B4a1: a branch of the left medial inferior subsegmental duct; B4a2 + 3 + 2: a branch of the left medial inferior subsegmental duct plus left lateral inferior and superior segmental ducts.

Figure 5. Balloon occluded cholangiography depicts wall irregularity of the bile duct extending up to the hepatic segmental ducts (arrows) (A). Peroral cholangioscopy showed papillary mucosa of the bile duct up to the orifice of the left caudate lobe branch (arrow) and to the right anterior and posterior sectional ducts (arrowheads) (B). Ant: right anterior sectional duct; Post: right posterior sectional duct; B1l: left caudate lobe branch.

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

191

Figure 6. Peroral cholangioscopy shows a papillary tumor.

along the bile duct is evaluated by combined use of selective cholangiography through a PTBD catheter and endoscopic retrograde cholangiography (ERCP) or MRCP. On the other hand,

Figure 7. Intraductal ultrasonography depicts intraluminal growth of the tumor (arrow) (A) and low papillary tumor (arrow) (B).

192

Recent Advances in Liver Surgery

Figure 8. The tumor was resected by a right hemihepatectomy, caudate lobectomy and pancreatoduodenectomy (A). Resected specimen shows a distal bile duct cancer (arrows) with marked superficial mucosal spreading along the bile duct (arrowheads) (B). B1l: an orifice of the left caudate lobe branch.

additional PTBD should urgently be performed for patients who develop segmental cholangitis (Fig. 9), which is a significant risk factor for postoperative morbidity and mortality.13 Thanks to recent advance in imaging techniques: MDCT and three-dimensional CT angiography has replaced conventional invasive angiography to assess the extent of vascular involvement and to delineate the vascular anatomy in individual case of HC (Fig. 10). The present dilemma in the treatment of HC is finding the best balance between aggressive surgery and its safety. Which side of the liver should be resected in terms of tumor location or extent (Fig. 11)? At the same time, functional reserve of the future remnant liver must be carefully estimated. In case of Bismuth type I with right hepatic arterial invasion, right hemihepatectomy is ideal to perform R0 resection, but for patients with poor functional reserve undergoing right hemihepatectomy, left hemihepatectomy with right hepatic arterial resection and reconstruction is one of the alternative strategies. In summary, resectional procedure for HC should be designed according to of the tumor extent, local anatomy of the hilar structure and hepatic functional reserve in each individual case. Thus meticulous evaluation for each case is mandatory.

Preoperative Management

Preoperative periodical bile culture for possible positive bacteria should routinely be made for appropriate use of sensitive antibiotics in patients with PTBD. Perioperative septic complications considerably influence surgical outcome.13 To prevent severe septic complications, appropriate use of antibiotics as well as urgent biliary drainage is mandatory. In patients without PTBD, the first or second age cephalosporin is administered for prophylactic purposes. Impaired intestinal barrier function does not recover by PTBD without bile replacement. Bile replacement during external biliary drainage can restore the intestinal barrier function in patients with biliary obstruction, primarily due to repair of physical damage to the intestinal mucosa. Thus externally drained bile should be replaced as perioperative management for patients

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

193

Figure 9. Emergency percutaneous transhepatic biliary drainage (PTBD) for segmental cholangitis was carried out. Abscess formation is noted. B4a: left medial inferior subsegmental duct; B4b: left medial superior subsegmental duct.

Figure 10. Three-dimensional angiography demonstrates obstruction of the left portal vein, right portal vein invasion (arrow, A) and right hepatic arterial invasion (arrow, B). Ant: right anterior sectional portal vein; Post: right posterior sectional portal vein; 7d: a paracaval branch of the right posterosuperior segmental portal vein.

194

Recent Advances in Liver Surgery

Figure 11. Schematic illustration of the proximal resection limit of intrahepatic segmental ducts according to type of hepatectomy. Numerals indicate Couinauld’s segment of the liver. U: umbilical portion of the left portal vein; P: right posterior section.

with HC.14,15 On the other hand, preoperative oral administration of synbiotics can enhance immune responses, attenuate systemic postoperative inflammatory responses and improve intestinal microbial environment.16 These procedures likely reduce postoperative infectious complications after major hepatobiliary resection, so perioperative use of synbiotics is one of the treatment of choice for patients with HC. CT-volumetry is used to estimate the volume of the entire liver and the part of the hepatic segment to be resected. PVE for the liver segment to be resected, has been advocated as a useful option to induce compensatory hypertrophy of the future remnant liver6,7 (Fig. 12). It has been indicated if the estimated resection volume exceeds 55-60% of the whole liver, taking into consideration the hepatic functional reserve or invasiveness of the additional procedure of concomitant vascular resection and/or HPD. In CT-volumetry two weeks after PVE, there is an approximately 10% volume gain in the future remnant liver, whereas there is a 10% volume loss in the liver to be resected.6,7 Although clinical utility and feasibility have been reported, the indication of preoperative PVE has still not been established. Definitive surgery was planned 2 to 4 weeks after PVE and was usually carried out when the serum total bilirubin level decreased below 2 mg/dL.

Surgery General Procedures in Resectional Surgery for HC

Skin incision is done by a right subcostal incision with an upper midline extension. After laparotomy, it is mandatory to explore the abdominal cavity to check the presence of peritoneal seeding, paraaortic lymph node involvement, liver metastasis and the resectability in terms of the local tumor extension using intraoperative ultrasonography. The PTBD catheter, if any, should

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

195

Figure 12. Percutaneous transhepatic portography shows no abnormality (A). The right portal vein is not visualized after portal vein embolization using absolute ethanol (B).

be fixed to the liver surface in order to maintain intraoperative bile drainage and prevent bile contamination in the operative field. Before liver transection, it is crucial to monitor the central venous pressure (CVP); if it is higher than 3 cm H2O the surgeon should consult with the anesthesiologist to keep the CVP below 3 cm H2O. At first, the Kocher’s maneuver is performed to mobilize the duodenum and allow regional lymphadenectomy in the hepatoduodenal ligament and around the retropancreatic and celiac artery. Simultaneously, the distal bile duct is isolated and resected at the intrapancreatic portion.

196

Recent Advances in Liver Surgery

The distal margin of the bile duct should be submitted to the pathologist for intraoperative frozen section examination. After confirming negative resection margin, the bile duct stump is closed with interrupted or continuous sutures of monofilament string. If the distal bile duct margin is positive for cancer, selection of additional surgery: resection of the intrapancreatic bile duct or pancreaticoduodenectomy should be decided depending on the status of the proximal and/or dissected margins. To secure a longer distal bile duct margin in the pancreas, the posterior superior pancreatoduodenal artery should be divided in some cases. Insertion of a drainage catheter from the distal end of the bile duct for intraoperative biliary drainage is recommended for patients with endoscopic biliary drainage or without preoperative biliary drainage.

Left Hemihepatectomy with Caudate Lobectomy (Figs. 13-17)

During hilar preparation the right gastric artery is ligated and divided, then the hepatogastric ligament is dissected. The left hepatic artery is ligated, transfixed and divided. Similarly, the middle hepatic artery is divided. The main portal vein is skeletonized and encircled by a vessel loop. Tiny

Figure 13. Schematic illustrations of a left hemihepatectomy. Numerals indicate Couinaud’s segment of the liver. PV: portal vein; IVC: inferior vena cava.

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

197

caudate branches around the portal bifurcation should be carefully dissected; thereafter the left portal vein is ligated, transfixed and divided at its origin. An alternative way to manage the left portal vein is to use a vascular clamp on the proximal side and oversew the venous stump with a running suture of 5-0 prolene. After cholecystectomy, the right hepatic artery should carefully be isolated and encircled with a vessel loop and the procedure is progressed to isolate the right anterior and posterior branches. The cystic artery is ligated and divided at its origin. Meticulous manipulations for skeletonization of the right hepatic artery are advisable. It is also advisable to use topical application of 1% xylocaine solution for the skeletonized hepatic artery to prevent the spastic reaction of the artery followed by unexpected thrombosis. The right posterior or posteroinferior hepatic artery sometimes runs along the caudal side of the right portal vein into Rouviere’s sulcus. Preoperative assessment for anatomical variation of the right hepatic artery on MDCT is crucial. A demarcation line appearing on the Cantlie line is marked with an electric cautery. For complete mobilization of the left liver, the falciform and coronary ligaments are incised, then the triangle ligament is ligated and divided. The root of the left and middle hepatic vein should be identified; the MHV and the LHV make a common trunk in many cases. Next, the Arantius canal is isolated, ligated and divided, making it thus easier to encircle the common trunk of the middle and the left hepatic vein. The caudate lobe is completely detached from the inferior vena cava (IVC) in the caudal to the cranial direction. The short hepatic veins (SHV) are carefully ligated divided. Thick SHV such as the caudate vein located around the one third of cranial portion of the left caudate lobe should be ligated and clamped with a vascular forceps, then divided and closed with running sutures.17 Liver parenchymal transection is performed using the forceps clamp crushing method or CUSA at the discretion of the operating surgeon during both hepatic artery and portal vein occlusion for 15 minutes at 5-minute intervals (Pringle’s maneuver). The MHV appears on the transection

Figure 14. Schematic illustration showing the division line of the bile duct during the left hemihepatectomy. LHV: left hepatic vein; MHV: middle hepatic vein; RPPV; posterior branch of the right portal vein; RHA: right hepatic artery; B5 + 8: right anterior sectional duct.

198

Recent Advances in Liver Surgery

Figure 15. Schematic illustration showing the division of the right anterior segmental ducts and posterior sectional duct (line) during the left hemihepatectomy. RAHA; anterior branch of the right hepatic artery; RPHA: posterior branch of the right hepatic artery; RHA: right hepatic artery; B5: right anteroinferior segmental duct; B8: right anterosuperior segmental duct; B6 + 7: right posterior sectional duct.

Figure 16. Legend viewed on following page.

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

199

Figure 16, viewed on previous page. Selective cholangiography for the right anterior section (A) and the right posterior section (B) are presented. The estimated resection lines (dotted lines) were decided based on selective cholangiography through percutaneous transhepatic biliary drainage catheters. 5a: a ventral branch of the right anteroinferior segmental duct; 5bc: dorsal plus lateral branches of the right anteroinferior segmental duct; 8a: a ventral branch of the right anterosuperior segmental duct; 8c: a dorsal branch of the right anterosuperior segmental duct; 6a: a ventral branch of the right posteroinferior segmental duct; 6b: a dorsal branch of the right posteroinferior segmental duct; 6c: a lateral branch of the right posteroinferior segmental duct; 7a: a ventral branch of the right posterosuperior segmental duct; 7b: a dorsal branch of the right posterosuperior segmental duct; 7d: a paracaval branch of the right posterosuperior segmental duct.

plane and the confluence of the MHV and LHV is clearly identified. The root of the left hepatic vein is clamped with a vascular forceps, divided and closed with running sutures of 4-0 or 5-0 prolene. The left lateral aspect of the MHV is exposed and the liver parenchymal transection progresses to the right edge of the IVC, an important landmark of the right border of the right caudate lobe. Also, division between the caudate process and posterior section progresses in the cranial direction. After confirming the adequate dissection of the branches of the right hepatic artery and the right portal vein, the bile duct is finally transected just beneath the MHV or the expected point determined preoperatively. Bile duct transection starts from the caudo-ventral border to the cranio-dorsal border just like making around the right portal vein and the right hepatic arterial branches. Usually, the orifices of the anteroinferior segmental duct, ventral part of the anterosuperior segmental duct, dorsal part of the anterosuperior segmental duct and the posterior sectional duct appear in order (Fig. 17B). Frozen sections of the proximal bile duct margins should be submitted for the pathologist to confirm the absence of cancer invasion. After the liver resection, the right side wall of the IVC is clearly exposed. If tumor invasion of the MHV is suspected, concomitant MHV resection (extended left hemihepatectomy) is indicated in order to achieve negative surgical margin. After completing hemostasis, hepaticoplasty prior to bilio-enterostomy is advisable to reduce the number of anastomoses and simplify the procedure. Bilio-enteric continuity is reestablished by bilio-enterostomy using a Roux-en-Y jejunal limb and external biliary stents are placed across the bilio-enteric anastomosis. The interrupted or continuous suture is completed at the discretion of the operator using 5-0 monofilament absorbable strings. A tube for postoperative early enteral

Figure 17. Intraoperative photography shows portal vein resection and reconstruction with arrow (A). Hepatic arterial reconstruction is completed (arrow) and openings of the intrahepatic segmental bile ducts of the right liver are documented (B). B5: a right anteroinferior segmental bile duct; B8: a right anterosuperior segmental bile duct; B7d: a paracaval branch of the right posterosuperior segmental duct; P: right posterior sectional duct.

200

Recent Advances in Liver Surgery

feeding and replacement of externally drained bile is placed through the proximal end of the jejunal limb. A retrocolic and retrogastric route18 is preferable to elevate the jejunal limb. After lavaging the peritoneal cavity, closed suction drains are placed around the hepaticojejunostomy and along the raw surface of the liver and the abdomen is closed.

Right Hemihepatectomy with Caudate Lobectomy (Figs. 18-22)

During skeletonization of the hepetoduodenal ligament, identification and taping of the common hepatic, gastroduodenal and proper hepatic arteries are undertaken with the vessel loops. The right gastric artery is ligated and divided. The distal bile duct is then dissected similar to left hemihepatectomy. The middle hepatic and the left hepatic arteries should be identified and the right hepatic artery is ligated, transfixed and divided at its origin. The portal vein is taped and skeletonized up to the hepatic hilum. Next, the serosal membrane of the Rex’s recess is incised and the ventral part of the umbilical portion of the left portal vein should be clearly exposed (Fig. 20). The left hepatic artery runs into the liver from the left side of the umbilical portion of the portal vein and the middle hepatic artery, in many cases, runs into the liver between the medial sectional branches of the portal vein and the bile duct. Occasionally the middle hepatic artery arises from the left hepatic artery in the umbilical plate (Fig. 20). Careful manipulation for the skeletonization of these arteries is advisable. Tiny branches of the caudate lobe or the quadrate lobe are ligated and divided and the Arantius canal is ligated and divided, leaving the left portal vein skeletonized and readily encircled.

Figure 18. Schematic illustrations of right hemihepatectomy. Numerals indicate Couinauld’s segment of the liver. PV: portal vein; IVC: inferior vena cava.

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

201

Figure 19. Schematic illustration showing the resection line of the left hepatic duct during the right hemihepatectomy. I: caudate bile duct branch; II: left lateral inferior segmental duct; III: left lateral superior segmental duct; IV: left medial segmental duct.

Figure 20. An intraoperative photograph after skeletonization and hilar preparation shows the expected resection line of the inferior aspect of the left medial section (arrowheads). The line is marked approximately 1 cm above (ventral to) to keep away from the hilar plate during liver transection. The umbilical portion of the left portal vein is adequately mobilized to transect the left intrahepatic segmental ducts (arrow).

202

Recent Advances in Liver Surgery

Figure 21. An intraoperative photograph shows the resection line of the left hepatic duct during right hemihepatectomy. The right and left livers are connected with the left hepatic duct.

PVE should be carried out before right hemihepatectomy or more extended hepatectomy. The tip of the embolic material in the right portal vein potentially extends into the portal bifurcation. Thus, the main and the left portal vein are clamped with vascular forceps, and the origin of the right portal vein is transversely incised to observe the absence of the embolic materials in the residual portal venous system. No back flow from the stump of the right portal vein is usually documented due to PVE. The embolic materials, if detected, should be removed and washed out from the opening of the right portal vein with heparinized saline. This opening is closed with transverse running suture to prevent stricture of the portal bifurcation. On the other hand, if tumor invasion is observed or suspected around the portal bifurcation, combined portal vein resection and reconstruction should be performed to obtain clear dissection margins.19 When a demarcation line appeared along the Cantlie line, it is marked with an electric cautery. On the inferior aspect of the left medial section, liver transection is progressed transversely approximately 1 cm above (ventral to) the hilar plate. During mobilization of the right liver, detachment of the right adrenal gland is carefully performed because dense adhesion between the right liver and the adrenal gland is encountered in some patients. The right hepatic vein is encircled, divided and closed with running sutures. In order to divide and close large hepatic veins such as the right hepatic vein, a stapler device can be used instead of manual sutures. An endoscopic gastrointestinal anastomosis vascular stapler is quite useful to divide the hepatic vein faster and simpler. The right hepatic vein is usually divided behind the liver before liver transection. Complete detachment of the entire caudate lobe from the inferior vena cava (IVC) progresses step by step by dividing the short hepatic veins and thick short hepatic veins should be closed with a stapler. Liver parenchymal transection starts along the demarcation line during both hepatic artery and portal vein occlusion for 15 minutes at 5-minute intervals. The middle hepatic vein (MHV) appears on the transection plane and the tributaries from the right liver should be carefully ligated

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

203

Figure 22. An intraoperative photograph after right hepatectomy shows the clearly exposed middle hepatic vein on the raw surface of liver and openings of the left intrahepatic segmental ducts. Hepaticoplasty had already been performed. B2; left lateral inferior segmental duct; B3: left lateral superior segmental duct; B4: left medial segmental duct; MHV: middle hepatic vein; IVC: inferior vena cava.

and divided. From the confluence of the IVC, the dorsal aspect of the MHV is exposed and the operator at the same time pulls and turns the left caudate lobe right dorsally with left fingers. The rule is to keep away from the hilar plate during liver transection on the inferior aspect of the medial section to secure the negative surgical margin. Finally, the right and the left livers are connected with the left hepatic duct. The right liver and caudate lobe are located at the left hand of the operator and the left hepatic duct is incised in the ventral to the dorsal direction (Fig. 21). Usually, orifices of the left medial sectional (B4), the left lateral superior segmental (B3) and the left lateral inferior segmental (B2) bile ducts are identified in order (Fig. 22). After hepaticoplasty, bilioenterostomy is created.

204

Recent Advances in Liver Surgery

Figure 23. Schematic illustrations depicting segmental portal vein resection (A) and reconstruction between the left and main portal veins (B, C).

Portal Vein Resection and Reconstruction (Figs. 23-26)

In case of right-sided hepatectomies, portal vein resection and reconstruction prior to liver transection is feasible. The wedge resection or segmental resection with end-to-end anastomosis is possible in many cases and segmental resection with an autologous vein interposition is not frequent in a right-sided hepatectomy. If the length of the portal vein resection exceeds 5 or 6 cm, an interposition graft is required. An external iliac vein is usually harvested by an extraperitoneal approach as an autologous graft for portal vein reconstruction, because the diameter of the external iliac vein is similar to that of the reconstructing portal veins. Approximately one-fourth of the external iliac veins have a valve, so normograde reconstruction of the portal vein using an external iliac vein is essential. In the case of a portal vein reconstruction using an interposition graft, the mesenteric side precedes to the hepatic side. After declamping of the mesenteric side forceps to provide adequate graft expansion, the hepatic side anastomosis is done. In the left sided-hepatectomies, portal vein resection and reconstruction prior to liver parenchymal resection are difficult and an autologous vein graft is sometimes required for reconstruction (Figs. 25, 26). Depending upon the defect of the portal vein to be reconstructed, a direct transverse suture, patch graft repair, or sequential vein grafting is selected for portal vein reconstruction. The key to the portal vein resection and reconstruction during right-sided hepatectomies is the feasibility of cross-clamping of the root of the umbilical portion of the left portal vein. In left-sided hepatectomies, isolation and clamping of the right posterior section or the right anterior section portal vein are the key manipulations. During end-to-end portal vein anastomosis, an intraluminal technique is usually applied for the posterior wall, then oversew the anterior wall using a single string of 5-0 prolene (Figs. 23, 24).

Right Trisectionectomy with Caudate Lobectomy (Figs. 27-30)

In the cases indicated for right-sided hepatectomy, the proximal tumor extension beyond the confluence of the left medial section bile duct is proposed for the right trisectionectomy in order to secure the proximal bile duct margin. During the right trisectionectomy, an important and peculiar procedure is mobilization of the umbilical portion of the left portal vein (Fig. 30A). The middle hepatic artery is ligated with transfixing and divided. The ventral connective tissue of the umbilical

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

205

Figure 24. End-to-end anastomosis of the portal vein during a right hemihepatectomy (A). There is no obvious caliber change in the reconstructed portal vein (B).

Figure 25. Schematic illustrations depicting segmental portal vein resection and reconstruction using an external iliac vein graft. Distal anastomosis is followed by proximal anastomosis. A: stay sutures; B: posterior wall anastomosis; C: anterior wall anastomosis; D: stay sutures; E: anterior anastomosis

portion of the left portal vein is dissected and portal vein branches of the left medial section are ligated and divided step by step. The Arantius canal is ligated and divided at the portal elbow. In case of anatomical (extended) right trisectionectomy, all portal vein branches arising from the dorsal aspect of umbilical portion of the left portal vein should be completely ligated and

206

Recent Advances in Liver Surgery

Figure 26. Left hepatectomy, caudate lobectomy, extrahepatic bile duct resection, combined portal vein and hepatic artery resection and reconstruction are completed. The arterial anastomosis is indicated with arrow. The interposed external iliac vein is indicated with arrowheads.

divided.20 This procedure provides complete mobilization of the umbilical portion of the left portal vein which can completely be turned out and we can confirm the root of the left lateral inferior (P2) and the left lateral superior (P3) segmental branches of the portal vein. Also, the left hepatic artery and its branches run through the left side of the umbilical portion of the left portal vein and can be clearly identified between the bile ducts and the portal veins of the left lateral section. Careful manipulation for isolation of the left hepatic artery to prevent injury is of great importance. The demarcation line appears not on the right but rather on the left side of the falciform ligament. The fissural vein should be identified by intraoperative ultrasonography and preserved as far as possible (Fig. 30B). After complete mobilization of the right liver and caudate lobe similar to the right hemihepatectomy, liver parenchymal transection along the demarcation line starts using intermittent inflow occlusion. The middle hepatic vein is divided at its root with a stapler or the ordinary technique. Finally, the bile ducts are transected in the ventral to dorsal direction and the left lateral superior segmental duct (B3) and left lateral inferior segmental duct (B2) are identified in order (Fig. 30B). Separate hepaticojejunostomies for B2 and B3 are sometimes required especially in the case of anatomical right trisectionectomy.

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

207

Figure 27. Schematic illustrations of right trisectionectomy. Numerals indicate Couinauld’s segment of the liver. PV: portal vein; IVC: inferior vena cava.

Left Trisectionectomy with Caudate Lobectomy (Figs. 31-34)

After lymph node dissection for the retropancreatic and around the common hepatic artery, the distal bile duct is divided. The right gastric, left hepatic, middle hepatic and cystic artery are identified, ligated and divided. Finally, the anterior branch of the right hepatic artery is ligated and divided. Both the right posterior branch of the portal and hepatic artery are encircled with vessel loops and should be skeletonized further upstream of the expected resection line of the posterior sectional bile duct. For most patients scheduled to undergo left trisectionectomy, preoperative PVE is indicated.21 The left portal vein and the anterior branch of the right portal vein are ligated, transfixed and divided to confirm the absence of the embolic material in the portal system. If the embolic material extends into the right or the main portal vein, the embolic material must be removed from the origin of the right posterior branch. Tiny branches of the portal vein of the caudate lobe are carefully ligated and divided. After these manipulations, a demarcation line corresponding to the right portal fissure appears and is marked with an electric cautery. The distal portion of the Arantius canal is ligated and divided and then mobilization of the left liver and caudate lobe is

208

Recent Advances in Liver Surgery

Figure 28. Schema of right trisectionectomy depicting dissection along the cranial aspect of the umbilical portion of the left portal vein and exposure of the umbilical plate. B4: a left medial segmental duct; A4: a medial branch of the left hepatic artery; P4: a left medial branch of the left portal vein.

Figure 29. Schema depicting division of the middle hepatic vein followed by division of the left lateral segmental ducts. B1; a caudate lobe bile duct branch; B2; left lateral inferior segmental duct; B3: left lateral superior segmental duct; B4: left medial segmental duct; P4: a left medial branch of the left portal vein; MHV: middle hepatic vein; LHV: left hepatic vein; LPV: left portal vein; RPV: stump of the right portal vein.

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

209

Figure 30. Intraoperative photographs during a right trisectionectomy and caudate lobectomy with pancreatoduodenectomy, showing left lateral segmental ducts that connected the left lateral section and the right trisection of the liver. The umbilical portion of the left portal vein is completely mobilized (A). After bile duct resection, multiple openings of the left lateral segmental ducts are noted (B). S1; caudate lobe; A2 + 3: left lateral inferior + left lateral superior branch of the left hepatic artery; B2; left lateral inferior segmental duct; B3: left lateral superior segmental duct; UP: umbilical portion of the left portal vein.

Figure 31. Schematic illustrations of a left trisectionectomy. Numerals indicate Couinauld’s segment of the liver. PV: portal vein; IVC: inferior vena cava.

210

Recent Advances in Liver Surgery

completed in the same way as for left hemihepatectomy. During mobilization of the left liver, the common trunk of the left and the middle hepatic vein is encircled and transected with the ordinary technique or a stapler. Liver parenchymal transection along the demarcation line starts under intermittent inflow occlusion. The right hepatic vein should be exposed on the raw surface of the liver toward the confluence of the IVC and the parenchymal transection between caudate lobe and right posterior sector then starts along the right edge of the IVC. Another critical landmark for transection is the root of the right posterior sectional branch of the portal vein. The transection of the dorsal part of the right portal vein proceeds from the caudal side and the transection plane is connected to the cranial plane. At this point the left trisection of the liver and the caudate lobe are just interconnected with the right posterior section through the posterior sectional bile duct. Finally, the bile duct is divided after confirming adequate isolation of the right posterior portal and hepatic artery and the resection is then completed. The bile duct openings of the right posterosuperior and the right posteroinferior branches are occasionally identified separately.

Hepatopancreatoduodenectomy (Figs. 5-8, 30)

Hepatopancreatoduodenectomy (HPD) usually involves concomitant pancreatoduodenectomy in a right hemihepatectomy or more extended hepatobiliary resection in surgery for HC. This procedure is one of the ultimate operations in terms of the degree of invasiveness, patients with extensive bile duct cancer are possible candidates for HPD to secure a negative distal bile duct margin. Although refinements in imaging diagnosis and perioperative management have improved the short-term outcome for patients undergoing HPD, the results are still not satisfactory at the present time. On the other hand, there is no alternative curative treatment for some patients. While resected cases of biliary malignancies by HPD remain few, the accumulation and analyses of HPD cases will serve to profile more clearly patients who have a beneficial effect from this aggressive operation.3,22,23

Figure 32. Schema representing exposure of the right hepatic vein and division of the right posterior sectional duct. B5 + 8; right anterior sectional duct; B6 + 7; right posterior sectional duct; RHV: right hepatic vein; LHA: left hepatic artery; RHA: right hepatic artery.

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

211

Figure 33. Schemas representing division of the right posterior sectional ducts. RAPV: stump of the right anterior sectional portal vein; RAHA: stump of the right anterior sectional hepatic artery; B6: right posteroinferior segmental duct; B7: right posterosuperior segmental duct; A6: right posteroinferior branch of the right hepatic artery; A7: right posterosuperior branch of the right hepatic artery.

Figure 34. The right hepatic vein is clearly exposed on the raw surface of the liver after left trisectionectomy (arrowheads). The opening of posterior sectional bile duct is noted (arrow).

212

Recent Advances in Liver Surgery

Hepatic Arterial Resection and Reconstruction during Hepatobiliary Resection (Figs. 17, 26)

Most of the hepatic arterial resection and reconstruction is indicated in left-sided hepatectomy and reconstruction of the right hepatic artery with an end-to-end anastomosis is common. Microsurgical technique is used for arterial reconstruction using right gastroepiploic artery or radial artery.24 When arterial reconstruction is impossible, one possible countermeasure is arterialization of the portal blood. Oblique-to-side anastomosis is performed between the common hepatic artery and the main portal vein. Three weeks after surgery, trans catheter arterial embolization of the common hepatic artery is carried out to prevent further portal hypertension.

Conclusions

Surgical treatment of hilar cholangiocarcinoma still poses a difficult challenge for the surgeon. In these circumstances, aggressive surgical approaches to difficult HC, using PTBD, PVE and major hepatectomy, has been established as a safe management strategy.10 Not only the surgical technique but also refinements of perioperative management have contributed to the improvement in the treatment of HC. The many issues remaining to be resolved include major hepatectomy8-10,25-31 versus parenchyma-preserving hepatobiliary resection,1,32 necessity of preoperative biliary drainage,33 percutaneous or endoscopic approach for biliary drainage, bilobar or hemilobar biliary drainage and indication of preoperative PVE. Although only a few large surgical series treating HC have been published,8-10,25-37 the ongoing accumulation of cases and evaluation of the surgical outcome will serve to delineate future problems to be addressed.

References

1. Nimura Y, Hayakawa N, Kamiya J et al. Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the hepatic hilus. World J Surg 1990; 14:535-543. 2. Nimura Y, Hayakawa N, Kamiya J et al. Hepatopancreatoduodenectomy for advanced carcinoma of the biliary tract. Hepatogastroenterology 1991; 38:170-175. 3. Ebata T, Nagino M, Nishio H et al. Right hepatopancreatoduodenectomy: improvements over 23 years to attain acceptability. J Hepatobiliary Pancreat Surg 2007; 14:131-135. 4. Nagino M, Nimura Y, Hayakawa N et al. Logistic regression and discriminant analyses of hepatic failure after liver resection for carcinoma of the biliary tract. World J Surg 1993; 17:250-255. 5. Makuuchi M, Thai BL, Takayasu K et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990; 107:521-527. 6. Nagino M, Nimura Y, Kamiya J et al. Changes in hepatic lobe volume in biliary tract cancer patients after right portal vein embolization. Hepatology 1995; 21:434-439. 7. Imamura H, Shimada R, Kubota M et al. Preoperative portal vein embolization: an audit of 84 patients. Hepatology 1999; 29:1099-1105. 8. Nagino M, Kamiya J, Nishio H et al. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 2006; 243:364-372. 9. Nimura Y, Kamiya J, Kondo S et al. Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J Hepatobiliary Pancreat Surg 2000; 7:155-162. 10. Sano T, Shimada K, Sakamoto Y et al. One hundred two consecutive hepatobiliary resections for perihilar cholangiocarcinoma with zero mortality. Ann Surg 2006; 244:240-247. 11. Bismuth H, Corlette MB. Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet 1975; 140:170-178. 12. Nimura Y. Staging of biliary carcinoma: cholangiography and cholangioscopy. Endoscopy 1993; 25:76-90. 13. Kanai M, Nimura Y, Kamiya J et al. Preoperative intrahepatic segmental cholangitis in patients with advanced carcinoma involving the hepatic hilus. Surgery 1996; 119:498-504. 14. Kanazawa H, Nagino M, Kamiya S et al. Synbiotics reduce postoperative infectious complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy. Langenbecks Arch Surg 2005; 390:104-113. 15. Kamiya S, Nagino M, Kanazawa H et al. The value of bile replacement during external biliary drainage: an analysis of intestinal permeability, integrity and microflora. Ann Surg 2004; 239:510-517.

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

213

16. Sugawara G, Nagino M, Nishio H et al. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Ann Surg 2006; 244:706-714. 17. Takayama T, Makuuchi M, Kubota K et al. Living-related transplantation of left liver plus caudate lobe. J Am Coll Surg 2000; 190:635-638. 18. Nagino M, Kamiya J, Kanai M et al. Hepaticojejunostomy using a Roux-en-Y jejunal limb via the retrocolic-retrogastric route. Langenbecks Arch Surg 2002; 387:188-189. 19. Ebata T, Nagino M, Kamiya J et al. Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases. Ann Surg 2003; 238:720-727. 20. Nagino M, Kamiya J, Arai T et al. “Anatomic” right hepatic trisectionectomy (extended right hepatectomy) with caudate lobectomy for hilar cholangiocarcinoma. Ann Surg 2006; 243:28-32. 21. Shimada K, Sano T, Sakamoto Y et al. Safety and curativity of left hepatic trisectionectomy for hilar cholangiocarcinoma. World J Surg 2005; 29:723-727. 22. D’Angelica M, Martin RC 2nd, Jarnagin WR et al. Major hepatectomy with simultaneous pancreatectomy for advanced hepatobiliary cancer. J Am Coll Surg 2004; 198:570-576. 23. Miyagawa S, Makuuchi M, Kawasaki S et al. Second-stage pancreatojejunostomy following pancreatoduodenectomy in high-risk patients. Am J Surg 1994; 168:66-68. 24. Sakamoto Y, Sano T, Shimada K et al. Clinical significance of reconstruction of the right hepatic artery for biliary malignancy. Langenbeck Arch Surg 2006; 391:203-208. 25. Nagino M, Kamiya J, Arai T et al. One hundred consecutive hepatobiliary resections for biliary hilar malignancy: preoperative blood donation, blood loss, transfusion and outcome. Surgery 2005; 137:148-155. 26. Lee SG, Lee YJ, Park KM et al. One hundred and eleven liver resections for hilar bile duct cancer. J Hepatobiliary Pancreat Surg 2000; 7:135-141. 27. Seyama Y, Kubota K, Sano K et al. Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate. Ann Surg 2003; 238:73-83. 28. Kawasaki S, Imamura H, Kobayashi A et al. Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and hemihepatic portal vein embolization. Ann Surg 2003; 238:84-92. 29. Neuhaus P, Jonas S, Bechstein WO et al. Extended resections for hilar cholangiocarcinoma. Ann Surg 1999; 230:808-818. 30. Hemming AW, Reed AI, Fujita S et al. Surgical management of hilar cholangiocarcinoma. Ann Surg. 2005; 241:693-702. 31. Jarnagin WR, Bowne W, Klimstra DS et al. Papillary phenotype confers improved survival after resection of hilar cholangiocarcinoma. Ann Surg 2005; 241:703-714. 32. Miyazaki M, Ito H, Nakagawa K et al. Parenchyma-preserving hepatectomy in the surgical treatment of hilar cholangiocarcinoma. J Am Coll Surg 1999; 189:575-583. 33. Cherqui D, Benoist S, Malassagne B et al. Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg 2000; 135:302-308. 34. Klempnauer J, Ridder GJ, von Wasielewski R et al. Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 1997; 15:947-954. 35. Kondo S, Hirano S, Ambo Y et al. Forty consecutive resections of hilar cholangiocarcinoma with no postoperative mortality and no positive ductal margins: results of a prospective study. Ann Surg 2004; 240:95-101. 36. Gerhards MF, van Gulik TM, de Wit LT et al. Evaluation of morbidity and mortality after resection for hilar cholangiocarcinoma—a single center experience. Surgery 2000; 127:395-404. 37. Tabata M, Kawarada Y, Yokoi H et al. Surgical treatment for hilar cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2000; 7:148-154.

Chapter 16

Resection of Noncolorectal Cancer Liver Metastases Cristina R. Ferrone and Kenneth K. Tanabe*

Abstract

T

he liver remains second only to the regional lymph nodes as the most common site of metastases from gastrointestinal tract malignancies. Other primary tumors outside of the gastrointestinal tract also metastasize to the liver, but with a lower frequency. The safety of hepatic resection has improved with lower morbidity and mortality rates. Improved surgical techniques and more effective chemotherapy have increased the interest in resecting metastatic disease. Hepatic resection of colorectal cancer metastases results in 3-year survival rates of 27% to 72% and 5-year survival rates of 14% to 60%.1,2 The accumulated experience documenting the survival potential for hepatic resection for selected patients with colorectal metastases has prompted an evaluation of this approach for any malignancy that metastasizes to the liver. Hepatic resection for noncolorectal tumors is being examined and re-examined by multiple groups. Unfortunately, the published series are retrospective and contain small numbers. Therefore, conclusions are difficult to discern. For a highly select group of patients there may be a benefit to resection of hepatic metastases.

Noncolorectal Hepatic Metastases

Many series combine multiple tumor types to be able to achieve adequate numbers of patients for analysis. However, the number of patients in these series remains small. Recent advances in imaging and understanding of segmental anatomy have provided an environment in which hepatic resections can be performed safely. Advances in surgical technique and perioperative care have decreased the post operative mortality to <5% at tertiary referral centers.1,2 Patients with noncolorectal hepatic metastases usually do not have cirrhosis, further reducing the risk of hepatic resection. Multiple series have been published on hepatic resection of neuroendocrine metastases and noncolorectal nonneuroendocrine metastases, which we will summarize and review. Radiofrequency ablation remains a good option for some patients with noncolorectal carcinoma liver metastases. This and other ablation technologies are discussed in other sections of this chapter.

Neuroendocrine Tumors

Neuroendocrine tumors represent a diverse group of rare neoplasms with unique clinical presentations and growth patterns. Hepatic metastases develop in 46-93% of patients with neuroendocrine tumors. Several clinical observations have made hepatic resection an interesting therapeutic option. The prolonged natural history, compared to other gastrointestinal cancers and the prolonged duration of hepatic metastasis before progression to extra-hepatic sites enables hepatic resection to render a patient free of disease. A lack of effective systemic therapies also contributes *Corresponding Author: Kenneth K. Tanabe. Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School. Email: [email protected].

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

215

Resection of Noncolorectal Cancer Liver Metastases

to the interest in hepatic resection as a treatment option. For patients who are symptomatic hepatic resection is a good option for symptom control, since the intrahepatic volume of disease seems to correlate with the associated endocrinopathies. Hepatic resection for neuroendocrine tumors should be considered for cytoreduction in addition to complete remission. Cytoreduction allows for both symptom control and debulking of slow growing tumors for which chemotherapy is ineffective. Patients with untreated hepatic metastases reveal a 20-40% 5-year survival, with a median survival of 2-4 years. Multiple retrospective series suggest a survival benefit to hepatic resection, however, all of these studies are retrospective and have a significant selection bias. Musunuru et al compared patients undergoing medical treatment, hepatic artery emobilization and resection.4 Patients undergoing resection had a significantly longer survival of 83% at three years. Although the difference in overall volume of disease in the liver was not statistically different between the groups, patients undergoing medical treatment and hepatic artery embolization were more likely to have bilobar disease and a higher number of hepatic lesions. Touzios et al compared patients with similar hepatic burdens who underwent non-aggressive treatment, hepatic resection and embolization in addition to resection.11 Patients had similar burdens of disease in terms of the percent liver involved, bilobar disease and mean tumor size. The non-aggressive group was more likely to have the primary in place and to receive systemic chemotherapy. There was a significant difference in symptom control (42% vs 91%) and 5-year survival (25% vs 62%). Whether resection of hepatic metastases improves survival is a difficult question to answer. Performing a prospective randomized trial is difficult due to the small numbers of patients. Retrospective series suggest that there is a survival benefit to the resection of neuroendocrine hepatic metastases.

Noncolorectal Nonneuroendocrine Hepatic Metastases

Multiple series have beenpublished on hepatic resection of noncolorectal non neuroendocrine metastases (Table 1). Weitz et al published on 141 patients undergoing hepatic resection for noncolorectal nonneuroendocrine metastases with 0% mortality and 33% morbidity. The actuarial 3-year survival was 57% with the primary tumor type and a disease free interval of >24 months as independent prognostic factors. O’Rourke et al published on 114 hepatic resections for noncolorectal non neuroendocrine metastases in 102 patients with a mortality of <1%. At five years, the overall survival was 38.5%. Adverse prognostic factors included metastases >5 cm in size and extra-hepatic nodal disease. The largest series was published by the Association Francaise de Chirurgie which analyzed 1452 patient who underwent hepatic resection for noncolorectal, nonneuroendocrine hepatic metastases.3 Patients with adrenal, breast, choroid melanoma, cutaneous melanoma, exocrine pancreatic, gastric/gastroesophageal junction/esophageal, head and neck, ovarian, pulmonary, Table 1. Series of resected neuroendocrine hepatic metastases First Author

Year

n

Operative Mortality(%)

Survival

Chen5 Chamberlain6 Grazi7 Jaeck8 Nave9 Sarmiento10 Touzios11 Musunuru4

1998 2000 2000 2001 2001 2001 2005 2006

15 34 19 13 31 170 37 13

0 6 0 0 0 1.2 5 0

73% at 5y 76% at 5y 92% at 4y 91% at 3y 47% at 5y 61% at 5y 62% at 5y 83% at 3y

*Value is approximate.

216

Recent Advances in Liver Surgery

renal, small bowel, testicular and uterine were included. Hepatic metastases were unilateral in 71% and solitary in 56%. Extra-hepatic metastases were present in 22%. An R0 resection was achieved in 83% of patients. Overall 60-day mortality was 2.3% and a major complication rate of 21.5%. After a mean follow-up of 31 months, overall and disease free survival at five years were 36% and 21%. Actual 5-year and 10-year survivors were 14% (n = 209) and 4% (n = 46), respectively. Median recurrence-free survival was 11 months with recurrent hepatic metastases identified in 49% of patients. Adverse prognostic factors identified in multivariate analysis included age >60 yrs, nonbreast primary, melanoma and squamous cell primaries, disease free interval <12 months, extra-hepatic metastases, R2 resection and resection of >2 segments. A prognostic model assigned each factor one point and stratified patients into a low risk group with 0-3 points, medium risk with 4-6 points and high risk with >6 points. Five-year survival was 46%, 33% and <10%, respectively for the three groups. These results are in line with several smaller published reports of patients undergoing resection of liver metastases from melanoma, breast cancer and sarcoma liver as noted below.

Breast Cancer

Approximately 178,480 women will develop breast cancer in the United States in 2007. Of these women approximately 50% will develop distant metastases. Approximately half of the women who develop distant metastases will develop liver metastases, with the liver as the first site of relapse in 25%.12-14 Approximately 10% of women with hepatic metastases from breast cancer will have isolated hepatic metastasis.15 The standard of care for patients with metastatic breast cancer is a combination of chemotherapy, hormonal therapy and/or biological therapy. An increasing number of studies have addressed the role of hepatic resection for breast cancer metastasis in a highly select group of patients (Table 2). The first reported case of liver resection for breast cancer liver metastases was reported by Alexander Brunschwig in 1963, from the Memorial Hospital for Allied Diseases (now known as Memorial Sloan Kettering Cancer Center). That patient survived for one year and eight months. The first modern series was published in 1991 by Elias et al16 He reported on 12 patients who underwent hepatectomy for breast cancer liver metastases with a median survival of 47 months. Subsequently, numerous small series have been published documenting median survivals of 27-57 Table 2. Series of resected breast cancer hepatic metastases

† ‡

Reference

No. Patients

Median Survival (mo)†

Raab et al31 1998

34

41.5‡

Seifert et al21 1999 Pocard et al32 2000

15 49

57 42

Selzner et al22 2000 Yoshimoto et al33 2000 Carlini et al25 2002 Elias et al34 2003 Vlastos et al26 2004 Adam et al28 2006

17 25 17 54 31 85

27 34 53 34 63 32

Overall Survival. For patients undergoing R0 resection.

Adverse Prognostic Factors R1 resection; local recurrence of primary tumor None Short disease-free interval; node positive primary Short disease-free interval None None Negative receptor status None Failure to respond to preoperative chemotherapy, R2 resection, absence of repeat hepatectomy

Resection of Noncolorectal Cancer Liver Metastases

217

months (5-year survival of 18-61%).3,17-24 Most recently Adam et al reported on a consecutive series of 85 patients with a median survival of 32 months and a 5-year survival of 37%.25 Study variables independently associated with poor survival were failure to respond to preoperative chemotherapy (p = 0.008), an R2 resection (p = 0.0001) and the absence of repeat hepatectomy (p = 0.01). The Association Francaise de Chirurgie published a series of 460 patients undergoing hepatic resection for breast cancer metastases with a median survival of 45 months and a 5-year survival of 41%.3 Although all these series are retrospective, historical data demonstrates median survivals for patients with isolated breast cancer metastases to the liver who are not resected of 23 months, with few if any patients surviving five years.26,27 All the currently published series have small numbers with heterogeneous patient populations and inclusion criteria. Even large tertiary referral centers that have published their results of resection for breast cancer liver metastases identify only a handful of patients per decade that were selected for liver resection. For stage IV breast cancer patients with hepatic metastases no conclusions can be drawn regarding patients with extra-hepatic disease, length of disease free interval or the role of pre hepatic resection chemotherapy. Although metastatic disease represents systemic disease, in a highly selected group of patients hepatic resection may confer a survival benefit and/or a chemotherapy holiday and should be considered as one component of a multidisciplinary approach.

Sarcoma

Patients with liver metastases from soft tissue sarcoma are primarily treated with chemotherapy or supportive care. Considerable data support an improved outcome with the resection of pulmonary metastases from sarcoma, with an actual 5-year survival of 15%.28 The role of hepatic resection, however, has not been well studied. The largest series is from Memorial Sloan-Kettering Cancer Center and consists of 56 patients who underwent complete surgical resection of all gross liver disease.29 The majority of the patients (34/56, 61%) had a metastatic GIST or a leiomyosarcoma (11/56, 20%). For patients who were completely resected the median survival was 39 months and the 5-year overall survival was 30%. If a complete resection was not achieved 5-year overall survival was only 4%. Adverse prognostic factors were the inability to completely resect all disease and a time interval to the development of hepatic metastases of less than 2 years. Lang et al documented a median survival of 40 months and a 5-year overall survival of 33% in 15 patients undergoing an R0 resection for hepatic metastases from leiomyosarcoma.30 The group at MD Anderson reported on 66 patients with hepatic metastases from sarcoma, of whom 35 patients underwent resection, 18 underwent resection and radiofrequency ablation and 13 underwent radiofrequency ablation alone.31 GIST and leiomyosarcoma comprised 55% (36/66) and 27% (18/66) of the patients. At a median follow up of 36 months the median 3- and 5-year overall survivals were 65% and 27%, respectively. Patients treated with RFA alone or in conjunction with hepatic resection had a shorter disease free interval (7.4 months) than patient who underwent hepatic resection alone (18.6 months). On univariate analysis metastasis <3 cm, hepatic resection alone and adjuvant therapy were associated with an improved survival. Specifically, patients with GISTs receiving imatinib, similar to the other series, demonstrated the longest median survival. Based on these series, sarcoma metastatic to the liver should be considered for hepatic resection if an R0 resection can be achieved. The management of GIST is rapidly changing due to the introduction of targeted therapy with imatinib mesylate, sunitinib and other tyrosine kinase inhibitors. Resection is considered when patients reach their maximal response to therapy and all gross tumor can be removed.

Melanoma

Almost every organ is at risk when melanoma recurs.32 Of the one third of patients who have recurrences after potentially curative resections, 10-20% are diagnosed with hepatic metastases. In a survey of 26,204 melanoma patients diagnosed between 1971-1999, 1705 (6.7%) had hepatic metastases, but only 34 underwent surgical exploration for an attempted liver resection.33 Of the

218

Recent Advances in Liver Surgery

18 patients rendered free of disease median overall survival was 28 months compared to 6 months for patients with hepatic metastases treated non-operatively. Pawlik et al reported on 24 patients with cutaneous melanoma who underwent hepatic resection for metastases.34 The median disease free interval between the primary and hepatic metastases was 63.1 months. Median time to recurrence post resection, which was an extrahepatic recurrence in 83% of patients, was 4.7 months with no survivors at five years. Hepatic resection for cutaneous melanoma should be performed as part of a multidisciplinary approach, because recurrence is common. Occular or uveal melanoma has a distinct biology and a predilection for metastasizing to the liver. As many as 80% of patients who develop distant metastases will develop hepatic metastases. The Association Francaise de Chirurgie reported on 104 patients who received hepatic resections for choroidal melanoma with a 5-year survival of 21%.3 The largest comparative study looked at 112 patients with metastatic uveal melanoma, of whom 78 patients had hepatic metastases. Surgical resection was possible in 24 patients, resulting in a median survival of 38 months and 5-year survival of 39% compared to a median survival of 9 months and a 5-year survival of 0% for those patients not resected.35 Pawlik et al reported on 16 patients who underwent hepatic resection for ocular melanoma, after a median disease free interval of 63 months.34 The median time to recurrence after hepatic resection was 8.8 months and a 5-year survival rate of 20.5%. Hepatic resection for uveal melanoma may confer a survival benefit in a highly select group of patients.

Noncolorectal Gastrointestinal Tumors

This group includes patients with metastases from small bowel, gastric, gastroesophageal, ampullary and pancreatic cancer. The patients who are candidates for hepatic resection are a very small highly selected cohort of patients, resulting in extremely small series, often with single digit patients. Gastric adenocarcinoma is the most commonly resected of this group of primary tumors, however hepatic resection is performed in <1% of patients who had their primary gastric cancer resected.36 Shirabe et al reported on 36 patients who underwent an R0 resection for hepatic metastases from gastric cancer.37 The overall survival was 43% at 2 years and 26% at 3, 5 and 10 years. Multivariate analysis identified lymphatic invasion or venous invasion in the primary gastric cancer and >3 hepatic metastases as adverse prognostic factors. Adam et al reported on 64 patients who underwent hepatic resection for gastric adenocarcinoma with a median survival of 15 months and a 5-year survival of 27%.3 Patients with esophageal (n = 20) and gastroesophageal junction (n = 25) tumors have a significantly lower median survival of 14-16 months. Hepatic resection for small bowel adenocarcinoma has the best prognosis of the GI tumors. The Association Francaise de Chirurgie reported a median survival of 58 months and 5-year survival of 49% for the 28 patients who had their small bowel metastases resected.3 For patients with duodenal cancer the median survival was lower at 34 months and 5-year survival was 21%. Patients with pancreaticobiliary primary tumors (n = 84) had an intermediate survival of 27% at 5 years. Patients with ampullary tumors (n = 15) had the most favorable prognosis with a median survival of 38 months and 5-year survival of 46%.

Genitourinary and Reproductive Tract Primary Tumors

Hepatic metastases from renal cell carcinoma have an ominous prognosis with <10% of patients surviving beyond 1 year. Approximately 2-4% of patients with renal cell carcinoma develop hepatic metastases amenable to resection. Alves et al reported on 14 patients who were resected with a median survival of 26 months and overall survival of 26% at 3 years.38 Adverse prognostic factors included a disease free interval <24 months, size >5 cm and the inability to perform a repeat hepatectomy if necessary. Thelen et al reported on 31 patients who underwent hepatic resection for renal cell carcinoma metastases.39 The overall 3- and 5-year survival rates were 54.3% and 38.9%, respectively. On multivariate analysis, only negative resection margins were identified as an independent prognostic factor after liver resection. The Association Francaise de Chirurgie reported a median survival of 36 months and 5-year survival of 38% for the 85 patients who underwent hepatic resection for renal cell cancer.3

Resection of Noncolorectal Cancer Liver Metastases

219

The development of hepatic metastases is an adverse prognostic factor for patients with germ cell tumors. Rivoire et al attempted to define guidelines for the resection of hepatic metastases from germ cell tumors.40 They evaluated 37 patients, of whom 35 underwent an R0 resection. Twenty-three of 37 patients (62%) were alive with no evidence of disease after a median follow-up of 66 months (range, 31-134 months). On univariate analysis the presence of pure embryonal carcinoma in the primary tumor, liver metastases measuring >3 cm in greatest dimension at the time of surgery and the presence of viable, active residual disease were adverse prognostic factors. Less than 3% of patients with metastatic testicular cancer will be amenable to hepatic resection. Hahn et al evaluated 57 (57/2219) patients who underwent hepatic resection for treatment of metastatic nonseminomatous testicular carcinoma between June 1974 and May 1996.41 The overall 2-year survival was 97%. Response to chemotherapy was the most important prognostic marker for overall survival. Cytoreductive surgery that reduces disease to less than 1 cm combined with chemotherapy is the standard of care for ovarian cancer. Recurrence is usually diffuse. Hepatic resection may be necessary for true hepatic metastases or hepatic involvement due to peritoneal disease. Yoon et al reported on 24 patients with recurrent ovarian or fallopian tube carcinoma who underwent complete gross resection or optimal debulking of their hepatic metastases and disease at other sites.42 The median interval between primary diagnosis and liver resection was 69 months. All patients had a primary resection or cytoreduction and chemotherapy as part of their initial treatment. Additional resection of disease outside the liver was performed in 18 patients (75%). Twenty-one patients (88%) had removal of all gross disease and three patients (13%) had optimal tumor debulking to less than 1 cm. Overall median survival was 62 months after hepatic resection. No significant prognostic factors for overall survival could be identified on univariate analysis.

Conclusions

In summary resection of noncolorectal carcinoma liver metastases in a highly select group of patients can confer a survival benefit. Achieving an R0 resection and a prolonged disease free interval between the diagnosis of the primary tumor and development of hepatic metastases appear to be consistent independent prognostic factors.

References

1. Jarnagin WR, Gonen M, Fong Y et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002; 236(4):397-406; discussion 407. 2. Belghiti J, Hiramatsu K, Benoist S et al. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 2000; 191(1):38-46. 3. Adam R, Chiche L, Aloia T et al. Hepatic resection for noncolorectal nonendocrine liver metastases: analysis of 1,452 patients and development of a prognostic model. Ann Surg 2006; 244(4):524-535. 4. Musunuru S, Chen H, Rajpal S et al. Metastatic neuroendocrine hepatic tumors: resection improves survival. Arch Surg 2006; 141(10):1000-1004; discussion 1005. 5. Chen H, Hardacre JM, Uzar A et al. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival? J Am Coll Surg 1998; 187(1):88-92; discussion 93. 6. Chamberlain RS, Canes D, Brown KT et al. Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg 2000; 190(4):432-445. 7. Grazi GL, Cescon M, Pierangeli F et al. Highly aggressive policy of hepatic resections for neuroendocrine liver metastases. Hepatogastroenterology 2000; 47(32):481-486. 8. Jaeck D, Oussoultzoglou E, Bachellier P et al. Hepatic metastases of gastroenteropancreatic neuroendocrine tumors: safe hepatic surgery. World J Surg 2001; 25(6):689-692. 9. Nave H, Mossinger E, Feist H et al. Surgery as primary treatment in patients with liver metastases from carcinoid tumors: a retrospective, unicentric study over 13 years. Surgery 2001; 129(2):170-175. 10. Sarmiento JM, Heywood G, Rubin J et al. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 2003; 197(1):29-37. 11. Touzios JG, Kiely JM, Pitt SC et al. Neuroendocrine hepatic metastases: does aggressive management improve survival? Ann Surg 2005; 241(5):776-83; discussion 83-85. 12. Hoe AL, Royle GT, Taylor I. Breast liver metastases—incidence, diagnosis and outcome. J R Soc Med 1991; 84(12):714-716.

220

Recent Advances in Liver Surgery

13. Zinser JW, Hortobagyi GN, Buzdar AU et al. Clinical course of breast cancer patients with liver metastases. J Clin Oncol 1987; 5(5):773-782. 14. Jardines L, Callans LS, Torosian MH. Recurrent breast cancer: presentation, diagnosis and treatment. Semin Oncol 1993; 20(5):538-547. 15. Insa A, Lluch A, Prosper F et al. Prognostic factors predicting survival from first recurrence in patients with metastatic breast cancer: analysis of 439 patients. Breast Cancer Res Treat 1999; 56(1):67-78. 16. Elias D, Lasser P, Spielmann M et al. Surgical and chemotherapeutic treatment of hepatic metastases from carcinoma of the breast. Surg Gynecol Obstet 1991; 172(6):461-464. 17. Raab R, Nussbaum KT, Werner U et al. [Liver metastases in breast carcinoma. Results of partial liver resection]. Chirurg 1996; 67(3):234-237. 18. Seifert JK, Weigel TF, Gonner U et al. Liver resection for breast cancer metastases. Hepatogastroenterology 1999; 46(29):2935-2940. 19. Selzner M, Morse MA, Vredenburgh JJ et al. Liver metastases from breast cancer: long-term survival after curative resection. Surgery 2000; 127(4):383-389. 20. Pocard M, Pouillart P, Asselain B et al. [Hepatic resection for breast cancer metastases: results and prognosis (65 cases)]. Ann Chir 2001; 126(5):413-420. 21. Pocard M, Falcou MC, Salmon RJ. On the prognosis criteria for hepatic resection in cases of breast metastasis. Surgery 2001; 129(5):651-652. 22. Carlini M, Lonardo MT, Carboni F et al. Liver metastases from breast cancer. Results of surgical resection. Hepatogastroenterology 2002; 49(48):1597-1601. 23. Vlastos G, Smith DL, Singletary SE et al. Long-term survival after an aggressive surgical approach in patients with breast cancer hepatic metastases. Ann Surg Oncol 2004; 11(9):869-874. 24. Sakamoto Y, Yamamoto J, Yoshimoto M et al. Hepatic resection for metastatic breast cancer: prognostic analysis of 34 patients. World J Surg 2005; 29(4):524-527. 25. Adam R, Aloia T, Krissat J et al. Is liver resection justified for patients with hepatic metastases from breast cancer? Ann Surg 2006; 244(6):897-907; discussion 908. 26. Atalay G, Biganzoli L, Renard F et al. Clinical outcome of breast cancer patients with liver metastases alone in the anthracycline-taxane era: a retrospective analysis of two prospective, randomised metastatic breast cancer trials. Eur J Cancer 2003; 39(17):2439-2449. 27. Wyld L, Gutteridge E, Pinder SE et al. Prognostic factors for patients with hepatic metastases from breast cancer. Br J Cancer 2003; 89(2):284-290. 28. Billingsley KG, Burt ME, Jara E et al. Pulmonary metastases from soft tissue sarcoma: analysis of patterns of diseases and postmetastasis survival. Ann Surg 1999; 229(5):602-10; discussion 10-12. 29. DeMatteo RP, Shah A, Fong Y et al. Results of hepatic resection for sarcoma metastatic to liver. Ann Surg 2001; 234(4):540-7; discussion 7-8. 30. Lang H, Nussbaum KT, Kaudel P et al. Hepatic metastases from leiomyosarcoma: A single-center experience with 34 liver resections during a 15-year period. Ann Surg 2000; 231(4):500-505. 31. Pawlik TM, Vauthey JN, Abdalla EK et al. Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver. Arch Surg 2006; 141(6):537-43; discussion 43-44. 32. Allen PJ, Coit DG. The surgical management of metastatic melanoma. Ann Surg Oncol 2002; 9(8):762-770. 33. Rose DM, Essner R, Hughes TM et al. Surgical resection for metastatic melanoma to the liver: the John Wayne Cancer Institute and Sydney Melanoma Unit experience. Arch Surg 2001; 136(8):950-955. 34. Pawlik TM, Zorzi D, Abdalla EK et al. Hepatic resection for metastatic melanoma: distinct patterns of recurrence and prognosis for ocular versus cutaneous disease. Ann Surg Oncol 2006; 13(5):712-720. 35. Hsueh EC, Essner R, Foshag LJ et al. Prolonged survival after complete resection of metastases from intraocular melanoma. Cancer 2004; 100(1):122-129. 36. Ochiai T, Sasako M, Mizuno S et al. Hepatic resection for metastatic tumours from gastric cancer: analysis of prognostic factors. Br J Surg 1994; 81(8):1175-1178. 37. Shirabe K, Shimada M, Matsumata T et al. Analysis of the prognostic factors for liver metastasis of gastric cancer after hepatic resection: a multi-institutional study of the indications for resection. Hepatogastroenterology 2003; 50(53):1560-1563. 38. Alves A, Adam R, Majno P et al. Hepatic resection for metastatic renal tumors: is it worthwhile? Ann Surg Oncol 2003; 10(6):705-710. 39. Thelen A, Jonas S, Benckert C et al. Liver resection for metastases from renal cell carcinoma. World J Surg 2007; 31(4):802-807. 40. Rivoire M, Elias D, De Cian F et al. Multimodality treatment of patients with liver metastases from germ cell tumors: the role of surgery. Cancer 2001; 92(3):578-587. 41. Hahn TL, Jacobson L, Einhorn LH et al. Hepatic resection of metastatic testicular carcinoma: a further update. Ann Surg Oncol 1999; 6(7):640-644. 42. Yoon SS, Jarnagin WR, Fong Y et al. Resection of recurrent ovarian or fallopian tube carcinoma involving the liver. Gynecol Oncol 2003; 91(2):383-388.

Chapter 17

Current Role of Laparoscopic Surgery for Liver Malignancies Andrew A. Gumbs and Brice Gayet*

Abstract

S

ince the first report of a laparoscopic liver resection, laparoscopic hepatic resection has become increasingly more common in the surgical treatment of both benign and malignant tumors. The minimally invasive approach to resections of the entire liver including the posterior and deep segments, however, is still only being performed in highly specialized centers. Minimally invasive techniques for hepatic resections of the entire liver are feasible and safe and high volume centers that specialize in these procedures can have results similar and even superior to historical open series. Although some centers utilize ablative procedures for liver malignancies such as cryoablation and radiofrequency ablation, we currently favor laparoscopic resection whenever feasible and reserve radiofrequency techniques for palliation or as an adjunct to resection.

Introduction

Since Gagner et al’s pioneering work in the field of minimally invasive hepato-pancreato-biliary surgery in the early 1990’s, interest in minimally invasive techniques for liver surgery has risen over the years mainly because of the successes seen with other types of major laparoscopic surgery.1,2 However, because of the risk of massive hemorrhage in all forms of hepatic surgery, concern for the ability to obtain adequate of resection margins with laparoscopic techniques and theoretical risk of gas embolism, only a few specialized centers attempt and perform major hepatic resections with minimally invasive techniques. Because of these concerns, many centers approach liver pathology with a hand-assisted approach and are reluctant to approach lesions that are in the deep or posterior segments.3,4 At our institution, however, we approach all segments of the liver with totally laparoscopic techniques. Absolute contraindications to pneumoperitoneum include: intracranial hypertension, bullous emphysema and closed angle glaucoma. Relative contraindications to the laparoscopic approach include need for complex biliary or vascular reconstruction. In this setting the laparoscopic approach can be used during the initial part of the procedure and has the potential benefit of decreasing the ultimate length of the laparotomy incision. The great disparity in laparoscopic experience and ability has revealed that aside from anesthetic considerations, the only absolute contraindication to a laparoscopic procedure is operator ability and not the patient’s pathology. Nonetheless, some general guidelines can be identified for surgeons beginning to embark on laparoscopic surgery of the liver.

Indications

Indications for minimally invasive surgery of benign liver diseases are the same as for open surgery. Symptomatic hemangiomas that cannot be adequately embolized are excised laparoscopically as are symptomatic lesions in patients with focal nodular hyperplasia. As a rule, we also resect hepatic adenomas, if the position or the patient status is not a problem because there is a risk of hemorrhage *Corresponding Author: Brice Gayet—Department of Digestive Diseases, Institut Mutualiste Montsouris, University René Descartes, Paris V, 42 Boulevard Jourdan, Paris 75014 France. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

222

Recent Advances in Liver Surgery

and/or degeneration. Hepatic cysts usually undergo surveillance and aspiration with alcohol or tetracycline injection if they become symptomatic. Large or symptomatic cysts that communicate with the biliary system are unroofed laparoscopically and if a bile leak is found it is closed with a running suture. The bed of the cyst can be covered with a tongue of omentum and a cholecystectomy is also done to eliminate future problems with right upper quadrant pain. Although it is rare that this treatment is not sufficient or that the leak cannot be found, the cyst can be drained with a laparoscopic Roux-en-Y cyst-jejunostomy in refractory cases. When medical therapy fails in hydatid cyst disease, the same concerns for spillage exist when they are treated laparoscopically. When pus is aspirated, an amebic abscess is ruled out with agglutination and complement fixation tests because the treatment is medical. Hepatic bacterial abscesses can be drained percutaneously via imaging guidance, however, laparoscopic drainage is sometimes required. All complex cysts that are not hydatid in origin require resection to rule out the possibility of cystadenoma or malignancy. Symptomatic polycystic liver disease should be approached with minimally invasive techniques whenever possible despite the fact that these cysts can often be extremely large. Simple cysts that cannot be resected can be fenestrated via laparoscopy. When possible we prefer laparoscopic resection over ablative procedures so that diagnosis can be confirmed. As opposed to patients in Asia and Africa where primary hepatocellular carcinoma from chronic viral hepatitis is the main indication for hepatic resection, hepatic resection is usually performed for the treatment of hepatic metastases secondary to colorectal cancer in Europe and the United States. As in open surgery, we plan to leave patients with at least 30% of functioning hepatic parenchyma after resection. In patients with cirrhosis or other forms of chronic liver disease we increase our target functional hepatic reserve to more than 40%. Although the Clinical Risk Score developed by Fong et al can help preoperatively predict the risk of occult intrahepatic or extrahepatic disease that may render patients unresectable, this is sometimes confirmed only after abdominal exploration. Because of this, one of the main advantages of using laparoscopy is in cases where resectability is uncertain or unexpected prior to surgery. As a result, the routine use of minimally invasive techniques and laparoscopic ultrasound can spare patients unnecessary laparotomy.5

Preoperative Work-Up

All patients that are candidates for surgical resection undergo preoperative helical CT scan and MRI with 3-dimensional reconstruction for all lesions that are located next to large vascular or biliary structures. Transabdominal ultrasound is also obtained to confirm that tumors are visible with sonography and PET scans are considered on a case by case basis. Intra-operative laparoscopic ultrasound is then performed on sonographically visible lesions to rule-out additional lesions and confirm respectability.

Operating Room Set-Up

All patients receive pre-operative deep venous thrombotic prophylaxis with subcutaneous heparin and are placed supine on the operating table. Patients with lesions of the right side of the liver have their right upper abdomen elevated with padding to enhance exposure of this area. After intubation, a foley catheter and an orogastric tube are placed and a central venous line is placed in patients with a history of congestive heart failure, or with poor peripheral access, or if a major resection is planned. The patient’s arms are then tucked along the sides of the patient. The patient is then placed in the low lithotomy position with the legs bent at the knees and spread apart to allow for the operator to stand in-between the legs without limitation of the laparoscopic instruments. Gel pads are placed below the right flank for patients undergoing right hepatectomies to elevate the right liver into the field of view. For patients with lesions in the deep and posterior segments they are put in a modified left lateral position with their right arm supported above their head. Their lower body is still placed with the legs spread. The patient’s chest is then strapped in place to prevent slipping during the procedure. An autostatic self-retaining table-mounted liver retractor is then placed on the right side of the operating table as high up as possible. A robotically-controlled camera holder (AESOP 3000—Intuitive Surgical Inc., Sunnyvale, CA, USA) is placed on the left side of the patient (Fig. 1). The surgical technician stands on the patients right and the assistant on the left.

Current Role of Laparoscopic Surgery for Liver Malignancies

223

Figure 1. Positioning of patient and operative equipment. Abbreviations: AESOP: robotically controlled laparoscope holder placed on the left side of the patient; ALR: autostatic liver retractor, mounted to right side of operating table; M: high-definition monitor; UD: laparoscopic ultrasound device; USS: ultrasonic shear system.

Specific surgical equipment that will be necessary include a bipolar cautery forceps (Medtronic France S.A.S., Boulogne-Billancourt, France) and ultrasonic shears (UltraCision Harmonic Scalpel, Ethicon Endosurgery, Cincinnati, OH, USA) are particularly useful for the dissection around the portal triad and portal vein and for division through the hepatic parenchyma. Multiple laparoscopic linear staplers will be required for transection of larger vessels. We do not use stapler devices to transect the hepatic parenchyma, although, this has been reported. As mentioned, a flexible laparoscopic ultrasound probe with color-flow Doppler is indispensable to confirm resectability of tumors and to identify other lesions. A hand-port and full laparotomy tray is kept in every room should urgent conversion be needed.

Trochar Placement

Using the Veress needle, pneumoperitoneum is obtained and maintained at a pressure of 8-12 mmHg. Barring previous surgery in the right upper quadrant, a 10 mm camera port is placed approximately 7 cm. below the right costal margin along a line in-between the mid-clavicular line and midline. All the peritoneal surface and contents of all 4 quadrants are visually inspected with a 0˚ laparoscope to rule-out additional undiagnosed pathology, of note, a 30˚ laparoscope is also a good option. If concern for the feasibility of resection exists at this point, the ultrasonic probe can be carefully passed blindly into this trochar and a limited sonographic examination of the liver can be performed. If there is no pathology found that would preclude surgery, the next port is placed just below the costal margin along the nipple line under direct visualization. This second port is a 12 mm trochar to permit for the introduction of the laparoscopic ultrasound. The laparoscopic ultrasound is place in the upper port and a complete staging sonographic exam of the liver is carried out to confirm the location of pathology and to search for undiagnosed disease, thus, confirming resectability. If

224

Recent Advances in Liver Surgery

Figure 2. Port placement. The camera port (12 mm) is placed approximately 1 hand-breadth below the right costal margin along a line in-between the mid-clavicular line and midline. A second port (12 mm) is placed just below the costal margin along the mid-axillary line. Two working ports (5 mm) are placed to the left and the right of the camera port. A fifth port (5 mm) is placed along the right anterior axillary line for liver retraction and the final port (5 mm) is placed in the sub-xiphoid region.

resection is to proceed, the remaining 4 ports are placed under direct visualization and are all 5 mm in size. Two working ports are placed to the left and right of the camera port. Another port is placed in the subxiphoid region for the surgical assistant and the last port is placed along the anterior axillary line and is used for the autostatic liver retractor device when needed (Fig. 2).

Mobilization of the Liver

If the decision is made to proceed with major resection any remaining adhesions to the abdominal wall are taken down and the patient is placed in reverse-Trendelenberg and the round ligament is retracted anteriorly to enhance exposure of the hepatoduodenal ligament. For left lateral lobectomies, the left triangular ligament is taken down, but the falciform ligament is preserved to maintain upward retraction of the liver. For left hepatectomies the falciform ligament must be taken down sharply, however, this can be done at the end of the procedure if the upward retraction of this structure is helpful. When possible the left triangular ligament is followed to the ligamentum venosum and the left aspect of the coronary ligament and the upper aspect of the retrocaval ligaments on the left are identified and transected. The increased mobility of the liver sometimes enables isolation of the left hepatic vein retrohepatically at this stage of the procedure. For right hepatectomies, the falciform ligament is preserved, but as with the contralateral side the right triangular ligament is incised. The

Current Role of Laparoscopic Surgery for Liver Malignancies

225

right triangular ligament is followed until it joins the right aspects of the coronary and retrocaval ligaments (upper part) and the right hepatic vein can sometimes be isolated at this stage of the procedure if the anterior aspect of the Vena Cava has been dissected free.

Isolation and Transection of the Hepatic Inflow

The self-retaining liver retractor can be placed to aid in retraction. An umbilical tape should be placed around the portal triad by passing through the Foramen of Winslow during the early part of one’s experience during major resections, however, we no longer perform this part of the procedure for minor resections and routine major resections. This will allow for clamping of the hepatic inflow laparoscopically if massive hemorrhage occurs during the division of the hepatic parenchyma. The structures of the portal triad should be dissected out and identified for selective ligation during major resections, however, when possible transection of more than one structure with a laparoscopic stapling device is a valid option. This is particularly useful for left hepatectomies because of the length of the pars transversus of the left branch of the portal vein before it trifurcates. For left lateral lobectomies, the structures of the portal triad supplying segments 2 and 3 are dissected directly in the umbilical fossa. Starting from the confluence of the cystic and common bile duct (CBD), the hepatoduodenal ligament is dissected cranially for major hepatectomies. For left hepatectomies lateral retraction of the CBD will expose the left hepatic artery as it comes off the bifurcation (Fig. 3). This structure is doubly clipped and transected. The CBD is retracted medially for right hepatectomies to expose the right hepatic artery, which is then similarly clipped and cut. The RHA often bifurcates early into an anterior and posterior branch and these structures may need to be taken separately (Fig. 4). For an extended right hepatectomy it is also necessary to take the right branch of the left hepatic artery as it supplies segment IV. This structure and the anterior branch of the right hepatic artery need to be clipped and transected for a central hepatectomy. The anterior branch of the right hepatic artery also needs to be taken when performing extended left hepatectomies.

Figure 3. Left hepatic artery (solid red) shown as it bifurcates from the proper hepatic artery. The right hepatic artery is outlined in red. A color version of this image is available at www. landesbioscience.com/curie

226

Recent Advances in Liver Surgery

Figure 4. The posterior branch (POST.) of the right hepatic artery (RHA) is shown in red, the anterior branch has been clipped and transected and is shown below. The common bile duct (CBD) is highlighted in green. A color version of this image is available at www.landesbioscience.com/curie

The left branch of the portal vein can be found in the umbilical fossa as it trifurcates into branches supplying segment IV and segments II and II (Fig. 5). As with the arterial supply, the right branch of the portal vein can be found in the hilar plate (Fig. 6). Once these structures are skeletonized for approximately 1 centimeter, they can be clipped and cut or transected with a stapler as necessary. We have started reinforcing clips on the portal vein stumps with a suture ligature due to delayed massive hemorrhage in one patient. In some cirrhotic patients with large portal vein branches, 2 firings of the vascular stapler may be required. The final structure of the portal triad that needs to be located and isolated for major hepatectomy is the biliary tree (Fig. 7). It can sometimes be difficult to locate the hepatic ducts, as a result, when the duct in question is believed to be isolated, it is transected with the laparoscopic shears until bile is seen for confirmation (Fig. 8). The bile duct is then oversewn with absorbable suture. Although the entire portal triad supplying a hepatic lobe can be transected with a laparoscopic stapler we prefer to isolate each structure separately. By identifying the bile ducts and oversewing them individually it is believed that post-operative bile leaks can be kept to a minimum.

Isolation of the Hepatic Outflow

If not already isolated during the hepatic mobilization, the hepatic veins are approached retrohepatically. The dissection begins along the anterior surface of the inferior vena cava (IVC) and proceeds in a cranial fashion. Most perforators can be controlled with the bipolar forceps, however, larger venous branches may need to be clipped or cut prior to transection. Once the hepatic inflow is controlled, a more aggressive retrohepatic dissection of the hepatic veins can be attempted. For a left hepatectomy the left hepatic vein is dissected until a window between it and the middle hepatic vein is formed. Ideally, the diaphragm between these structures is found and the left hepatic vein is skeletonized for 1 cm until a laparoscopic vascular stapler can be

Current Role of Laparoscopic Surgery for Liver Malignancies

227

Figure 5. The left branch of the portal vein (in blue) shown as it trifurcates into the umbilical fossa into branches to segment II-IV. A color version of this image is available at www. landesbioscience.com/curie

Figure 6. Right branch of the portal vein (RPV) in blue, common bile duct (CBD) in green and transected anterior and posterior branches of right hepatic artery in red. A color version of this image is available at www.landesbioscience.com/curie

228

Recent Advances in Liver Surgery

Figure 7. Laparoscopic view of the common bile duct (CBD) highlighted in green. The anterior branch of the right hepatic duct is shown between the 2 instruments. The left hepatic duct can be seen in-between the bipolar forceps. A color version of this image is available at www. landesbioscience.com/curie

Figure 8. Transection of the left bile duct with the scissors to confirm the proper identification of this structure. The oversewn left portal vein stump can be seen in the right side of the picture.

Current Role of Laparoscopic Surgery for Liver Malignancies

229

placed. As for the open procedure, the right hepatic vein will need to be transected to perform a right hepatectomy and branches of V and VIII going to the median hepatic vein will need to be clipped and the middle vein will need to be isolated for transection with an endoscopic stapler for a central hepatectomy. Both of these veins can also be isolated retro-hepatically. It is sometimes not possible to isolate the necessary hepatic vein prior to the next part of the procedure and the transection of this structure is only possible after division of the hepatic parenchyma, thus, performing a major hepatectomy via an “anterior” approach. More and more surgeons are utilizing this approach for larger hepatic tumors.

Transection of the Hepatic Parenchyma

The key to this stage of the procedure is to lower the central venous pressure (CVP) as much as possible, which will decrease blood loss from the divided parenchyma. Unfortunately, due to the effect of pneumoperitoneum on the central line transducer, CVP readings are not reliable during laparoscopy. Because of this, visual examination is the best way to assess true filling pressures, although CVP readings prior to insufflation can give a valid estimate of filling pressures. Optimal CVP is when the IVC looks half-empty and fluctuates with the movements of the heart and ventilator. To reduce the risk of CO2 gas embolism, the intra-abdominal pressure is reduced to 10 mmHg, although this is dependent on operative visibility and maintenance of domain. For normal hepatic parenchyma, hepatotomy is performed laparoscopically with the harmonic scalpel in the dominant hand and with the laparoscopic bipolar forceps in the other. When larger segmental vessels are encountered they are clipped or suture ligated. Notably, most branches can be controlled with the bipolar cautery forceps. Although the harmonic scalpel is also effective during the division of the hepatic parenchyma, it is mainly useful during the dissection of larger vessels. On its lowest setting and in the open position, its active blade works like the Cavitron ultrasonic dissector (CUSA™, Radionics, Burlington, MA, USA). In our hands the CUSA decreases visibility because of the constant oozing of the irrigation fluid and deflation of the pneumoperitoneum, as a result, we have stopped using it. The LigaSure vessel sealing system (Valleylab, Boulder, CO, USA) provides superior hemostasis to either the CUSA or the ultrasonic dissecting scalpel for parenchymal division in cirrhotic patients, in particular. Once the major vessels of the liver are dissected with the ultrasonic scalpel, the laparoscopic shears are used to complete the isolation of these structures. The line of transection for major hepatectomies follows the lines of demarcation caused by transection of the arterial and portal flow of the respective segments. Prior to division of the hepatic parenchyma, Glisson’s capsule is scored and any large segmental branches are clipped prior to division with the ultrasonic scalpel. Because of the amount of smoke created during this part of the procedure, a smoke evacuator or filtering device is recommended to maintain visibility.

Transection of the Hepatic Outflow

If not done prior, the complete mobilization of the respective attachments to the side of the liver to be resected are taken down. The transection of the hepatic veins is performed with a laparoscopic GIA vascular stapler. The proper identification and isolation of the hepatic veins may be the most difficult aspect of these procedures. To facilitate this part of the procedure, the upper aspect of the corresponding retrocaval ligament should be transected to maximize the visualization and control of these vessels (Fig. 9). When difficulty arises, a hand-port can be placed in the subcostal region to permit manual palpation of this region and ensure adequate dissection. Prior to transection with the endoscopic stapler, a laparoscopic vascular clamp should be passed into the abdomen in case urgent clamping is necessary. As mentioned, if it is not possible to identify the hepatic veins retrohepatically they can be isolated anteriorly after transection of the hepatic parenchyma (Fig. 10).

230

Recent Advances in Liver Surgery

Figure 9. Transection of the upper aspect of the right retrocaval ligament (in yellow), the inferior vena cava (IVC) is shown in purple. Notice that the IVC appears half-full and is not tensely distended, which is ideal for the hepatic parenchymal division portion of the procedure. A color version of this image is available at www.landesbioscience.com/curie

Figure 10. Anterior view of the bifurcation of the left hepatic vein (LHV) in blue and the middle hepatic vein (MHV) in purple after hepatic parenchymal division in preparation for an extended left hepatectomy. The LHV is shown as it drains into the inferior vena cava (IVC) in violet. A small branch draining segment VIII (Vein Seg. VIII) has been clipped and transected. A color version of this image is available at www.landesbioscience.com/curie

Current Role of Laparoscopic Surgery for Liver Malignancies

231

Figure 11. Lateral view of right hepatic vein (RHV) in blue and middle hepatic vein (MHV) also in blue, the supra-hepatic inferior vena cava is shown in purple. A color version of this image is available at www.landesbioscience.com/curie

The Lateral Approach

The hepatic inflow is approached with patients in a modified partial left lateral position with the surgeon between the legs. An umbilical tape is placed around the hepatoduodenal ligament in case of massive hemorrhage. As opposed to major hepatectomies, this tape should be long enough to protrude from a trochar so that clamping can occur with the surgeon standing in the lateral position. The hepatic outflow is then controlled laterally if not already done so retro-hepatically with the surgeon standing to the right of the patient. The lateral ports are placed with the camera port along the axillary line in approximately the 8-11th costal interspace. Two working ports are placed superiorly and inferiorly to this. The respective hepatic vein (right or middle) is isolated prior to parenchymal division to allow for rapid clamping in the case of massive hemorrhage (Fig. 11). At the end of the procedure, the 2 superior ports that traverse the thorax should be removed under suction to reduce any chance of residual pneumothorax, which in reality would be termed a “carbothorax”. To date none of our patients have had a chest tube pla ced or been diagnosed with a post-operative carbothorax and we no longer obtain post-operative chest X-rays.

Post Operative Management

Because of the need to keep CVP as low as possible during the transection of the hepatic parenchyma, patients are maintained on ventilatory settings with pressures as low as tolerated. Arterial CO2 levels are followed and maintained between 35-40 mm Hg. Patients are kept “dry” throughout hepatic resection by keeping intravenous hydration to a minimum and rehydrated just at the end of the procedure to prevent cardiovascular collapse upon extubation. Because of the decreased hepatic reserve in patients with chronic liver disease who undergo more than two segmentectomies, they may respond more like patients who have undergone a major hepatectomy. Because of this we monitor these patients like we do for normal patients who have undergone a major hepatectomy.

232

Recent Advances in Liver Surgery

As a rule, patients who undergo laparoscopic hepatectomies are sent to the regular ward regardless of the degree of resection. Patients do not require as intensive monitoring after totally laparoscopic major hepatectomies as they do after open liver resections. Patients are only sent to the intensive care unit when they have pre-operative comorbidities that require additional monitoring in the post-operative period. Complete blood counts and chemistries including phosphorus levels are obtained and repleted as needed. Liver function tests are only obtained when they are elevated pre-operatively. Patients are encouraged to ambulate on post-operative day #1. Low molecular weight heparin is used for deep venous thrombosis prophylaxis until patients are ambulating without assistance. Urinary catheters are also removed unless concerns for fluid management or need for prolonged narcotic use in males exist and patients are started on a clear liquid diet and advanced as tolerated to a regular diet. We have found that hospital stay, analgesic requirements and time to ambulation are significantly decreased when compared to our open patients.

Discussion

To date no prospective randomized controlled trials have been published comparing laparoscopic to open liver resections. One case-controlled study comparing 18 laparoscopic left lateral segmentectomies to open controls exists. Longer operative and portal clamping times were noted when minimally invasive approaches were used, however, intra-operative blood loss was found to be significantly less. Complications occurred in 11% of patients in the laparoscopic group and rose to 15% in the open group. No mortalities were noted in either group. Complications relating specifically to the hepatic surgery only occurred in the open group and consisted of biliary leak, sub-phrenic abscess and hemorrhage.6 In the beginning of our experience, laparoscopic resection was considered contraindicated if major venous or biliary reconstruction was required, however, over the last few years even malignant tumors located near the hepatic vein confluences with the vena cava have been approached with minimally invasive techniques. As in open surgery right hepatectomy remains a challenging procedure and the majority of our complications occur in this patient population. In a report of our experience, the outcomes of 89 laparoscopic liver resections done over a 10-year period were reviewed.7 We reported that the majority of cases (73%) were performed for malignant tumors. Conversion to open was necessary in 13% of cases with major hepatectomy being performed in 43% of patients. Complications occurred in 16% of patients that underwent minor hepatectomies and increased to 29% after major resections. Mortality was reported in 1 patient (1.1%) and occurred in a patient whose operative course was initially complicated by a cerebro-vascular accident during anesthesia in a cirrhotic patient. Because of these results, it was felt that totally laparoscopic liver resections of all types were feasible and safe for even malignanttumors with similar long-term survival. Nonetheless, it is still important to remember that there is a considerable learning curve associated with these procedures. As the utilization of the laparoscopic approach to resection of malignant hepatic tumors has grown world-wide, increasing numbers of centers have also noted short term benefits. In a study of patients undergoing laparoscopic minor hepatic resections, decreased analgesic requirements and shorter hospital stays were noted for patients that underwent the laparoscopic procedure when compared to open controls.8 The use of the laparoscopic approach has even been validated for Childs A cirrhotic patients with primary liver tumors.9 Some Authors have appropriately concluded that laparoscopic resections of simpler hepatic segments such as a bisegmentectomy of segments II and III, should probably be considered the standard of care.10 As mentioned, some authors continue to believe that hepatic tumors in the deep/posterior segments are contraindicated in the laparoscopic approach.5,11 In our experience, however, tumors in these segments can be safely resected with minimally invasive techniques through a lateral approach. To date we have not had any mortalities when the lateral approach is utilized laparoscopically and complication rates are approximately 5%. As a result, it appears that the laparoscopic approach to resection of malignant tumors throughout the liver are feasible and safe. Larger randomized

Current Role of Laparoscopic Surgery for Liver Malignancies

233

studies are still necessary to see if the apparent short-term advantages with the minimally invasive approach will also translate into long-term advantages.

Acknowledgements

Andrew A. Gumbs, MD was supported by a fellowship grant from KARL STORZ GmbH and Co. KG, Tuttlingen, Germany (2006-7). This work was supported by grants from the Association pour la Recherche contre le Cancer (ARC) of France and the Philippe Foundation in Paris, France.

References

1. Gagner M, Pomp A. Laparoscopic pylorus-preserving pancreatoduodenectomy. Surg Endosc 1994; 8:408-410. 2. Cherqui D, Husson E, Hammoud R et al. Laparoscopic liver resections: a feasibility study in 30 patients. Ann Surg 2000; 232(6):753-762. 3. Cherqui D. Laparoscopic liver resection. Br J Surg 2003; 90(6):644-646. 4. Jarnagin WR, Conlon K, Bodniewicz J et al. A clinical scoring system predicts the yield of diagnostic laparoscopy in patients with potentially resectable hepatic colorectal metastases. Cancer 2001; 91(6):1121-1128. 5. Lesurtel M, Cherqui D, Laurent A et al. Laparoscopic versus open left lateral hepatic lobectomy: a case-control study. J Am Coll Surg 2003; 196(2):236-242. 6. Vibert E, Perniceni T, Levard H et al. Laparoscopic liver resection. Br J Surg 2006; 93(1):67-72. 7. Mala T, Edwin B, Rosseland AR et al. Laparoscopic liver resection: experience of 53 procedures at a single center. J Hepatobiliary Pancreat Surg 2005; 12(4):298-303. 8. Cherqui D, Laurent A, Tayar C et al. Laparoscopic liver resection for peripheral hepatocellular carcinoma in patients with chronic liver disease: midterm results and perspectives. Ann Surg 2006; 243(4):499-506. 9. Chang S, Laurent A, Tayar C et al. Laparoscopy as a routine approach for left lateral sectionectomy. Br J Surg 2007; 94(1):58-63. 10. Dulucq JL, Wintringer P, Stabilini C et al. Laparoscopic liver resections: a single center experience. Surg Endosc 2005; 19(7):886-891.

Chapter 18

Loco-Regional Ablative Therapies for Colorectal Metastases Riccardo Lencioni,* Laura Crocetti and Dania Cioni

Abstract

D

uring the past decade, several methods for local ablation of hepatic colorectal metastases have been developed and clinically tested. Among these methods, radiofrequency (RF) ablation is currently established as the primary ablative modality at most institutions. Despite several cohort studies have shown that RF ablation can result in complete tumor eradication in properly selected candidates and have provided indirect evidence that the treatment improves survival, the place of RF ablation in the management of colorectal cancer metastatic to the liver remains controversial. In this chapter, we review eligibility criteria, technique, complications and clinical outcomes of RF ablation in the treatment of unresectable or medically inoperable patients with liver-dominant hepatic metastatic disease from colorectal cancer. In addition, we describe basic concepts and preliminary results of other ablative methods, including microwave ablation and laser ablation.

Introduction

Hepatic metastases are a frequency event in colorectal cancer natural history. It has been estimated that over one-half of patients who die of colorectal cancer have liver metastases at autopsy and that metastatic liver disease is the cause of death in the majority of these patients.1 Surgery is established as the standard of care for colorectal metastases isolated to the liver. Recent reports have shown 5-year survival rates following resection of hepatic colorectal metastases exceeding 50%.1 However, only a minority of the patients are suitable candidates for resection, because of associated extrahepatic disease, extent and location of the lesions in the liver, or concurrent medical conditions. Unfortunately, the best reported survival outcomes of any systemic or intra-arterial chemotherapy regimens in metastatic colorectal cancer approach 0% at 5 years.1 The use of image-guided techniques for local tumor ablation to treat unresectable or medically inoperable patients with liver-dominant hepatic metastatic disease from colorectal cancer was proposed 10 years ago.2,3 Since then, several methods for thermal tumor destruction through localized heating or freezing have been developed and clinically tested.4 While hypertermic ablation techniques have been widely performed via a percutaneous approach, most of the experience with cryotherapy has involved an open or laparoscopic approach. The present chapter is focused on the percutaneous use of radiofrequency (RF) ablation, that is currently established as the primary ablative modality at most institutions.5

Eligibility Criteria

A careful clinical, laboratory and imaging assessment has to be performed in each individual patient by a multidisciplinary team to evaluate eligibility for percutaneous ablation. Laboratory *Coresponding Author: Riccardo Lencioni—Division of Diagnostic and Interventional Radiology, University of Pisa, Via Roma 67, I-56125 Pisa, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Loco-Regional Ablative Therapies for Colorectal Metastases

235

tests should include measurement of carcinoembryonic antigen as well as a full evaluation of patient’s coagulation status. A prothrombin time ratio (normal time/patient’s time) greater than 50% and a platelet count higher than 50,000/μl are required to keep the risk of bleeding at an acceptable low level. The tumor staging protocol must be tailored to the individual patient and should include whole-body spiral computed tomography (CT) and positron emission tomography (PET) or PET/CT. Percutaneous ablation is generally indicated for nonsurgical patients with colorectal cancer oligometastases isolated to the liver. Selected patients with limited hepatic and pulmonary colorectal metastatic disease, however, may qualify for percutaneous treatment.6,7 The number of lesions should not be considered an absolute contraindication to percutaneous ablation if successful treatment of all metastatic deposits can be accomplished. Nevertheless, most centers preferentially treat patients with four or fewer lesions. Tumor size is of utmost importance to predict the outcome of percutaneous ablation. Imaging studies underestimate the size of metastatic deposits. Therefore, the target tumor should not exceed 3-4 cm in longest axis to ensure complete ablation with most of the currently available devices. Pre-treatment imaging must carefully define the location of each lesion with respect to surrounding structures. Lesions located along the surface of the liver can be considered for percutaneous ablation, although their treatment requires adequate expertise and may be associated with a higher risk of complications. Thermal ablation of superficial lesions that are adjacent to any part of the gastrointestinal tract must be avoided because of the risk of thermal injury of the gastric or bowel wall.8 The colon appears to be at greater risk than the stomach or small bowel for thermally mediated perforation. Gastric complications are rare, likely owing to the relatively greater wall thickness of the stomach or the rarity of surgical adhesions along the gastrohepatic ligament. The mobility of the small bowel may also provide the bowel with greater protection compared with the relatively fixed colon. A laparoscopy approach or the use of special techniques—such as intraperitoneal injection of dextrose to displace the bowel—can be considered in such instances. Treatment of lesions adjacent to the gallbladder or to the hepatic hilum is at risk of thermal injury of the biliary tract. In experienced hands, thermal ablation of tumors located in the vicinity of the gallbladder was shown to be feasible, although associated in most cases with self-limited iatrogenic cholecystitis.9 In contrast, thermal ablation of lesions adjacent to hepatic vessels is possible, since flowing blood usually protects the vascular wall from thermal injury: in these cases, however, the risk of incomplete treatment of the neoplastic tissue close to the vessel may increase because of the heat loss by convection. The potential risk of thermal damage to critical structures should always be weighted against benefits.

Technique

The goal of RF ablation is to induce thermal injury to the tissue through electromagnetic energy deposition. In RF ablation, the patient is part of a closed-loop circuit, that includes a RF generator, an electrode needle and a large dispersive electrode (ground pads). An alternating electric field is created within the tissue of the patient. Because of the relatively high electrical resistance of tissue in comparison with the metal electrodes, there is marked agitation of the ions present in the target tissue that surrounds the electrode, since the tissue ions attempt to follow the changes in direction of alternating electric current. The agitation results in frictional heat around the electrode. The discrepancy between the small surface area of the needle electrode and the large area of the ground pads causes the generated heat to be focused and concentrated around the needle electrode.10 The thermal damage caused by RF heating is dependent on both the tissue temperature achieved and the duration of heating. Heating of tissue at 50-55˚C for 4-6 minutes produces irreversible cellular damage. At temperatures between 60˚C and 100˚C near immediate coagulation of tissue is induced, with irreversible damage to mitochondrial and cytosolic enzymes of the cells. At more than 100-110˚C, tissue vaporizes and carbonizes. For adequate destruction of tumor tissue, the entire target volume must be subjected to cytotoxic temperatures. Thus, an essential objective of ablative therapy is achievement and maintenance of a 50-100˚C temperature throughout the entire

236

Recent Advances in Liver Surgery

Figure 1. Schematic model of a thermal ablation. The target diameter of the ablation zone (D*) must be ideally 2 cm larger than the diameter of the tumor that undergoes treatment (D).

target volume for at least 4-6 minutes. However, the relatively slow thermal conduction from the electrode surface through the tissues increases the duration of application to 10-30 minutes. On the other hand, the tissue temperature should not be increased over these values to avoid carbonization around the tip of the electrode due to excessive heating. Another important factor that affects the success of RF thermal ablation is the ability to ablate all viable tumor tissue and an adequate tumor-free margin. The most important difference between surgical resection and RF ablation of hepatic tumors is the surgeon’s insistence on a 1-cm-wide tumor-free zone along the resection margin. To achieve rates of local tumor recurrence with RF ablation that are comparable to those obtained with hepatic resection, physicians should produce a 360˚, 1-cm-thick tumor-free margin around each tumor.11 This cuff will assure that all microscopic invasions around the periphery of a tumor have been eradicated. Thus, the target diameter of an ablation must be ideally 2 cm larger than the diameter of the tumor that undergoes treatment (Fig. 1). Otherwise, multiple overlapping ablations can be performed.11 Heat efficacy is defined as the difference between the amount of heat produced and the amount of heat lost. Therefore, effective ablation can be achieved by optimizing heat production and minimizing heat loss within the area to be ablated. The relationship between these factors has been characterized as the bio-heat equation. The bio-heat equation governing RF-induced heat transfer through tissue has been described by Pennes12 and subsequently simplified to a first approximation by Goldberg and colleagues13 as follows: coagulation = energy deposited × local tissue interactions−heat loss Heat production is correlated with the intensity and duration of the RF energy deposited. Tissues cannot be heated to greater than 100˚-110˚C without vaporizing and this process produces significant gas that both serves as an insulator and retards the ability to effectively establish a RF field. On the other hand, heat conduction or diffusion is usually explained as a factor of heat loss in regard to the electrode tip. Heat is lost mainly through convection by means of blood circulation. These processes together with the rapid decrease in heating at a distance from the electrode, essentially limits the extent of induced coagulation from a single, unmodified monopolar electrode to no greater than 1.6 cm in diameter. Therefore, most investigators devoted their attention to strategies that increase the energy deposited into the tissues and several corporations have manufactured new RF ablation devices based on technologic advances that increase heating efficacy. To accomplish this increase, the RF output of all commercially available generators has been increased to 150-250 watts, which may potentially increase the intensity of the RF current deposited at the tissue. Multiple or multitined expandable electrodes permit the deposition of this energy over a larger volume and ensure more uniform heating that relies less on heat conduction over a large distance. Additional strategies to increase the energy deposited have also been developed. Tyco/Radionics uses an internally cooled electrode design to minimize carbonization and gas formation around the needle tip by eliminating excess heat near the electrode. AngioDynamics/RITA Medical Systems markets multitined

Loco-Regional Ablative Therapies for Colorectal Metastases

237

Figure 2. Radiofrequency ablation devices (AngioDynamics / RITA Medical Systems). A wide armamentarium is available, including straight (A) and multitined expandable electrodes with perfusion (B).

perfused electrode: administration of saline solution—at a very low rate—during the application of RF current increases tissue conductivity and thereby allows greater deposition of RF current and increased tissue heating and coagulation (Fig. 2). The commercially available devices were also strategically developed to monitor the ablation process so that high-temperature coagulation may occur without exceeding a 110˚C maximum temperature threshold. One device (AngioDynamics/RITA Medical Systems) relies on direct temperature measurement throughout the tissue to prevent any electrode in a multitined configuration from exceeding 110˚C. Two other commercially available devices (Tyco/Radionics and Boston Scientific/Radiotherapeutics) rely on an electrical measurement of tissue impedance to determine that tissue boiling is taking place. These impedance rises can be detected by the generator, which can then reduce the current output to a preset level. To perform a typical ablation, two grounding pads are placed on the patient’s thighs. When using the AngioDynamics/RITA Medical Systems device, the needle is carefully advanced to the lesion and the electrodes are deployed either to the initial step of 2 cm or to full deployment (when a multitined perfused electrode is used). The generator is turned on and run by an automated program. The temperature at the tips of the electrodes are controlled and the peak power is maintined until the average temperature reaches the preselected target (typically 105˚C). After the target temperature is achieved, the curved electrodes can be further advanced—when required. When the electrodes are fully deployed, the program maintains the target temperature by regulating the wattage. As the tissue begins to desiccate, the amount of power needed to maintain the target temperature decreases. At the end of the procedure, when the generator runs off, a “cool down cycle” is automatically performed. After retracting the hooks, the coagulation of the needle track can be done by using the “track ablation” mode, which maintains the temperature above 70-80˚C. Thermal ablation is usually performed under intravenous sedation with standard cardiac, pressure and oxygen monitoring. Targeting of the lesion can be performed with ultrasound, CT, or MR imaging. The guidance system is chosen largely on the basis of operator preference and local availability of dedicated equipment such as CT fluoroscopy or open MR systems. Real-time ultrasound/CT (or ultrasound/MRI) fusion imaging substantially improves the ability to guide and monitor liver tumor ablation procedures.14 Current virtual navigation systems allow to define the extent of the liver tumor burden, plan and simulate the insertion of the needle and predict

238

Recent Advances in Liver Surgery

a

b

Figure 3. Radiofrequency ablation of small hepatic colorectal metastasis. Pretreatment computed tomography scanning hardly shows tiny hypovascular lesion. The tumor is treated with radiofrequency ablation under ultrasound guidance: an hyperechoic cloud covering the lesion is seen during the procedure.

Loco-Regional Ablative Therapies for Colorectal Metastases

239

c

d

Figure 3, continued. On computed tomography obtained one month after treatment the tumor is replaced by a hypoattenuating zone that fails to enhance both in the arterial (c) and the portal venous phase (d). The findings are consistent with complete response.

240

Recent Advances in Liver Surgery

the amount of the induced necrosis. During the procedure, important aspects to be monitored include how well the tumor is being covered and whether any adjacent normal structures are being affected at the same time. While the transient hyperechoic zone that is seen at ultrasound within and surrounding a tumor during and immediately after RF ablation can be used as a rough guide to the extent of tumor destruction, MR is currently the only imaging modality with validated techniques for real-time temperature monitoring. Contrast-enhanced ultrasound performed after the end of the procedure may allow an initial evaluation of treatment effects. However, contrast-enhanced CT or MR imaging are recognized as the standard modalities to assess treatment outcome. CT and MR images obtained after treatment show successful ablation as a non-enhancing area with or without peripheral enhancing rim (Fig. 3). The enhancing rim that may be observed along the periphery of the ablazion zone appears a relatively concentric, symmetric and uniform process in an area with smooth inner margins. This is a transient finding that represents a benign physiologic response to thermal injury (initially, reactive hyperemia; subsequently, fibrosis and giant cell reaction). Benign periablational enhancement needs to be differentiated from irregular peripheral enhancement due to residual tumor that occurs at the treatment margin. In contrast to benign periablational enhancement, residual unablated tumor often grows in scattered, nodular, or eccentric patterns.15 Later follow-up imaging studies should be aimed at detecting the recurrence of the treated lesion (i.e., local tumor progression), the development of new hepatic lesions, or the emergence of extrahepatic disease. Despite technologic advances and electrode modifications that have effectively increased RF energy deposition and tissue heating, inadequate coagulation can represent a clinical problem in some circumstances, due not only to large lesion dimensions. Key culprits implicated in reduced coagulation include the other two elements of the “bio-heat equation”: (a) heterogeneity of tissue composition, by which differences in tumor tissue density, including fibrosis and calcification, alter electrical and thermal conductance; and (b) blood flow, by which perfusion-mediated tissue cooling (vascular flow) reduces the extent of thermally induced coagulation. These limitations have led investigators to the study of manoeuvres or adjuvant therapies in an attempt to improve RF ablation, either in conjunction with or as an alternative to multiple ablations of a given tumor. In particular, several strategies for reducing blood flow during ablation therapy have been proposed. Total portal inflow occlusion (Pringle maneuver) has been used at open laparotomy and at laparoscopy. Angiographic balloon catheter occlusion of the hepatic artery or embolization of the tumor feeding artery have also been shown to be useful in hypervascularized tumors.16 Pharmacologic modulation of blood flow and antiangiogenesis therapy are also possible but should currently be considered experimental. Combining thermal ablation with other therapies such as chemotherapy or chemoembolization has to be taken into consideration. The findings of experimental studies suggested that adjuvant chemotherapy may increase the ablation volume compared with RF ablation therapy alone.17 Further research to determine optimal methods of combining chemotherapeutic regimens (both agent and route of administration) with RF ablation is ongoing.

Complications

Recently, three separate multicenter surveys have reported acceptable morbidity and mortality rates for a minimally invasive technique. The mortality rate ranged from 0.1% to 0.5%, the major complication rate ranged from 2.2% to 3.1% and the minor complication rate ranged from 5% to 8.9%.18 The most common causes of death were sepsis, hepatic failure, colon perforation and portal vein thrombosis, while the most common complications were intraperitoneal bleeding, hepatic abscess, bile duct injury, hepatic decompensation and grounding pad burns.19-21 Minor complications and side effects were usually transient and self-limiting. An uncommon late complication of RF ablation can be tumor seeding along the needle track. While these data indicate that RF ablation is a relatively safe procedure, a careful assessment of the risks and benefits associated the treatment has to be made in each individual patient by a multidisciplinary team.

Loco-Regional Ablative Therapies for Colorectal Metastases

241

Clinical Outcomes

Most early clinical research with RF ablation was conducted in the framework of feasibility studies, aimed at demonstrating the local effect and the safety of the procedure. Two early studies reported rates of complete response that did not exceed 60-70%.2,3 Subsequently, owing to the advances in RF technique, reported rates of successful local tumor control following RF treatment substantially increased. In two series, RF ablation allowed eradication of 91% of 100 metastases and 97% of 74 metastases, respectively.22,23 Recently, a few cohort studies have reported long-term survival outcomes of nonsurgical patients with hepatic colorectal metastases who underwent RF ablation24-29 (Table 1). In particular, in three series including patients with 5 or fewer lesions, each 5 cm or less in diameter, the 5-year survival rate ranged 24-44% at 5 years.25,26,28 A large single-institution series including patients refractory to chemotherapy, the median survival was 24 months.29 This calculation refers to the time elapsed from intervention to death. However, chemotherapy survival data are calculated from time of diagnosis to death. Since in the study the median lead time from diagnosis to RF ablation was 8 months, the median survival was in fact 32 months. The reported figures on 5-year and median survival are substantially higher than those obtained with any chemotherapy regimens and provide indirect evidence that RF ablation therapy improves survival in patients with limited hepatic metastatic disease. Recent studies analyzed the role of RF ablation with respect to surgical resection. In one study, 418 patients with colorectal metastases isolated to the liver were treated with hepatic resection, RF ablation plus resection, RF ablation only, or chemotherapy only. Overall survival for patients treated with RF ablation plus resection or RF ablation only was greater than for those who received chemotherapy only. However, overall survival was highest after resection: 4-year survival rates after resection, RF ablation plus resection and RF ablation only were 65%, 36% and 22%, respectively.30 In another paper, the outcome of patients with solitary colorectal liver metastasis treated by surgery or by RF ablation did not differ: the survival rate at 3 years was 55% for patients treated with surgery and 52% for those who underwent RF ablation.31 Other authors used RF ablation instead of repeated resection for the treatment of liver tumor recurrence after partial hepatectomy.32 The potential role of performing RF ablation during the interval between diagnosis and resection as part of a “test-of-time” management approach was investigated.33 Eighty-eight consecutive patients with colorectal liver metastases who were potential candidates for surgery were treated with RF ablation. Among the 53 patients in whom complete tumor ablation was achieved after RF treatment, 98% were spared surgical resection because they remained free of disease or because they developed additional metastases leading to unresectability. No patient in whom RF treatment did not achieve complete tumor ablation became unresectable due to the growth of the treated metastases. The number and dominant size of metastases, as well as preoperative carcinoembryonic antigen value, were shown to be strong predictors of survival.29 In contrast, the prognostic value of the presence of limited extrahepatic disease at initial referral is controversial. It is well established that different locations of extrahepatic disease do have different prognostic implications in colorectal cancer. No study was not structured to address the relationship of RF ablation with prior or subsequent chemotherapy. Since in all published series the accrual took place over several years, the clear change in chemotherapy agents and trends did not allow to drawn any conclusions in this regard.29

Other Ablative Therapies Microwave Ablation

Microwave ablation is the term used for all electromagnetic methods of inducing tumor destruction by using devices with frequencies greater than or equal to 900 kHz. The passage of microwaves into cells or other materials containing water results in the rotation of individual molecules. This rapid molecular rotation generates and uniformly distributes heat, which is instantaneous and continuous

242

Recent Advances in Liver Surgery

Table 1. Studies reporting long-term survival outcomes of patients with colorectal hepatic metastases who underwent radiofrequency ablation Author and Year

No. Patients

Survival Rates (%) 1-yr

3-yr

5-yr

117

93

46

NA

Lencioni et al 2004

423

86

47

24

Gillams et al 200426

73

99

58

30

Jackobs et al 200627

68

NA

68

NA

Sorensen et al 200728

102

96

64

44

Siperstein et al 200729

234

NA

20

18

Solbiati et al 200124 25

NA: not available.

until the radiation is stopped. Microwave irradiation creates an ablation area around the needle in a column or round shape, depending on the type of needle used and the generating power.34 Most clinical studies of microwave ablation investigated the usefulness of the technique in the treatment of hepatocellular carcinoma. Limited data have been reported thus far concerning the use of microwave ablation in the treatmenf of hepatic metastases. In one study, 30 patients with multiple metastatic colorectal tumors in the liver who were potentially amenable to hepatic resection were randomly assigned to treatment with microwave coagulation (14 patients) or hepatectomy (16 patients). One- and 3-year survival rates and mean survival times were 71%, 14% and 27 months, respectively, in the microwave group, whereas they were 69%, 23% and 25 months, respectively, in the hepatectomy group.35 The difference between these two groups was statistically not significant. Other authors have reported initial promising results, but further trials are clearly needed to establish the clinical efficacy of the treatment.36

Laser Ablation

The term laser ablation should be used for ablation with light energy applied via fibers directly inserted into the tissue. A great variety in laser sources and wavelength are available. In addition, different types of laser fibers, modified tips and single or multiple laser applicators can be used. From a single, bare 400-μm laser fiber, a spherical volume of coagulative necrosis up to 2 cm in diameter can be produced. Use of higher power results in charring and vaporization around the fiber tip. Two methods have been developed for producing larger volumes of necrosis. The first consists of firing multiple bare fibers arrayed at 2-cm spacing throughout a target lesion, while the second uses cooled-tip diffuser fibers that can deposit up to 30 W over a large surface area, thus diminishing local overheating.37 To date, few data are available concerning the clinical efficacy of laser ablation. No randomized trials to compare laser ablation with any other treatment have been published thus far. Two single-institution series of patients with liver metastases from colorectal cancer who underwent laser ablation reported very different 5-year survival rates, ranging 4-37%.38,39 Laser ablation appears to be relatively safe, with a major complication rate less than 2%.37 The major drawback of current laser technology appears to be the small volume of ablation that can be created with a single-probe insertion. Insertion of multiple fibers is technically cumbersome and may not be feasible in lesions that are not conveniently located. New devices could overcome this limitation.

Loco-Regional Ablative Therapies for Colorectal Metastases

243

Conclusions

Several techniques for local tumor ablation are currently available to treat nonsurgical patients with limited hepatic metastatic disease from colorectal cancer. In properly selected candidates, these minimally invasive procedures can achieve effective and reproducible tumor destruction with acceptable morbidity. RF ablation constitutes the most widely assessed technique. Long-term survival outcomes of RF-treated patients show that cure is possible and should be the goal for nonsurgical patients with hepatic colorectal cancer metastases amenable to image-guided local treatment. However, RF ablation does not seem to offer the same degree of radicality as resection, except for very small lesions. Further technological advances would be needed before image-guided ablation can challenge the role of surgery in resectable patients.

References

1. National Comprehensive Cancer Network (2007) Clinical practice guidelines in oncology. Colon Cancer. Version 1.2008. http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf accessed 2007. 2. Solbiati L, Goldberg SN, Ierace T et al. Hepatic metastases: percutaneous radio-frequency ablation with cooled-tip electrodes. Radiology 1997; 205:367-373. 3. Lencioni R, Goletti O, Armillotta N et al. Radio-frequency thermal ablation of liver metastases with a cooled-tip electrode needle: results of a pilot clinical trial. Eur Radiol 1998; 8:1205-1211. 4. Lencioni R, Cioni D. Percutaneous methods for ablation of hepatic neoplasms. In: Blumgart LH, ed. Surgery of the Liver, Biliary Tract and Pancreas. Fourth Edition. Philadelphia: Saunders 2007:1269-1277. 5. Lencioni R, Crocetti L. Radiofrequency ablation of liver cancer. Tech Vasc Interventional Rad 2007; 10:38-46. 6. Lencioni R, Crocetti L, Cioni R et al. Radiofrequency ablation of lung malignancies: where do we stand? Cardiovasc Intervent Radiol 2004; 27:581-590. 7. Berber E, Pelley R, Siperstein AE. Predictors of survival after radiofrequency thermal ablation of colorectal cancer metastases to the liver: a prospective study. J Clin Oncol 2005; 23:1358-1364. 8. Rhim H, Dodd GD III, Chintapalli KN et al. Radiofrequency thermal ablation of abdominal tumors: lessons learned from complications. Radiographics 2004; 24:41-45. 9. Chopra S, Dodd GD III, Chanin MP et al. Radiofrequency ablation of hepatic tumors adjacent to the gallbladder: feasibility and safety. AJR Am J Roentgenol 2003; 180:697-701. 10. Rhim H, Goldberg SN, Dodd GD III et al. Essential techniques for successful radio-frequency thermal ablation of malignant hepatic tumors. Radiographics 2001; 21:S17-S35. 11. Dodd GD III, Frank MS, Aribandi M et al. Radiofrequency thermal ablation: computer analysis of the size of the thermal injury created by overlapping ablations. AJR Am J Roentgenol 2001; 177:777-782. 12. Pennes HH. Analysis of tissue and arterial blood temperatures in the resting human forearm. J Appl Physiol 1948; 1:93-122. 13. Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancies: a unfied approach to underlyng principles, techniques and diagnostic imaging guidance. AJR Am J Roentgenol 2000; 174:323-331. 14. Crocetti L, Lencioni R, De Beni S et al. Targeting liver lesions for radiofreqwuency ablation. An experimental feasibility study using a CT-US fusion imaging system. Invest Radiol 2008; 43:33-39. 15. Goldberg SN, Charboneau JW, Dodd GD III et al. International working group on image-guided tumor ablation. Image-guided tumor ablation: proposal for standardization of terms and reporting criteria. Radiology 2003; 228:335-345. 16. Rossi S, Garbagnati F, Lencioni R et al. Percutaneous radio-frequency thermal ablation of nonresectable hepatocellular carcinoma after occlusion of tumor blood supply. Radiology 2000; 217:119-126. 17. Goldberg SN, Saldinger PF, Gazelle GS et al. Percutaneous tumor ablation: increased necrosis with combined radio-frequency ablation and intratumoral doxorubicin injection in a rat breast tumor model. Radiology 2001; 220:420-427. 18. Rhim H. Complications of radiofrequency ablation in hepatocellular carcinoma. Abdom Imaging 2005; 30:409-418. 19. Livraghi T, Solbiati L, Meloni MF et al. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003; 26:441-451. 20. De Baere T, Risse O, Kuoch V et al. Adverse events during radiofrequency treatment of 582 hepatic tumors. AJR Am J Roentgenol 2003; 181:695-700. 21. Bleicher RJ, Allegra DP, Nora DT et al. Radiofrequency ablation in 447 complex unresectable liver tumors: lessons learned. Ann Surg Oncol 2003; 10:52-58.

244

Recent Advances in Liver Surgery

22. De Baere T, Elias D, Dromain C et al. Radiofrequency ablation of 100 hepatic metastases with a mean follow-up of more than 1 year. AJR Am J Roentgenol 2000; 175:1619-1625. 23. Helmberger T, Holzknecht N, Schopf U et al. Radiofrequency ablation of liver metastases. Technique and initial results. Radiologe 2001; 41:69-76. 24. Solbiati L, Livraghi T, Goldberg SN et al. Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 2001; 221:159-166. 25. Lencioni R, Crocetti L, Cioni D et al. Percutaneous radiofrequency ablation of hepatic colorectal metastases. Technique, indications, results and new promises. Invest Radiol 2004; 39:689-697. 26. Gillams AR, Lees WR. Radio-frequency ablation of colorectal liver metastases in 167 patients. Eur Radiol 2004; 14:2261-2267. 27. Jackobs TF, Hoffmann RT, Trumm C et al. Radiofrequency ablation of colorectal liver metastases: mid-term results in 68 patients. Anticancer Res 2006; 26:671-680. 28. Sorensen SM, Mortensen FV, Nielsen DT. Radiofrequency ablation of colorectal liver metastases: long-term survival. Acta Radiol 2007; 48:253-258. 29. Siperstein AE, Berber E, Ballem N et al. Survival after radiofrequency ablation of colorectal liver metastases. 10-year experience. Ann Surg 2007; 246:559-567. 30. Abdalla EK, Vauthey JN, Ellis LM et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation and combined resection/ablation for colorectal liver metastases. Ann Surg 2004; 239:818-825. 31. Oshowo A, Gillams A, Harrison E et al. Comparison of resection and radiofrequency ablation for treatment of solitary colorectal liver metastases. Br J Surg 2003; 90:1240-1243. 32. Elias D, De Baere T, Smayra T et al. Percutaneous radiofrequency thermoablation as an alternative to surgery for treatment of liver tumour recurrence after hepatectomy. Br J Surg 2002; 89:752-756. 33. Livraghi T, Solbiati L, Meloni F et al. Percutaneous radiofrequency ablation of liver metastases in potential candidates for resection: the ‘‘test-of-time approach’’. Cancer 2003; 97:3027-3035. 34. Lu MD, Chen JW, Xie XY et al. Hepatocellular carcinoma: US-guided percutaneous microwave coagulation therapy. Radiology 2001; 221:167-172. 35. Shibata T, Niinobu T, Ogata N et al. Microwave coagulation therapy for multiple hepatic metastases from colorectal carcinoma. Cancer 2000; 89:276-284. 36. Liang P, Dong B, Yu X et al. Prognostic factors for percutaneous microwave coagulation therapy of hepatic metastases. AJR Am J Roentgenol 2003; 181:1319-1325. 37. Vogl TJ, Straub R, Eichler K et al. Malignant liver tumors treated with MR imaging-guided laser-induced thermotherapy: experience with complications in 899 patients (2,520 lesions). Radiology 2002; 225:367-377. 38. Christophi C, Nikfarjam M, Malcontenti-Wilson C et al. Long-term survival of patients with unresectable colorectal liver metastases treated by percutaneous interstitial laser thermotherapy. World J Surg 2004; 28:987-994. 39. Vogl TJ, Straub R, Eichler K et al. Colorectal carcinoma metastases in liver: laser-induced interstitial thermotherapy—local tumor control rate and survival data. Radiology 2004; 230:450-458.

Chapter 19

Sepsis after Liver Resection:

Predisposition, Clinical Relevance and Synergism with Liver Dysfunction Gennaro Nuzzo,* Ivo Giovannini, Felice Giuliante, Francesco Ardito and Carlo Chiarla

Abstract

L

iver resection, compared with other abdominal operations, is characterized by greater predisposition to septic complications. This may be explained by several factors, including the major role of the liver in immune defence, anatomical features such as the close relationship of the hepato-biliary system with the intestine, underlying liver disease if present and specific preoperative treatments favouring postoperative sepsis. A critical point is that sepsis does not always present with immediately recognizable signs, such as fever or leukocytosis. At times it presents with more subtle signs, for instance hyperbilirubinemia and encephalopathy. After liver resection these may be misinterpreted as simple consequences of transient parenchymal insufficiency, therefore resulting in failure to recognize and promptly treat underlying sepsis. Particular caution is needed in this setting to avoid dismal outcomes. This chapter focuses on these aspects, describing underlying mechanisms and preventive measures and further characterizing the powerful synergism of sepsis overimposed on postoperative liver dysfunction in determining poor outcome.

Introduction

Postoperative sepsis is a frequent complication after hepatic resection, with a relevant impact on morbidity, hospital costs and mortality.1-13 This is related to general predisposing factors including the role of the liver in acute phase response and immune defense, to the anatomical location of the liver, to underlying diseases, preoperative treatments and factors associated with the resection itself. The clinical relevance depends on the frequently elusive presentation of sepsis, which may dangerously delay its recognition and on the dismal impact of sepsis overimposed on postoperative parenchymal insufficiency in worsening outcome.

General Predisposing Factors

The greater predisposition to postoperative sepsis after liver resection, compared with other abdominal operations, is related to several factors. A peculiar feature of liver resection is that it involves damage to an organ which has a major role in immune defence. Furthermore anatomical features such as the close relationship of the hepato-biliary system with the intestine, underlying liver disease if present and specific preoperative treatments may all enhance the predisposition to sepsis. The liver provides a barrier to enteric bacteria and toxins contained in portal blood. It has long been known that in the presence of liver cirrhosis this barrier function may be bypassed, not *Corresponding Author: Gennaro Nuzzo—Hepatobiliary Unit, Department of Surgery, Catholic University of the Sacred Heart School of Medicine, Largo Agostino Gemelli 8, I-00168 Rome, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

246

Recent Advances in Liver Surgery

only because of portal hypertension with porto-systemic shunting, if present, but also because of Kupffer cell dysfunction14-16 with access of bacteria and bacterial products to the systemic circulation. The Kupffer cells filter endotoxins from the portal blood flowing in liver sinusoids, phagocytose bacteria, regulate sinusoidal vascular resistance, present antigens to T-cells, secrete a variety of cytokines and are also intimately cooperating with hepatocytes.17-24 There are remarkable impacts of this cooperation in the expression of the acute phase response, including for instance the release of cytokines by activated Kupffer cells to stimulate hepatocyte synthesis of acute phase proteins; furthermore after liver resection Kupffer cells are involved in the stimulation of hepatic regeneration.18,25,26 The role of other immunologically active cells present within the liver may be less relevant or less well studied. The barrier to ascending biliary infection from the intestine is provided by the sphincter of Oddi. Contamination of bile through an endoscopic, percutaneous or a surgical route may not result in microbial proliferation and true infection if the flushing effect of bile flow is maintained. In addition, the production of mucus by epithelial biliary cells, the presence of hepatic tight junctions sealing the walls of bile canaliculi and other mechanisms, help to prevent the passage of bacteria from bile into hepatic sinusoidal blood. Secretion of IgA in bile and the presence of opsonizing factors may contribute to this barrier function and IgA is also present in pancreatic ductal fluid.24,27-30 Furthermore bile salts optimize bacterial flora in the intestine, through their bacteriostatic, bactericidal, antifungal and antiendotoxin properties and contribute to maintaining integrity of the gut mucosal barrier.24,31-34 Therefore, several mechanisms cooperate in preventing the liver and the biliary tract from infection and the spread of bacteria and bacterial products into the systemic circulation.

Underlying Diseases and the Disease Requiring Liver Resection

Immune depression may be related to malnutrition, age, major organ system dysfunction, neoplastic diseases, autoimmune diseases, or the use of medications. As already mentioned, there may also be underlying hepatic disease (chronic hepatitis, cirrhosis, other forms of liver dysfunction, toxin-induced dysfunction). Liver dysfunction may be associated with reduced bile flow and therefore with reduced flushing effect of bile and reduction of its effect in favour of gut bacterial flora and mucosal barrier integrity. This has been well studied in biliary obstruction, which is associated with depressed Kupffer cell function, increasing bacterial entry into the bloodstream and altered function of other immune cells within the liver, however altered cellular immunity may be an issue also in chronic hepatitis and cirrhosis.34-42 The mechanism by which Kupffer cell function becomes depressed in biliary obstruction (bile salt toxicity, ineffective fibronectin, decreased major histocompatibility complex expression, endotoxin toxicity mediated by reactive oxygen species) is still poorly understood. This is compounded by the loss of the effect of bile on gut bacterial flora and mucosal integrity. Within the biliary system, contaminated bile cannot be flushed away and alterations of the hepatic tight junctions predispose to cholangiovenous reflux, especially if pressure within the biliary system increases.37 Finally hepatocyte dysfunction is associated with less efficient synthesis of proteins involved in immune defence. It has long been known that biliary obstruction predisposes to a higher risk of morbidity and mortality in liver resections. Biliary decompression, in particular with internal drainage, may promote recovery of several aspects of immune defence, however this is not the safest solution in practice. Experimental models do not reproduce all the variables involved in clinical practice. Patients with hilar cholangiocarcinoma often have segmental bile duct involvement and complete biliary drainage may be impossible despite multiple stent insertion. Ineffective drainage of segmental ducts, including a caudate branch, may result in sepsis, especially after opacification during endoscopic examination.43 This has lead to the use of routine percutaneous biliary drainage with increasing frequency.8,21,24,43-46 Indeed, ascending infection related to endoscopic drainage increases the risk of postoperative sepsis, in particular in hilar cholangiocarcinoma patients. In our own experience,

Sepsis after Liver Resection

247

most of the morbidity and mortality observed after liver resection for hilar cholangiocarcinoma could be related to preoperative biliary infection associated with endoscopic biliary drainage. Percutaneous drainage has a lesser risk of infection, however several precautions are suggested to further minimize it, such as change of the catheter every two weeks if it must remain in place for longer periods before surgery.46 Furthermore oral ingestion of bile, or bile replacement through a naso-duodenal tube is recommended by some authors (see later in this Chapter). The risk of causing biliary infection is so high that, when preoperative percutaneous drainage is not needed to relieve long-lasting biliary obstruction but for other reasons, it is advised to perform it the day just before surgery, not to allow time for the development of infection.46

Liver Resection (the Operation)

Liver resection involves the removal of functional tissue mass, with reduction of the Kupffer cell volume and of the efficiency of the reticuloendothelial system.47,48 Furthermore, in the case of associated bilio-enteric anastomoses, there is no more protection against ascending infection by the sphincter of Oddi and if a biliary drainage is inserted in the biliary system, this will be a foreign body facilitating access and permanence of bacteria. Finally hepatic pedicle clamping, performed to limit intraoperative bleeding, may determine Kuppfer cell dysreactivity related to ischemia/reperfusion and determines intestinal hypoperfusion with altered gut mucosal integrity, although the clinical relevance of this is not yet ascertained;4,49 the same may be true for the postoperative reduction of portal venous drainage with portal hypertension determined by the partial hepatectomy. With regard to hepatic pedicle clamping, in our own experience the strong protection offered by this technique against the consequences of bleeding and blood transfusion prevails over the fear of potentially dismal biological effects.50 Therefore we make fairly frequent use of intermittent clamping, obviously refraining from indiscriminate use, for instance when it is not strictly necessary, or to avoid edema of the bowel when intestinal anastomoses must simultaneously be performed. Normally there is redundancy of liver function, which may compensate for the loss of parenchyma, however with increasing the extent of resection this capability to accommodate may reach a critical point, especially in the presence of preoperatively impaired liver function. Again, the resection is associated with a decreased production of bile and bile salts and a reduction of their effects on gut bacterial population, endotoxin and gut mucosal integrity.21,24,51 In the early state after liver resection a combination of decreased bile flow, postoperative ileus and intestinal hypoperfusion may favour bacterial overgrowth and impair gut mucosal trophism, with translocation of bacteria and bacterial products in a condition of impaired Kupffer cell function. Although this may be considered mostly an hypothesis, several studies have shown the presence of bacteria in the mesenteric lymph nodes, portal venous blood and systemic vasculature after liver resection.11,52-56 Increased translocation has additionally been related to blood transfusion, most likely through its immune depressant effect.56 Finally, reduced hepatocyte volume and function is associated with less efficient synthesis of proteins involved in host defence. In this setting of increased predisposition, clinically relevant infection is favoured by the presence of necrotic tissue on the surface of resection (or on the sites where ablative techniques have been associated), by the presence of a residual space favouring fluid collections, by the attendant inhibition of peritoneal macrophages by blood or bile collections; obvious concomitant factors may be the field contamination from simultaneously performed bilio-enteric anastomoses or bowel resections and the predisposition related to preoperative biliary drainage, or pre-existing hepatobiliary sepsis.4,10,57-61 These factors and other less specific factors, together with the high incidence of bacteriemia do not simply contribute to intra-abdominal sepsis, but also to wound, pulmonary, urinary tract and venous line infection and to other types of infection. In the clinical setting, postoperative sepsis has been found to be frequently associated with advanced age and comorbidities, presence of a neoplastic disease, preoperative jaundice, preoperative biliary drainage, bleeding and blood transfusion, major resection, length of operation, simultaneous

248

Recent Advances in Liver Surgery

performance of bilio-enteric anastomoses, postoperative bleeding and reoperation.5,10-13,60,62-67 The association with advanced age also regards liver resection for blunt trauma.68

Microbiology

In accordance with the hypothesis of the gut origin of sepsis, common intestinal gram-negative aerobic bacteria are frequently involved. However this is not a rule; enterococci and other gram positive aerobes, anaerobic bacteria and candida species may also be involved and polymicrobial infections may occur, especially in the presence of a preoperative history of complex disease, of long-term biliary stenting, of prolonged sepsis and antibiotic treatment.13,64,69-72 Pseudomonas and various multiresistant strains with unpredictable antibiotic sensitivity may also be associated with nosocomial infections. Therefore antibiotic treatment and in relevant cases also prophylaxis, should be based on accurate microbiological monitoring and isolations. The presence of high candida antigen titers may not always reflect true infection, but has been found to be associated in any case with immune depression and higher incidence of bacterial infection.73

Prevention of Sepsis

These concepts on the pathophysiology of sepsis should produce as a corollary a series of precautions to minimize the impact of predisposing and causative factors. These include: • Careful preoperative selection of patients according to comorbidities; • Preoperative obtainment of bile cultures in patients with stents;46 • Preoperative portal vein embolization to accommodate for increasing loss of functional liver mass;74 • Use of prophylactic antibiotics and common precautions, skin preparation, intraoperative wound protection; • Use of anatomical resections along vascular planes, with minimization of the amount of necrotic tissue left on the transection surface; • Sparing of liver parenchyma by reducing the number of resected segments, whenever feasible;10 • Minimization of the blood loss and of the need for transfusions56 by maintaining a low central venous pressure during resection and by using intermittent pedicle clamping or other liver ischemia techniques; • Careful hemostasis and biliostasis and insertion of a biliary drain in case of doubt (for instance insertion of a Roux linear drain through the cystic duct after cholecystectomy) and careful ligation of lymphatic pedicles during lymphadenectomy; • Careful final irrigation of the operative field to clean residual debris and bile, blood, any contamination with enteric materials and irrigation of a contaminated wound. We are in favour of the use of abdominal drains, although this is a matter of debate.75 We share with other authors76 the concern about the appropriate intraoperative placement of the drains and about a timely postoperative removal (early removal as soon as they appear no longer useful, especially to limit loss of ascites, rapid removal if they become occluded). It is also obvious, in relevant cases, that proper postoperative microbiological monitoring by culturing drainages, bile and other biological fluids, may set in advance the stage for a targeted use of antibiotics. Several examples highlight the concern for the maintenance of optimal gut permeability, integrity and microflora in the prevention of sepsis. These include for instance bile replacement (either orally or through a naso-duodenal tube) in patients with externally drained bile, starting already from the preoperative period, the administration of probiotics and other substances and in particular perioperative symbiotic treatment and nutritional regimens involving early postoperative enteral feeding.76-81 Although the efficacy of symbiotics needs to be more broadly proved and controversial issues should be resolved, their use seems to result also in immune-enhancement and attenuation of the postoperative inflammatory response.80,81

Sepsis after Liver Resection

249

Bile Leaks as the Cause of Sepsis

In spite of the advances in prevention and management of bile leaks82-88 these continue to be an important cause of postoperative sepsis. Percutaneous drainage of the infected bile collection and of the leak, with endoscopic decompression of the biliary system, when needed, provide adequate non-invasive treatment.When the leak is from a segregated bile duct, endoscopy may not be helpful. If less invasive treatments fail, a septic state must not be allowed to persist by unduly delaying reoperation.76 At times, surveillance of the patient is still needed after apparent resolution of the problem. In a recently observed case of ours, after apparently successful percutaneous drainage of an infected sub-diaphragmatic bile collection and discharge of the patient, slow extention of the process into the right pleural cavity evolved into a pyothorax. In another recently observed case transient episodes of sepsis, repeatedly occurring after irrigation of a percutaneous biliary drainage, were related to the presence of a bilio-venous fistula with bilhemia.

Postoperative Recognition of Sepsis

The main issue may not be the identification of the septic focus and its treatment. In modern care, with a widespread diffusion of efficient imaging techniques and of other efficient tools, the identification and the aggressive treatment of a septic focus are not formidable tasks. Indeed, the main issue is the difficult recognition of sepsis when it presents with elusive symptoms and signs. A critical point is that sepsis does not always present with a promptly recognizable pattern, such as fever and leukocytosis. It may present with more subtle signs, for instance unexplained hyperbilirubinemia, or encephalopathy. After liver resection these signs may be misinterpreted as consequences of transient parenchymal insufficiency, therefore delaying the recognition and the treatment of sepsis. There may also be sepsis overimposed on liver insufficiency and particular caution is needed in this setting: indeed, the unfavourable implications extend much beyond the well-know consequences of sepsis, because there is strong synergism between sepsis and liver insufficiency in worsening outcome.

Synergism between Sepsis and Liver Insufficiency

There is a close bi-directional relationship between impairment of liver function and sepsis. Impaired liver function, in addition to predisposing to sepsis, may severely alter host defense, while in turn sepsis may induce liver dysfunction through several mechanisms. These interactions translate into a powerful synergism of the two conditions, when simultaneously present, in determining lethal outcome.8 Although many deaths after liver resection offer crude and realistic examples of this synergism, the basic mechanisms are not yet satisfactorily understood. The awareness of a predisposition to bacterial infection in patients with liver cirrhosis, as mentioned already, is almost anecdotal and the synergism of the two conditions in predisposing to further complications and death is constantly emphasized.15,89-93 Given the role of the liver in host defence, the negative impact of liver dysfunction in this interplay is more easily understood. This also explains the frequent absence of defined boundaries between the classical manifestations of liver insufficiency (altered bilirubin and prothrombin time, ascites, encephalopathy) and the manifestations of an amplified inflammatory response, including the development of adult respiratory distress syndrome, with sepsis or with a suspicion of sepsis not confirmed by microbiological examination. This pattern is consistent with the concept that one facet of liver insufficiency is the insufficient clearance of proinflammatory mediators, bacteria and bacterial products by Kupffer cells, which may explain the amplification of the inflammatory response, in addition to the occurrence of real septic complications after hepatectomy.94 The impact of sepsis in altering liver function is less intuitive, although it has been the object of intense study. Several aspects have been characterized, ranging from septic hepatic histology to abnormal metabolism with altered substrate and energy availability.95 One of the key-features seems to be the impact of several pro-inflammatory mediators, mostly released by hyper-reactive Kupffer cells, on the function of nearby hepatocytes. Predisposition to hyper-reactivity may depend on several factors, including genetic components and, in the setting of liver resection, the priming

250

Recent Advances in Liver Surgery

effect of the resection itself, liver ischemia and gut-derived endotoxin load and the consequences may extend to the induction of microcirculatory disturbances with hepatocyte necrosis. Indeed, the protection exerted by preoperative portal vein embolization against postoperative liver failure has also been explained by a positive impact on these interactions,96 although the clarification of the effect of portal vein embolization on liver cells is still in progress.97 Enhanced expression of toll-like receptors,98 genetically determined predisposition to sepsis with amplification of the inflammatory response and tissue damage99 and a contribution from the leukocyte and lymphocyte population100,101 may represent other potentially involved factors. A key-point remains that the survival response to sepsis is based on the increase of the functional capacities of the liver, while at the same time sepsis inhibits many liver functions through a variety of mechanisms, which are not limited to excessive amplification of the inflammatory response.102 The real key-point in clinical practice is that, although some morbidity from sepsis may be unavoidable after hepatectomy, timely and appropriate treatment and careful and uninterrupted support of the patient, may largely reduce the consequent mortality.76 Among the supportive measures, we make considerate use of plasma and albumin and particularly prize the metabolic support by parenteral nutrition if the enteral route of feeding is impracticable.103 This includes 30-35 kcal/kg/day and 1.5 g/kg/day amino acids, with 50-70% of calories from dextrose and the remainder from fat and with micronutrients according to common guidelines. Regarding fat, our preference has long been for mixed long- and medium-chain triglyceride emulsions, with or without fish oil supplementation. Regarding amino acids, our preference has long been for the inclusion of 35-50% of the total dose as branched-chain amino acids.103 A somewhat similar regimen has independently been reported by another group.104,105

Synergism of Sepsis and Liver Dysfunction on Blood Chemistries Hypocholesterolemia

There is a cumulative effect of sepsis and liver dysfunction in decreasing plasma cholesterol. Plasma cholesterol behaves as a negative acute phase reactant, therefore decreasing in acute phase response, especially in sepsis; liver dysfunction may contribute through impaired synthesis of cholesterol and/or lipoproteins.106-108 After liver resection hypocholesterolemia is additively related to the magnitude of the operation, hemodilution from blood loss, presence of liver dysfunction, sepsis and hypoalbuminemia. Because these variables reflect severity of surgical trauma and of complications, degree of hypocholesterolemia may turn into a cumulative index of severity of illness, with prognostic implications.106,108,109 Transient hypocholesterolemia may be less relevant and the subsequent increase generally parallels recovery from illness. Persistently severe hypocholesterolemia tends to be associated with bad prognosis and in a previous study on liver resection, no patient survived after having cholesterol <1.5 mmol/L and a postoperative/preoperative ratio <0.4 for more than 6 days.109 It is possible that hypocholesterolemia does not just reflect adverse events, but rather actively contributes to clinical deterioration (because of the related impairment in plasma antioxidant capacity, in scavenging of proinflammatory bacterial products, in amino acid and energy availability and in synthesis of stress hormones and new cells for host defence).108 An adverse event increasing cholesterol (or moderating the decrease related to the other factors) is obstructive cholestasis, because of the reduced excretion of cholesterol with bile and of the enhanced circulating levels of cholesterol-rich lipoprotein X. This may explain the failure of severely ill patients to show very severe hypocholesterolemia when cholestasis is simultaneously present.106-110 Changes in plasma triglycerides may parallel those of cholesterol, or become dissociated from them. For instance, in sepsis with hypocholesterolemia the transition from hypo- to hyper-triglyceridemia (if unrelated to exogenous fat overinfusion) may be an important landmark of clinical deterioration. Hypertriglyceridemia in this setting may reflect impaired lipoprotein lipase activity, pathologic enhancement of hepatic liposynthesis, or other features associated with more severe septic illness and impending risk of death.108,111,112 A clinical corollary of these concepts is the need for an aggressive resolution of sepsis when these biochemical abnormalities tend to develop.

Sepsis after Liver Resection

251

Figure 1. Hypocholesterolemia after liver resection. Postoperative evolution of plasma cholesterol concentration (fraction of preoperative concentration, mean values) in liver resection patients with normal recovery, or with complications (mainly sepsis and/or liver insufficiency) followed by recovery or death. See text. Reproduced in simplified form with permission from Clin Chem 2003; 49:317-19.109 © 2003 AACC.

The multifactoriality of hypocholesterolemia does not allow sharp cut-offs to diagnose sepsis, however a persistently low value tends to be a landmark of severe illness and a trend toward increase (if unrelated to cholestasis) a landmark of clinical improvement (Fig. 1).

Hyperbilirubinemia

Changes in plasma bilirubin after liver resection deserve a detailed assessment. Distinction between the nonconjugated and conjugated components of hyperbilirubinemia is important. Hemoglobin catabolism from blood transfusion, hemolysis, or intracavitary bleeding causes nonconjugated hyperbilirubinemia, from bilirubin overproduction. By theoretically assuming no extravascular escape of bilirubin, the catabolism of 1.0 g hemoglobin could be estimated to increase plasma bilirubin by about 1.0 mg/dL. On the contrary, hyperbilirubinemia with an almost totally conjugated component, especially if associated with increased alkaline phosphatase and gamma glutamyl transpeptidase, suggests extrahepatic or diffuse intrahepatic biliary obstruction or hepatobiliary sepsis. The interpretation is less obvious with a mixed pattern of hyperbilirubinemia, which may develop and peak several days after liver resection. In general there is some prevalence of conjugated bilirubin (like a ratio of conjugated/total bilirubin of 2:3) with no increase or moderate increase of alkaline phosphatase and gamma glutamyl transpeptidase related to liver regeneration. This pattern reflects intracellular cholestasis and may correlate with magnitude of liver resection and transient residual parenchymal insufficiency, duration of previous intraoperative liver ischemia and, most importantly, with the presence of sepsis.113-121 There is a synergistic impact of these factors in determining the degree of hyperbilirubinemia and a main implication is the capability to recognize and treat sepsis, if present.121 If sepsis is not a problem and there are no other important features of liver insufficiency, this pattern may have a benign evolution, in spite of increases in total bilirubin up to greater than 30

252

Recent Advances in Liver Surgery

Figure 2. Hyperbilirubinemia after liver resection. Patient with colorectal liver metastases, after chemotherapy. Plasma bilirubin, mg/dL, following right hepatectomy (adequate remnant liver at inspection). Early liver insufficiency with increasing bilirubin, mostly nonconjugated and suggestive of heme hypercatabolism (initial white area). Reoperation for large sub-diaphragmatic hematoma and drainage. Steadily increasing bilirubin, now mostly conjugated (shaded area). Antibiotic treatment for the suspicion of occult sources of sepsis, excluded by repeated CT scans; nutritional and other supportive measures, plasmapheresis, anticoagulant therapy for pulmonary embolism. Final discharge in good condition, although with jaundice. The development of postoperative liver insufficiency could be explained by severe postchemotherapy liver steatosis. Although this extreme case does not allow generalizations, it shows how severe hyperbilirubinemia per se may not involve poor prognosis, when sepsis is not the issue (and irreversible liver damage is not the issue). Careful supportive measures and control of complications may lead to recovery, even through a complex course. On the contrary, when untreated sepsis is the major or concomitant cause of liver dysfunction, the prognosis turns rapidly poor, even in apparently less severe cases and in spite of any supportive treatment.

mg/dL; during the late phase of recovery from hyperbilirubinemia, several weeks after liver resection, the patients may still appear evidently jaundiced while being in very good clinical condition (Fig. 2). In some instances this might be partly related to residual delta-bilirubin, covalently bound to albumin and very slowly cleared from blood (like a residual “scar” of previous severe hyperbilirubinemia). Unfortunately there are other hyperbilirubinemic conditions with more complex or poor evolution, which may consist of almost totally conjugated hyperbilirubinemia, larger increases in alkaline phosphatase and gamma glutamyl transpeptidase and variable increases in aspartate and alanine aminotransferase (with biliary imaging obviously excluding extra-hepatic biliary obstruction). These may be related or unrelated to sepsis, which remains in any case an aggravating factor and include cholangitis lenta and poorly defined forms of ischemic and secondary sclerosing cholangitis.117,118,122 Biliary structures are particularly sensible to changes in arterial blood supply123 and irreversible ischemic damage to the intrahepatic biliary network may be implicated also in severe forms of small-for-size syndrome, mostly described in liver transplantation.124-129 Less benign evolutions may even require liver transplantation, if feasible.

Sepsis after Liver Resection

253

Table 1. Combinations of increased bilirubin, alkaline phosphatase (AP) and gamma glutamyl transpeptidase (GGT) after liver resection. partial listing

↑ Bilirubin (mostly nonconjugated): Transfusions, hemolysis, intracavitary blood collections ↑ Bilirubin (∼2/3 conjugated) + ↑ AP and GGT (slow and moderate*): Hepatocellular dysfunction (sepsis, previous ischemia, parenchymal insufficiency) ↑ AP and GGT (prominent): Biliary fistula ↑ Bilirubin (mostly conjugated) + ↑ AP and GGT (prominent): Biliary sepsis Extrahepatic biliary obstruction Ischemic cholangitis/secondary sclerosing cholangitis ↑ Bilirubin (mostly “direct”), late stages of recovery from hyperbilirubinemia High delta-bilirubin component** *Consistent with liver regeneration **Clinically irrelevant: bilirubin covalently bound to albumin, slowly cleared from blood, appearing as “direct” bilirubin in the direct/indirect reaction

Factors responsible for hyperbilirubinemia after liver resection also include vascular thrombosis, the toxic effect of drugs, liver ischemia from hypotension and shock and other causes. This may also explain why the descriptions of patterns of hepatic injury during sepsis vary markedly among studies.130 Concomitant events may prevent sharp characterizations of specific patterns and a critical judgement is always necessary. For instance, a rare exception to the previously described patterns is when bacteriemia causes acute hemolysis, in which case nonconjugated bilirubin clearly prevails. A more obvious exception is when liver resection is associated with relief of preoperative biliary obstruction, in which case the evolution of bilirubin consists of initial postoperative decrease, subsequently compounded by the effect of complications. In conclusion, although the mechanisms of hyperbilirubinemia remain in some cases unknown, the clinical application of the already well-understood concepts is helpful (Table 1). In the case shown in Figure 2, the early postoperative increase in bilirubin to 11.9 mg/dL with almost totally nonconjugated component, although disguised among multiple signs of liver insufficiency, prompted us to diagnose a large sub-diaphragmatic hematoma.

Sepsis as a Cause of Hyperbilirubinemia

Apart from the obvious circumstance in which biliary infection is the issue, sepsis is not so intuitively recognized as a cause of hyperbilirubinemia, especially in the absence of fever or leukocytosis. The problem is not limited to liver resection patients.131,132 However, as already mentioned, increased bilirubin after partial hepatectomy may just be attributed to transient liver insufficiency and other manifestations of sepsis may be similarly interpreted, including for instance increased lactate, hypocholesterolemia, hypoalbuminemia, encephalopathy, reduced vascular tone and reduced platelet count, when present. Likewise, signs of respiratory and cardiovascular instability induced by sepsis are more easily interpreted as primary cardiac or pulmonary dysfunction, therefore delaying the recognition of the authentic cause. A high index of suspicion is therefore necessary and accurate investigations should be carried out to confirm or exclude occult septic foci. The risk is to allow sepsis to progress until irreversible clinical deterioration. Hyperbilirubinemia in itself is not so relevant and is easily reversed by the successful treatment of sepsis. The mechanism by which a septic focus (even located at a distance from the liver) causes hyperbilirubinemia is imperfectly understood. The common picture is that of intracellular

254

Recent Advances in Liver Surgery

cholestasis, with some prevalence of conjugated bilirubin, with normal or moderately increased aspartate and alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase (unless the picture is compounded by other factors). It seems to be related to impaired transport of conjugated bilirubin from hepatocytes into biliary canaliculi, for instance because of impaired multidrug-resistance-associated protein-2 activity, related either to energy shortage or other forms of inhibition.48,117,118,133-139 Inhibition may be the consequence of intrahepatic cytokine synthesis (e.g., TNF-alpha, IL-1, 6 and 8) by Kupffer cells or other immunocompetent cells in the liver, resulting in high local cytokine concentrations which directly affect hepatocyte function and bilirubin disposal.117,118,139-141 Hepatocytes and cholangiocytes may partly contribute to the proinflammatory response. It was previously emphasized that in this setting Kupffer cell overreaction or dysfunction may be mediated by the trauma of resection, intraoperative ischemia and increased load of circulating proinflammatory products on a small residual Kupffer cell volume. These concepts may at least partly explain the synergism of sepsis, intraoperative liver ischemia and major parenchymal loss in determining this form of hyperbilirubinemia.121 Recent experimental findings also suggest a role of P-selectin-dependent leukocyte recruitment in the liver as a determinant of hepatic dysfunction and cholestasis in sepsis.142

Changes in Plasma Fibrinogen

Fibrinogen is an acute phase protein involved in host defence and commonly increases in sepsis. After liver resection, this is mostly observed when sepsis occurs late in the postoperative course, unless relevant liver failure is simultaneously present. Soon after liver resection, fibrinogen levels tend to reflect the balance between early postoperative liver dysfunction, competition for substrate for liver regeneration and efficiency of the acute phase response.135 Unfortunately absolute inferences from plasma fibrinogen changes, especially from decreases in fibrinogen, are difficult at any stage because of the simultaneous involvement of fibrinogen in coagulation processes.

Sepsis and Hypophosphatemia

Hypophosphatemia may have adverse consequences, whose real clinical impact is in many instances not well defined. One of these consequences is the impairment in immune defence, which is consistent with the fact that severe hypophosphatemia soon after liver resection may predict an increased likelihood of subsequent complications, including sepsis.143-145 This has increased the concern for perioperative phosphate supplementation in partial hepatectomy patients, although the issue and the mechanisms causing hypophosphatemia have not been sufficiently clarified.143-147

Impact of Postoperative Sepsis on Long-Term Outcome

The dismal implications of postoperative sepsis are not limited to increased morbidity, longer hospital stay, difficult recovery from secondary complications (for instance, critical illness neuropathy) and increased mortality. There are also consequences on long-term outcome of neoplastic diseases. It is sometimes perceived that patients with complex postoperative courses after cancer surgery, subsequently tend to show an accelerated progression of their neoplastic disease. Indeed a negative impact of postoperative sepsis and other complications on long-term outcome after liver resection has been reported.12,148-150 This may be related to an immune depressant effect of sepsis, or to angiogenic stimulation, favouring the progression of the neoplastic disease (similarly to blood transfusion) and is an additional reason to maximize the efforts for the prevention, the early diagnosis and treatment and the rapid resolution of sepsis after liver resection.

References

1. Doci R, Gennari L, Bignami P et al. Morbidity and mortality after hepatic resection of metastases from colorectal cancer. Br J Surg 1995; 82:377-381. 2. Brancatisano R, Isla A, Habib N. Is radical hepatic surgery safe? Am J Surg 1998; 175:161-163. 3. Melendez JA, Arslan V, Fischer ME et al. Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion and the risk of postoperative renal dysfunction. J Am Coll Surg 1998; 187:620-625.

Sepsis after Liver Resection

255

4. D’Amico D, Cillo U. Impact of severe infections on the outcome of major liver surgery: a pathophysiologic and clinical analysis. J Chemother 1999; 11:513-517. 5. Fan ST, Lo CM, Liu CL et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg 1999; 229:322-330. 6. Belghiti J, Hiramatsu K, Benoist S et al. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 2000; 191:38-46. 7. Cherqui D, Benoist S, Malassagne B et al. Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg 2000; 135:302-308. 8. Nagino M, Kamiya J, Uesaka K et al. Complications of hepatectomy for hilar cholangiocarcinoma. World J Surg 2001; 25:1277-1283. 9. Nuzzo G, Giuliante F, Giovannini I et al. Liver resections with or without pedicle clamping. Am J Surg 2001; 181:238-246. 10. Jarnagin WR, Gonen M, Fong Y et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002; 236:397-407. 11. Shigeta H, Nagino M, Kamiya J et al. Bacteremia after hepatectomy: an analysis of a single-center, 10-year experience with 407 patients. Langenbecks Arch Surg 2002; 387:117-124. Epub 2002. 12. Laurent C, Sa Cunha A, Couderc P et al. Influence of postoperative morbidity on long-term survival following liver resection for colorectal metastases. Br J Surg 2003; 90:1131-1136. 13. Garwood RA, Sawyer RG, Thompson L et al. Infectious complications after hepatic resection. Am Surg 2004; 70:787-792. 14. Nolan JP. Endotoxin, reticuloendothelial function and liver injury. Hepatology 1981; 1:458-465. 15. Siegel JH, Giovannini I, Coleman B et al. Pathologic synergy in cardiovascular and respiratory compensation with cirrhosis and sepsis. A manifestation of a common metabolic defect? Arch Surg 1982; 117:225-238. 16. Basista MH, Stauber RE, Van Thiel DH et al. Effect of isolated portal hypertension on Kupffer cell function. Dig Dis Sci 1994; 39:46-50. 17. Laskin DL. Nonparenchymal cells and hepatotoxicity. Semin Liver Dis 1990; 10:293-304. 18. Billiar TR, Curran RD. Kupffer cell and hepatocyte interactions: a brief overview. J Parenter Enteral Nutr 1990; 14(S5):175S-180S. 19. Wang X, Andersson R, Ding J et al. Reticuloendothelial system function following acute liver failure induced by 90% hepatectomy in the rat. HPB Surg 1993; 6:151-162. 20. Kimmings AN, van Deventer SJ, Obertop H et al. Inflammatory and immunologic effects of obstructive jaundice: pathogenesis and treatment. J Am Coll Surg 1995; 181:567-581. 21. Krige JEJ, Bornman PC. Infections in hepatic, biliary and pancreatic surgery. In: Blumgart LH Fong Y eds. Surgery of the Liver and Biliary Tract. Third Edition. Philadelphia: Saunders, 2000:151-166. 22. Kmiec Z. Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol 2001; 161: III-XIII, 1-151. 23. Fondevila C, Busuttil RW, Kupiec-Weglinski JW. Hepatic ischemia/reperfusion injury—a fresh look. Exp Mol Pathol 2003; 74:86-93. 24. Schmidt CM, Lillemoe KD. Infections in hepatic, biliary and pancreatic surgery. In: Blumgart LH, Belghiti J, Jarnagin WR, et al, eds. Surgery of the Liver, Biliary Tract and Pancreas. Fourth Edition. Philadelphia: Saunders Elsevier, 2007:125-135. 25. Takeishi T, Hirano K, Kobayashi T et al. The role of Kupffer cells in liver regeneration. Arch Histol Cytol 1999; 62:413-422. 26. Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int 2006; 26:1175-1186. 27. Wilton PB, Dalmasso AP, Allen MO. Complement in local biliary tract defense: dissociation between bile complement and acute phase reactants in cholecystitis. J Surg Res 1987; 42:434-439. 28. Scott-Conner CE, Grogan JB. The pathophysiology of biliary obstruction and its effect on phagocytic and immune function. J Surg Res 1994; 57:316-336. 29. Sumiyoshi K, Andoh A, Fujiyama Y et al. Biosynthesis and secretion of MHC class III gene products (complement C4 and factor B) in the exocrine pancreas. J Gastroenterol 1997; 32:367-373. 30. Emmrich J, Seyfarth M, Conradi P et al. Secretory immunoglobulin A in pancreatic juice and pancreatic tissue of patients with chronic pancreatitis. Gut 1998; 42:436-441. 31. Marshall SE, Marples BA, Salt WG et al. Aspects of the effect of bile salts on Candida albicans. J Med Vet Mycol 1987; 25:307-318. 32. Deitch EA, Sittig K, Li M et al. Obstructive jaundice promotes bacterial translocation from the gut. Am J Surg 1990; 159:79-84. 33. Sung JY, Shaffer EA, Costerton JW. Antibacterial activity of bile salts against common biliary pathogens. Effects of hydrophobicity of the molecule and in the presence of phospholipids. Dig Dis Sci 1993; 38:2104-2112.

256

Recent Advances in Liver Surgery

34. Clements B, Erwin P, Halliday J et al. Extrahepatic biliary obstruction promotes bacterial translocation. Am J Surg 1993; 165:749. 35. Pain JA, Collier DS, Ritson A. Reticuloendothelial system phagocytic function in obstructive jaundice and its modification by a muramyl dipeptide analogue. Eur Surg Res 1987; 19:16-22. 36. Stewart L, Pellegrini CA, Way LW. Cholangiovenous reflux pathways as defined by corrosion casting and scanning electron microscopy. Am J Surg 1988; 155:23-28. 37. Raper SE, Barker ME, Jones AL et al. Anatomic correlates of bacterial cholangiovenous reflux. Surgery 1989; 105:352-359. 38. Katz S, Yang R, Rodefeld MJ et al. Impaired hepatic bacterial clearance is reversed by surgical relief of obstructive jaundice. J Pediatr Surg 1991; 26:401-406. 39. Megison SM, Dunn CW, Horton JW et al. Effects of relief of biliary obstruction on mononuclear phagocyte system function and cell mediated immunity. Br J Surg 1991; 78:568-571. 40. Ding JW, Andersson R, Stenram U et al. Effect of biliary decompression on reticuloendothelial function in jaundiced rats. Br J Surg 1992; 79:648-652. 41. Tomioka M, Iinuma H, Okinaga K. Impaired Kupffer cell function and effect of immunotherapy in obstructive jaundice. J Surg Res 2000; 92:276-282. 42. Deignan T, Curry MP, Doherty DG et al. Decrease in hepatic CD56(+) T-cells and V alpha 24(+) natural killer T-cells in chronic hepatitis C viral infection. J Hepatol 2002; 37:101-108. 43. Liu CL, Fan ST, Lo CM et al. Improved operative and survival outcomes of surgical treatment for hilar cholangiocarcinoma. Br J Surg 2006; 93:1488-1494. 44. Nimura Y, Hayakawa N, Kamiya J et al. Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the hepatic hilus. World J Surg 1990; 14:535-544. 45. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992; 215:31-38. 46. Seyama Y, Makuuchi M. Current surgical treatment for bile duct cancer. World J Gastroenterol 2007; 13:1505-1515. 47. Schindl MJ, Redhead DN, Fearon KC et al. Edinburgh Liver Surgery and Transplantation Experimental Research Group (eLISTER). The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection. Gut 2005; 54:289-296. 48. Schindl MJ, Millar AM, Redhead DN et al. The adaptive response of the reticuloendothelial system to major liver resection in humans. Ann Surg 2006; 243:507-514. 49. Ferri M, Gabriel S, Gavelli A et al. Bacterial translocation during portal clamping for liver resection. A clinical study. Arch Surg 1997; 132:162-165. 50. Nuzzo G, Giuliante F, Ardito F et al. Influence of surgical margin on type of recurrence following liver resection for colorectal metastases: a single-center experience. Surgery 2008; 143:384-393. Epub 2007.. 51. Cahill CJ, Pain JA, Bailey ME. Bile salts, endotoxin and renal function in obstructive jaundice. Surg Gynecol Obstet 1987; 165:519-522. 52. Andersson R, Foss A. Abdominal sepsis following liver resection in the rat. Hepatogastroenterology 1991; 38:547-549. 53. Wang X, Andersson R, Soltesz V et al. Bacterial translocation after major hepatectomy in patients and rats. Arch Surg 1992; 127:1101-1106. 54. Wang XD, Pärsson H, Andersson R et al. Bacterial translocation, intestinal ultrastructure and cell membrane permeability early after major liver resection in the rat. Br J Surg 1994; 81:579-584. 55. Wang X, Parsson H, Soltesz V et al. Bacterial translocation and intestinal capillary permeability following major liver resection in the rat. J Surg Res 1995; 58:351-358. 56. Yeh DC, Wu CC, Ho WM et al. Bacterial translocation after cirrhotic liver resection: a clinical investigation of 181 patients. J Surg Res 2003; 111:209-214. 57. Schneierson SS, Amsterdam D, Perlman E. Enhancement of intraperitoneal staphylococcal virulence for mice with different bile salts. Nature 1961; 190:829-830. 58. Andersson R, Tranberg KG, Alwmark A et al. Factors influencing the outcome of E. coli peritonitis in rats. Acta Chir Scand 1989; 155:155-157. 59. Andersson R, Willen R, Massa G et al. Effect of bile on peritoneal morphology in Escherichia coli peritonitis. Scand J Gastroenterol 1990; 25: 405-411. 60. Andersson R, Saarela A, Tranberg KG et al. Intraabdominal abscess formation after major liver resection. Acta Chir Scand 1990; 156:707-710. 61. Hochwald SN, Burke EC, Jarnagin WR et al. Association of preoperative biliary stenting with increased postoperative infectious complications in proximal cholangiocarcinoma. Arch Surg 1999; 134:261-266. 62. Yanaga K, Kanematsu T, Takenaka K et al. Intraperitoneal septic complications after hepatectomy. Ann Surg 1986; 203:148-152.

Sepsis after Liver Resection

257

63. Yanaga K, Kanematsu T, Takenaka K et al. Hepatic resection for hepatocellular carcinoma in elderly patients. Am J Surg 1988; 155:238-241. 64. Pace RF, Blenkharn JI, Edwards WJ et al. Intra-abdominal sepsis after hepatic resection. Ann Surg 1989; 209:302-306. 65. Matsumata T, Yanaga K, Shimada M et al. Occurrence of intraperitoneal septic complications after hepatic resections between 1985 and 1990. Surg Today 1995; 25:49-54. 66. Koperna T, Kisser M, Schulz F. Hepatic resection in the elderly. World J Surg 1998; 22:406-412. 67. Kubo S, Kinoshita H, Hirohashi K et al. Risk factors for and clinical findings of liver abscess after biliary-intestinal anastomosis. Hepatogastroenterology 1999; 46:116-120. 68. Tsugawa K, Koyanagi N, Hashizume M et al. Anatomic resection for severe blunt liver trauma in 100 patients: significant differences between young and elderly. World J Surg 2002; 26:544-549. Epub 2002. 69. Lipsett PA, Pitt HA. Acute cholangitis. Surg Clin North Am 1990; 70:1297-1312. 70. Thompson J, Bennion RS, Pitt HA. An analysis of infectious failures in acute cholangitis. HPB Surg 1994; 8:139-145. 71. Nomura T, Shirai Y, Hatakeyama K. Enterococcal bactibilia in patients with malignant biliary obstruction. Dig Dis Sci 2000; 45:2183-2186. 72. Rerknimitr R, Fogel EL, Kalayci C et al. Microbiology of bile in patients with cholangitis or cholestasis with and without plastic biliary endoprosthesis. Gastrointest Endosc 2002; 56:885-889. 73. Shirabe K, Takenaka K, Yamatomto K et al. Impaired systemic immunity and frequent infection in patients with Candida antigen after hepatectomy. Hepatogastroenterology 1997; 44:199-204. 74. Farges O, Belghiti J, Kianmanesh R et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 2003; 237:208-217. 75. Gurusamy K, Samraj K, Davidson B. Routine abdominal drainage for uncomplicated liver resection. Cochrane Database Syst Rev 2007; (3):CD006232. 76. Imamura H, Seyama Y, Kokudo N et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg 2003; 138:1198-1206. 77. Shirabe K, Matsumata T, Shimada M et al. A comparison of parenteral hyperalimentation and early enteral feeding regarding systemic immunity after major hepatic resection—the results of a randomized prospective study. Hepatogastroenterology 1997; 44:205-209. 78. Kamiya S, Nagino M, Kanazawa H et al. The value of bile replacement during external biliary drainage: an analysis of intestinal permeability, integrity and microflora. Ann Surg 2004; 239:510-517. 79. Kanazawa H, Nagino M, Kamiya S et al. Synbiotics reduce postoperative infectious complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy. Langenbecks Arch Surg 2005; 390:104-113. Epub 2005. 80. Sugawara G, Nagino M, Nishio H et al. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Ann Surg 2006; 244:706-714. 81. Kinross J, Warren O, Silk D, Darzi A. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized control trial. Letter Ann Surg 2007; 245:1000. 82. Lo CM, Fan ST, Liu CL et al. Biliary complications after hepatic resection: risk factors, management and outcome. Arch Surg 1998; 133:156-161. 83. Lam CM, Lo CM, Liu CL et al. Biliary complications during liver resection. World J Surg 2001; 25:1273-1276. 84. Tanaka S, Hirohashi K, Tanaka H et al. Incidence and management of bile leakage after hepatic resection for malignant hepatic tumors. J Am Coll Surg 2002; 195:484-489. 85. Reed DN Jr, Vitale GC, Wrightson WR et al. Decreasing mortality of bile leaks after elective hepatic surgery. Am J Surg 2003; 185:316-318. 86. Terajima H, Ikai I, Hatano E et al. Effectiveness of endoscopic nasobiliary drainage for postoperative bile leakage after hepatic resection. World J Surg 2004; 28:782-786. Epub 2004. 87. Hayashibe A, Sakamoto K, Shinbo M et al. New method for prevention of bile leakage after hepatic resection. J Surg Oncol 2006; 94:57-60. 88. Li SQ, Liang LJ, Peng BG et al. Bile leakage after hepatectomy for hepatolithiasis: risk factors and management. Surgery 2007; 141:340-345. Epub 2007. 89. Rolando N, Wade J, Davalos M et al. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000; 32:734-739. 90. Navasa M. Bacterial infections in patients with cirrhosis: reasons, comments and suggestions. Dig Liver Dis 2001; 33:9-12. 91. Borzio M, Salerno F, Piantoni L et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001; 33:41-48. 92. Terra C, Guevara M, Torre A et al. Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score. Gastroenterology 2005; 129:1944-1953.

258

Recent Advances in Liver Surgery

93. Fasolato S, Angeli P, Dallagnese L et al. Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features. Hepatology 2007; 45:223-229. 94. Nuzzo G, Giuliante F, Gauzolino R et al. Liver resections for hepatocellular carcinoma in chronic liver disease: Experience in an Italian centre. Eur J Surg Oncol 2007; 33:1014-1018. Epub 2007. 95. Cerra FB, Siegel JH, Border JR et al. The hepatic failure of sepsis: cellular versus substrate. Surgery 1979; 86:409-422. 96. Yachida S, Ikeda K, Kaneda K et al. Preventive effect of preoperative portal vein ligation on endotoxin-induced hepatic failure in hepatectomized rats is associated with reduced tumour necrosis factor alpha production. Br J Surg 2000; 87:1382-1390. 97. Komori K, Nagino M, Nimura Y. Hepatocyte morphology and kinetics after portal vein embolization. Br J Surg 2006; 93:745-751. 98. Takayashiki T, Yoshidome H, Kimura F et al. Increased expression of toll-like receptor 4 enhances endotoxin-induced hepatic failure in partially hepatectomized mice. J Hepatol 2004; 41:621-628. 99. Kahlke V, Schafmayer C, Schniewind B et al. Are postoperative complications genetically determined by TNF-beta NcoI gene polymorphism? Surgery 2004; 135:365-375. 100. Wiezer MJ, Meijer C, Sietses C et al. Bactericidal/permeability-increasing protein preserves leukocyte functions after major liver resection. Ann Surg 2000; 232:208-215. 101. Fukazawa A, Yokoi Y, Kurachi K et al. Implication of B-lymphocytes in endotoxin-induced hepatic injury after partial hepatectomy in rats. J Surg Res 2007; 137:21-29. Epub 2006. 102. Novotny AR, Emmanuel K, Maier S et al. Cytochrome P450 activity mirrors nitric oxide levels in postoperative sepsis: predictive indicators of lethal outcome. Surgery 2007; 141:376-384. Epub 2007. 103. Giovannini I, Chiarla C, Giuliante F et al. The relationship between albumin, other plasma proteins and variables and age in the acute phase response after liver resection in man. Amino Acids 2006; 31:463-469. Epub 2006. 104. Fan ST, Lo CM, Lai EC et al. Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. N Engl J Med 1994; 331:1547-1552. 105. Ziegler TR. Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. JPEN J Parenter Enteral Nutr 1996; 20:91-92. 106. Giovannini I, Boldrini G, Chiarla C et al. Pathophysiologic correlates of hypocholesterolemia in critically ill surgical patients. Intensive Care Med 1999; 25:748-751. 107. Chiarla C, Giovannini I, Siegel JH. The relationship between plasma cholesterol, amino acids and acute phase proteins in sepsis. Amino Acids 2004; 27:97-100. Epub 2004. 108. Giovannini I, Chiarla C, Giuliante F et al. Hypocholesterolemia in surgical trauma, sepsis, other acute conditions and critical illness. In: Kramer MA, ed. Trends in Cholesterol Research. Hauppauge, NY: Nova Science Publisher, 2005:137-161. 109. Giovannini I, Chiarla C, Greco F et al. Characterization of biochemical and clinical correlates of hypocholesterolemia after hepatectomy. Clin Chem 2003; 49:317-319. 110. Giovannini I, Chiarla C, Giuliante F et al. Biochemical and clinical correlates of hypouricemia in surgical and critically ill patients. Clin Chem Lab Med 2007; 45:1207-1210. Epub 2007. 111. Siegel JH, Cerra FB, Coleman B et al. Physiological and metabolic correlations in human sepsis. Surgery 1979; 86:163-193. 112. Chiarla C, Giovannini I, Siegel JH. Patterns of correlation of plasma ceruloplasmin in sepsis. J Surg Res 2008; 144:107-110. Epub 2007. 113. Nakatani T, Endoh Y, Kobayashi K. Significance of the hepatic mitochondrial redox state in the development of posttraumatic jaundice. Surg Today 1995; 25:490-497. 114. Nuzzo G, Giovannini I, Boldrini G et al. Patterns of recovery after liver resection. In: A Cavallari, A Mazziotti, A Principe, Eds. Proceedings 2nd World Congress of the International Hepato-Pancreato-Biliary Association. Bologna, Italy: Monduzzi, 1996:325-328. 115. Igarashi Y, Ishiyama S, Urayama M et al. Experimental study on the bilirubin metabolism after major hepatectomy: alterations in the proportions of bile bilirubin subfractions. J Surg Res 1999; 82:67-72. 116. Suto K, Fuse A, Igarashi Y et al. Significance of altered bilirubin subfractions in bile following hepatectomy. J Surg Res 2002; 106:62-69. 117. Geier A, Fickert P, Trauner M. Mechanisms of disease: mechanisms and clinical implications of cholestasis in sepsis. Nat Clin Pract Gastroenterol Hepatol 2006; 3:574-585. 118. Geier A, Wagner M, Dietrich CG et al. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochim Biophys Acta 2007; 1773:283-308. Epub 2006. 119. Ferrero A, Vigano L, Polastri R et al. Postoperative liver dysfunction and future remnant liver: where is the limit? Results of a prospective study. World J Surg 2007; 31:1643-1651. 120. Giovannini I, Chiarla C, Giuliante F et al. Analysis of the components of hypertransaminasemia after liver resection. Clin Chem Lab Med 2007; 45:357-360.

Sepsis after Liver Resection

259

121. Giovannini I, Chiarla C, Giuliante F et al. Sepsis-induced cholestasis. Letter. Hepatology 2008; 47:361. 122. Sherlock S. The syndrome of disappearing intrahepatic bile ducts. Lancet 1987; 2(8557):493-496. 123. Northover JM, Terblanche J. A new look at the arterial supply of the bile duct in man and its surgical implications. Br J Surg 1979; 66:379-384. 124. Kita Y, Harihara Y, Hirata M et al. Factors influencing persistent hyperbilirubinemia following adult-to-adult living-related liver transplantation. Transplant Proc 2000; 32:2193-2194. 125. Hirano K, Sato Y, Kobayashi T et al. Carbon monoxide hemoglobin and bilirubin metabolism in adult living-related liver transplantation. Hepatogastroenterology 2003; 50:1745-1748. 126. Dahm F, Georgiev P, Clavien PA. Small-for-size syndrome after partial liver transplantation: definition, mechanisms of disease and clinical implications. Am J Transplant 2005; 5:2605-2610. 127. Tucker ON, Heaton N. The “small for size” liver syndrome. Curr Opin Crit Care 2005; 11:150-155. 128. Demetris AJ, Kelly DM, Eghtesad B et al. Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome. Am J Surg Pathol 2006; 30:986-993. 129. Sato Y, Yamamoto S, Takeishi T et al. Management of major portosystemic shunting in small-for-size adult living-related donor liver transplantation with a left-sided graft liver. Surg Today 2006; 36:354-360. 130. Pastor CM, Suter PM. Hepatic hemodynamics and cell functions in human and experimental sepsis. Anesth Analg 1999; 89:344-352. 131. Whitehead MW, Hainsworth I, Kingham JG. The causes of obvious jaundice in South West Wales: perceptions versus reality. Gut 2001; 48:409-413. 132. Forrest EH, Forrest JAH. Causes of obvious jaundice in South West Wales. Letter Gut 2002; 51:613-614. 133. Dhainaut JF, Marin N, Mignon A et al. Hepatic response to sepsis: interaction between coagulation and inflammatory processes. Crit Care Med 2001; 29(7 Suppl):S42-S47. 134. Moseley RH. Sepsis and cholestasis. Clin Liver Dis 2004; 8:83-94. 135. Giovannini I, Chiarla C, Giuliante F et al. Modulation of plasma fibrinogen levels in acute-phase response after hepatectomy. Clin Chem Lab Med 2004; 42:261-265. 136. Prins HA, Meijer C, Boelens PG et al. The role of Kupffer cells after major liver surgery. JPEN J Parenter Enteral Nutr 2005; 29:48-55. 137. Brienza N, Dalfino L, Cinnella G et al. Jaundice in critical illness: promoting factors of a concealed reality. Intensive Care Med 2006; 32:267-274. Epub 2006. 138. Bansal V, Schuchert VD. Jaundice in the intensive care unit. Surg Clin North Am 2006; 86:1495-1502. 139. Chand N, Sanyal AJ. Sepsis-induced cholestasis. Hepatology 2007; 45:230-241. 140. Trauner M, Fickert P, Stauber RE. Inflammation-induced cholestasis. J Gastroenterol Hepatol 1999; 14:946-959. 141. Gilroy RK, Mailliard ME, Gollan JL. Gastrointestinal disorders of the critically ill. Cholestasis of sepsis. Best Pract Res Clin Gastroenterol 2003; 17:357-367. 142. Laschke MW, Menger MD, Wang Y et al. Sepsis-associated cholestasis is critically dependent on P-selectin-dependent leukocyte recruitment in mice. Am J Physiol Gastrointest Liver Physiol 2007; 292:G1396-1402. Epub 2007. 143. George R, Shiu MH. Hypophosphatemia after major hepatic resection. Surgery 1992; 111:281-286. 144. Buell JF, Berger AC, Plotkin JS et al. The clinical implications of hypophosphatemia following major hepatic resection or cryosurgery. Arch Surg 1998; 133:757-761. 145. Giovannini I, Chiarla C, Nuzzo G. Pathophysiologic and clinical correlates of hypophosphatemia and the relationship with sepsis and outcome in postoperative patients after hepatectomy. Shock 2002; 18:111-115. 146. Salem RR, Tray K. Hepatic resection-related hypophosphatemia is of renal origin as manifested by isolated hyperphosphaturia. Ann Surg 2005; 241:343-348. 147. Giovannini I, Chiarla C, Giuliante F et al. Hepatic resection-related hypophosphatemia is of renal origin as manifested by isolated hyperphosphaturia. Letter. Ann Surg 2006; 243:429. 148. Nakeeb A, Pitt HA, Sohn TA et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar and distal tumors. Ann Surg 1996; 224:463-475. 149. Redaelli CA, Dufour JF, Wagner M et al. Preoperative galactose elimination capacity predicts complications and survival after hepatic resection. Ann Surg 2002; 235:77-85. 150. Nash G, Waller W. Influence of postoperative morbidity on long-term survival following liver resection for colorectal metastases. Letter Br J Surg 2003; 90:1610-1611.

Chapter 20

Percutaneous Treatment of Surgical Bile Duct Injury Gianpaolo Carrafiello, Domenico Laganà, Monica Mangini, Federico Fontana, Massimiliano Dizonno, Andrea Ianniello, Elisa Cotta, Riad Salem and Carlo Fugazzola*

Abstract

S

urgical bile duct injury (SBDI) is one of the most serious complications of hepato biliary surgery and liver transplantation. Regardless of the improvements in surgical techniques in recent years, SBDI remains a critical problem and a major cause of morbidity. Proper diagnosis and treatment of SBDI are paramount in preventing the life-threatening complications of cholangitis, intra-abdominal infection, biliary chirrosis and end-stage liver disease, possibly resulting in death. The interventional radiology approach has been proved to be highly effective in the treatment of SBDI, showing a morbidity of 5.5% and practically no mortality and has to be considered the first therapeutic option in case of leak, biloma and arteriobiliary or venousbiliary fistula. Nevertheless the initial treatment of choice for biliary stricture is surgical repair; percutaneous balloon dilation and stents placement may be beneficial in patients at high surgical risk, or in whom surgical repair has failed.

Introduction

Bile duct injury is one of the most serious complications of hepatobiliary surgery; regardless of the improvements of surgical techniques in recent years, surgical bile duct injury (SBDI) remains a critical problem and a major cause of morbidity. Moreover, the pattern of SBDI is also changed and has become more diversified in recent years.1-3 The main causes of SBDI are cholecystectomy, hepaticojejunal anastomosis, hepatic resection and liver transplantation; in particular SBDIs seem to be more frequent after laparoscopic cholecystectomy (0-2,7%) than after laparotomic procedures (0.2-0.5%).1-6 Laparoscopic bile duct injury is defined as any clinically evident damage to the main duct, occurring at any time during or after laparoscopic cholecystectomy. The most frequent cause is poor identification of the anatomical features of the Calot triangle (59.5%), followed by anatomical anomalies (12.7%), unspecified technical mistakes (11.0%), inappropriate manoeuvres for control of intraoperative hemorrhage (8.1%), operations with imprudent self-confidence (5.8%), retrograde cholecystectomies for safety (2.9%).7-9 As said, laparoscopic cholecystectomy carries an increased risk for biliary tract injury and, although most centres performing laparoscopic cholecystectomy are now well beyond the “learning curve” phase, the incidence of SBDI is still expected to be—for an unknown period of time—higher if compared with conventional cholecystectomy.1,10,11

*Corresponding Author: Carlo Fugazzola—Department of Radiology, University of Insubria Medical School, 21100 Varese, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Percutaneous Treatment of Surgical Bile Duct Injury

261

Surgical BDI occurs relatively often (6-34%) after liver transplantation and approximately 1% of graft is lost as a result of this type of complication.10-14 SBDI is the second most common cause of liver dysfunction after transplantation, exceeded only by rejection.15,16 Most biliary complications occur within the first 3 months, but some undetected injuries may cause late obstruction months or even years after transplantation.17 Diagnostic imaging and interventional radiology play a crucial role in the treatment of patients with SBDI for a number of reasons: 1. precise and accurate diagnosis can be rapidly established using non invasive or minimal invasive techniques; 2. critical conditions such as bile leaks, infections and jaundice can be resolved by means of percutaneous procedures, sometimes at the same time of diagnosis. This allows an appropriate and often definitive treatment, leading to the fast recovery of the patient’s clinical conditions. Moreover, laboratory investigations can be carried out on the drained fluid to identify possible germs responsible for infection and to initiate opportune treatment; 3. in the occurrence of reoperation, the biliary drainage catheter provides a convenient guidance for the surgeons, who often have to repair an injured bile duct in a context of diffused inflammation with adhesions, which make difficult exploration and identification of the structures involved.1-3 The interventional radiology approach has been proved to be highly effective in the treatment of SBDI, showing a morbidity of 5.5% and practically no mortality and has to be considered a first choice alternative. Surgery, showing a morbidity of 20-30% and a mortality of 5-30% in case with associated pathology, involves considerably longer hospital stay with increased risks for the patients and costs for the health system.3-5

Classification

Surgical bile duct injuries may range from small post-operative fluid collections containing bile with little or no clinical consequence to total excision of the bifurcation including damage to its vasculature. Several classifications of SBDI have been proposed, but none is accepted as a universal standard.8,18-24 The Corlette-Bismuth classification has been proposed in the open surgery era and is based on the length of the proximal biliary stump, but not on the nature and length of the lesion;20 this classification has a good correlation with the final outcome after surgical repair. A drawback is that patients with limited strictures, isolated occlusion of the right hepatic duct or lesion of the cystic duct cannot be classified (Table 1). In the Strasberg classification—the most detailed classification—all types of injuries, including leaks, are classified.22 The classification can easily be used for clinical multidisciplinary management and enables comparison of results from different institutions (Table 2). Wu’s classification, in addition to differentiate the extent of SBDI, suggests the possible surgical procedure for the management of the different types of injures (Table 3);24 for instance, Wu suggests

Table 1. SBDI: the Corlette-Bismuth classification20 Type 1: low common hepatic duct stricture, with a length of the common hepatic duct stump of >2cm; Type 2: middle stricture: length of common hepatic duct <2cm; Type 3: hilar stricture, no remaining common hepatic duct, but the confluence is preserved; Type 4: hilar stricture, with the involvement of confluence and loss of communication between right and left hepatic duct; Type 5: combined common hepatic and aberrant right hepatic duct injury, separating from the distal common bile duct.

262

Recent Advances in Liver Surgery

Table 2. SBDI: the Strasberg classification 22 Type A: bile leak from cystic duct or liver bed without further injury; Type B: partial occlusion of the biliary tree, most frequently of an aberrant right hepatic duct; Type C: bile leak from duct (aberrant right hepatic duct) that is not communicating with the common bile duct; Type D: lateral injury of biliary system, without loss of continuity; Type E: circumferential injury of biliary tree with loss of continuity.

that the management of type 1 injuries should consist in releasing the silk ligature or clip with T-tube placement and drainage, whereas type 4 injuries most probably need hepaticojejunostomy. Another pragmatic way to classify SBDI is simply related to the pathological features which are the result of different type of lesions and need percutaneous treatment. The lesions can be distinguished in: leak, biloma, stricture and arteriobiliary or venousbiliary fistula (hemobilia).

Leak

Bile leak is an extravasation of bile which could be due to laceration, tangential injuries or complete transection of the bile duct. The incidence of bile leak after liver transplantation has been reported to be 4.3%, after major hepatic resection 3-11% and after laparoscopic cholecystectomy 0.35-0.47%.8,9 Surgical BDIs may be limited to minor abnormal ducts without any loss of continuity in the main biliary tree; these minor injuries include bile leaks at the cystic duct or from small ducts at the gallbladder bed. Bile leaks at the cystic duct may occur when clips on the cystic duct remnant are displaced or do not surround entirely the duct. Leaks from the gallbladder bed may occur when the plane of dissection on the liver bed is too deep and the small right-sided biliary radicles are severed and not identified during surgery; this type of injury might happen when the presence of an anatomic abnormality (i.e., an intrahepatic position of the gallbladder) or a tenacious adhesion to liver parenchyma due to chronic cholecystitis make surgical access difficult.25,26 Up to 30% of the population present anomalies of the union of the intrahepatic bile ducts or cystic duct with the common hepatic duct that may predispose them to SBDI. Such anomalies include a low and medial-sided insertion of the cystic duct, a parallel course of the cystic duct alongside the common hepatic duct and an aberrant right hepatic duct. In particular, injuries to an accessory right hepatic duct, which connects the right lobe of the liver directly to the gallbladder, may also result in leaks. The identification of possible variations in intrahepatic ductal anatomy during hepatic resection and liver transplantation is mandatory to avoid bile duct complications. The unintended tear of the main duct is another possible cause of leak; the tear, very often partial, is related to inaccurate recognition of the extrahepatic biliary structures. Bile leakage after hepatic surgery may also originate from the site of a biliary anastomosis, or from a dislodged or recently removed T-tube; these types of leaks represent the most frequent Table 3. SBDI: the Wu classification24 Type 1: injuries originate from common bile duct occluded by silk ligature or metallic clips; Type 2: injuries involve part of the confluence of the cystic duct, common hepatic duct and common bile duct excised; Type 3: injuries involve part of the common bile duct and common hepatic duct excised; Type 4: injuries involve the common bile duct and common hepatic duct including the junction of the right and left hepatic ducts; Type 5: injuries include laceration or perforation of the right hepatic duct.

Percutaneous Treatment of Surgical Bile Duct Injury

263

acute biliary complications during the first weeks after liver transplantation.9 Non-anastomotic bile leaks and strictures after transplantation are probably caused by bile duct ischemia resulting in bile duct necrosis; reported causes of bile duct ischemia include hepatic artery thrombosis, prolonged cold ischemia time of the donor liver, ABO blood type incompatibility of the donor and recipient.26-29

Imaging

Usually a few days pass before a leak is diagnosed, because symptoms are frequently nonspecific and could be associated to other post-operative complications. Nevertheless, it is imperative to accurately diagnose and treat bile leaks in a timely manner, to limit associated morbidity and mortality.8,9 Patients frequently undergo some form of cross-sectional imaging such as Ultrasound (US) or Computed Tomography (CT); although the presence of a fluid collection on the right side of the abdomen may be suggestive of bile leak, it is not always feasible to distinguish bile from other post-operative collections such as pus, serous fluid, or blood. On US or CT, bile collections may appear to be loculate, multiloculate, or diffuse in the peritoneal cavity (Fig. 1A, B; Fig. 2A); in addition, they may be close to the site of the leak, or at a distant site, or may even be intrahepatic. If a fluid collection is identified, further investigation may be undertaken: if a T-tube is present, a trans-tube cholangiogram can usually reveal the presence and site of the leak; however, if a T-tube is not present, more invasive examinations such as Endoscopic Retrograde Cholangiopancreatography (ERCP: Fig. 2B, C), Percutaneous Transhepatic Cholangiography (PTC: Fig. 1E, F), or imaging-guided percutaneous puncture can confirm the diagnosis and eventually treat the bile leak. Magnetic Resonance Cholangiopancreatography (MRCP), performed without the use of contrast material (c.m.), is useful in the diagnosis of bile leaks; however, it does not provide functional information and generally shows only indirect evidence of bile leakage. Several authors have described the use of intravenously administered mangafodipir trisodium for the detection and localization of bile duct leaks at MRCP:9,30-33 this technique provides both anatomic and functional information about the biliary tract and enables the direct visualization of bile extravasation from injured ducts as well as the identification of bile collections.32,34,35 Excision injury is depicted at MRCP as a persistent discontinuity of a bile duct, a finding that should be confirmed by comparing Maximum Intensity Projection (MIP) images with the source images; sometimes it may associated with bile duct dilation upstream the lesion. MRCP allows exact definition of the level and length of the biliary injury, information that is essential for preoperative planning. However, the length of a bile duct injury may be overestimated in a patient with a peritoneal drain, because the main bile flow is into the drainage tube rather than the extrahepatic duct; so the signal intensity of the common bile duct distal to the lesion site is weak and therefore it is difficult to evaluate the duct on MR images.31 Hepatobiliary scintigraphy has the advantage of presenting the physiologically course of biliary excretion and showing the actual leakage of bile from the biliary tract. This technique is limited by poor spatial resolution that makes identification of the site of leak difficult; therefore, CT correlation may be required, especially if the leak is small.8,9

Mini-Invasive Treatment

Post-surgical biliary leaks are hard to manage; surgical re-exploration is difficult and requires an high degree of surgical competence because of edema and presence of scar tissue. To avoid surgical re-exploration, endoscopic or percutaneous management is preferred as the first therapeutic option. Management of bile leaks depends on the patient’s symptoms and leak’s morphological features. For symptomatic patients, small leaks diagnosed by ERCP can be treated with a sphincterectomy eventually associated with endoscopic placement of a nasobiliary drain or a plastic stent, to temporarily increase bile flow through the papilla, so facilitating a still possible healing.4,18,36 When endoscopic insertion of a stent can be achieved, a definitive closure of the leak is obtained in

264

Figure 1. Legend on following page.

Recent Advances in Liver Surgery

Percutaneous Treatment of Surgical Bile Duct Injury

265

Figure 1, continued. (A-F viewed on previous page). Leakage and biloma post laparoscopic cholecystectomy. A-B) Contrast enhanced abdominal CT scan demonstrates a biloma localized in the subfrenic area (asterisk), upper and anterior to the right liver lobe; in a more caudal plane (B) a fluid collection near to the common biliary duct (long arrow), communicating (short arrows) with the lower part of the biloma, can be seen. C) PTC is performed using a 22 G needle (arrows), inserted in a central bile duct. D) The puncture of a more peripheral bile duct is obtained with a 4 Fr needle (arrows). E) A guide wire is advanced through the papilla into the small bowel (arrows); injection of c.m. depicts the biliary leak arising from the cystic duct (arrowheads); stones are evident in the common bile duct. F) Placement of a 8 Fr internal-external biliary catheter drainage with the distal tip in duodenum (arrows); the leakage is still visible (arrowheads). G-H) A percutaneous US guided puncture is performed introducing a 18 G needle (g: arrows) inside the biloma; then a 8 Fr external drainage catheter (h: arrows) is placed. I) Contrast enhanced CT scan after 24 hours shows almost complete disappearance of biloma (asterisk) and decrease of the fluid collection near the common bile duct, in which the drainage is recognizable (arrow).

75-100% of the cases;37 in literature there are few works with a little case numbers of patients treated by nasobiliary drain associated with sphincterectomy with a successful rate of 90-100%.38 However, the retrograde intubation of the common bile duct above the lesion is sometimes difficult and a technical failure rate of 46% has been reported.37 Furthermore, ERCP is not feasible

266

Recent Advances in Liver Surgery

in patients with hepaticojejunal anastomosis and in all the cases when the access to the papilla is impracticable. In all these circumstances the treatment of choice is the percutaneous placement of an external-internal bile drainage. The basic principle of the conservative treatment of the leakage is to transform an uncontrolled fistulous tract in a controlled catheter tract: bile diversion away from the leakage point by means of a catheter favors healing, facilitating the formation of cicatricial tissue.37,39 The techniques for percutaneous transhepatic biliary drainage are different if intrahepatic biliary ducts are dilated or nondilated; generally intrahepatic biliary ducts are not dilated if there is a biliary leakage. After local anaesthesia, a microinvasive kit is used to perform PTC. The first liver puncture is performed intercostal with a 21G needle on the right lobe of the liver, across medial axillary line, up to the superior margin of the inferior rib, for the presence of nerves and vessels along the inferior margin of superior rib. Iodinated c.m. under fluoroscopic guidance is gently injected while retracting the needle until a bile duct is opacified. If a more central duct is entered (Fig. 1C), a second puncture is performed to keep a more peripheral duct (Fig. 1D).

Figure 2. Legend on following page.

Percutaneous Treatment of Surgical Bile Duct Injury

267

Figure 2, continued. (A-D viewed on previous page). Leak from the common bile duct post laparoscopic cholecystectomy. A) US shows a peri-hepatic fluid collection (arrows). B) Plain radiography shows the presence of a naso-biliary drainage (arrows) and a surgical drainage (arrowheads) C) Pre-procedural cholangiography performed through the naso-biliary drainage shows contrast extravasation at the upper tract of the common bile duct (arrowheads) and initial filling with c.m. of the surgical drainage (arrows). D) By percutaneous approach a 0,035 guide wire is inserted parallel to the naso-biliary drainage and advanced in duodenum (black arrows); complete filling with c.m. of the surgical drainage can be seen (white arrows). E) The naso-biliary drainage is removed and a 8F external-internal biliary drainage with the distal tip in duodenum (arrows) is subsequently positioned. F) Contrast enhanced CT scan after 2 weeks shows the complete disappearance of the peri-hepatic collection; the biliary drainage (arrow) can be seen. G) Cholangiogram performed the day after the CT scan through the biliary drainage shows the correct placement of the drainage, the absence of contrast extravasation and the normal flow of c.m. in duodenum. H) Cholangiogram performed 5 months after the procedure; the image, immediately after the biliary drainage removal, shows the complete recanalization of the common bile duct, without late cicatricial stenosis.

268

Recent Advances in Liver Surgery

Control opacifications should be performed with care, avoiding any rise of pressure in the biliary system or massive extravasation of c.m. If no ducts are opacified on the initial puncture, the needle is retracted, redirected and advanced into a different section of the right lobe (more anterior or more posterior). Multiple passes can be performed in this manner without risk of bleeding, having used a fine needle. After opacifying an appropriate duct, a 0.018 inch guidewire is used to engage the accessed duct and coaxial 4F and 6F dilators are advanced over this wire to dilate the tract. In difficult cases, a 0.018 inch guidewire with a hydrophilic tip is used. A flexible 0.035 inch guidewire is then advanced through the 6F dilator into the proximal small bowel. If necessary, a catheter is used to direct the guidewire through the ductal segment into the small bowel (Fig. 1E). The hydrophile 0.035 inch wire is exchanged for a 0.035 inch 180 cm superstiff guidewire through a 5F catheter (Fig. 2D). Finally, an 8F biliary drainage catheter is advanced with the distal tip located in the small bowel (Fig. 1F; Fig. 2E).23,40 The use of a relatively large drainage catheter for at least 8 or 20 weeks might prevent secondary stenosis of the bile duct and enables the healing of the lesion in most of the cases (Fig. 2G-H); however, a residual narrowing of the bile duct can be treated successfully by bilioplasty through the percutaneous route before withdrawal of the drainage catheter. Technical expertise and appropriate timing of the procedure allow success rate of more than 88%. There are, however, a few limitations involved in this method, especially in regard to long-term treatment; in fact, the percutaneous catheter may constitute a severe psychologic strain for the patient.41 Moreover, in patients with biliary leak, PTC and biliary drainage are sometimes technically very difficult because the intrahepatic bile ducts are not dilated at all; in these patients, for achieving percutaneous biliary access, a puncture of a great bile duct near the hilum can be necessary (Fig. 1C).41,42 This more central access carries the risk of damage to the hilar vascular structures.43 As concerns complications, arterial injury is responsible for severe bleeding, with a frequency of about 2%; this frequency is higher for benign stenoses and leaks than for malignant lesions.43-45 A subcapsular hematoma is usually a relative benign complication; cholangitis is another frequent complication and may be treated with catheter exchange and antibiotics.42,44,45 In patients with leak due to complete common bile duct transection it’s also possible to use a combined radiological and endoscopic approach (“Rendez-Vous”).46 After performing PTC, a peripheral bile duct is catheterised with a needle. Then, a 0.035 inch guidewire is inserted and advanced as far as the peribiliary space at the level of the leak; a 7F vascular sheath is then positioned. A 6F goose-neck snare with a 18 mm loop is pushed along the guidewire through the sheath and the distal end of the other guidewire inserted in the distal common bile duct through the endoscopic approach is grasped at the level of the peribiliary space and extracted. A 45 cm 7F vascular sheath is then positioned with the distal tip in duodenum. A 0.035 inch guidewire is changed with a 0.035 inch superstiff guidewire and an external-internal drainage catheter, with the distal tip in the duodenum, is subsequently positioned through the percutaneous approach. The catheter serves both as a tutor and drainage catheter and is able to restore continuity of the bile duct without the need for suturing. This process of “natural repair” takes 3-5 months and eventually results in cicatricial stenosis due to granulation tissue, which is later treated by bilioplasty.19,23,40

Biloma

Biloma is an extrahepatic or intrahepatic collection of bile resulting from bile duct injuries, solitary or multiple, encapsulated and located outside the biliary tree. Most bilomas are collections of bile fluid, but they may also contain blood, bacteria and inflammatory exudate. If the biloma is in communication with the biliary tract and there is a persistent bile leakage, then the collection of bile increases in size and the drainage is very often unsuccessful. Most of the bilomas are asymptomatic and the diagnosis could be delayed weeks or months after the initial lesion. If symptomatic, patients present abdominal pain and tenderness, fever, jaundice or anorexia.47

Percutaneous Treatment of Surgical Bile Duct Injury

269

Imaging

The US characteristics of biloma may include: a well-defined, anechoic mass with good through-transmission of sound, oval, round or elliptical in shape; a moderately echogenic fluid mass, caused by floating debris; a highly echogenic mass caused by cholesterol and lipoprotein aggregates, as well as debris; a well defined mass with a fluid-fluid level caused by layering of internal debris.48 CT generally shows a localized low-attenuation fluid collection in or around the liver (Fig. 1A, B); it usually appears encapsulated and has a CT attenuation of about 10-20 HU. CT may localize the biloma and show its anatomical relationships with other structures more precisely than US. CT and US signs of biloma are, however, non specific, as these findings may also be seen with resolving hematomas and abscesses. Percutaneous US or CT aspiration as well as hepatobiliary scintigraphy or MRCP with liver specific c.m. are needed to confirm the diagnosis.49 In particular, diagnostic aspiration should be carried out when fluid collection is detected in the post-operative period, if there are not obvious signs of the development of an abscess. A 18G needle is used for diagnostic aspiration; a 5 ml sample of fluid is aspirated and sent for immediate Gram stain and aerobic, anaerobic and fungal cultures.

Percutaneous Treatment

The appropriate treatment for most of the bilomas is percutaneous drainage, although small-size bilomas may resolve spontaneously. US and CT are crucial to determine the best anatomical approach for a safe aspiration: CT enables a more accurate representation of the adjacent organs, which could interfere with the proposed access route;49,50 US, being a real-time imaging modality, allows the monitoring of the progression of needles and catheters (Fig. 1G).39 There are a variety of commercially catheters available for percutaneous drainage. Most are variations of either a modified Seldinger technique or a Trocar catheter technique. The Seldinger technique uses a 0.035 inch guidewire inserted through the 18G needle, followed by the placement of a 8F pigtail catheter (Fig. 1H). The Trocar technique is a “one step” technique and uses a larger central stylet positioned within a 8-14F catheter. The choice of the catheter technique depends on the location of the fluid collection: with a small deep fluid collection a Seldinger-type system is recommended; when there is a large superficial fluid collection the Trocar system can be used more safely.40 After insertion of the drainage catheter, the biloma should be aspirated completely. To prevent accidental removal, it is recommended to suture the catheter to the skin; a collecting bag is used to harvest the drainage fluid. If septic, most of the patients become afebrile within 48 hours, but it may take 7-10 days for the leukocyte count to return to normal. Antibiotic therapy is recommended and lavage of the fluid collection cavity through the catheter should be performed 1-3 times a day; US/CT control is usually performed after 7 days, then weekly up to the complete resolution of the collection.51 The catheter can be removed when temperature and white blood cell count have returned to normal and drainage flow is less than 10 ml/24hr for 3 days.52 Other criterion to remove the catheter drainage is the persistent absence of the fluid collection at US or CT 3 days after its resolution and the closure of the external hole of the catheter left inside.52 If the leakage generating the biloma is visualized by imaging techniques, a biliary internal-external drainage is necessary (Fig. 1H).40 The complete resolution of the biloma can be achieved with percutaneous drainage in 82-100% of cases.53,54 The percutaneous management of fluid collections may have complications related to the procedure and catheter. Major complications due to the procedure are septicemia, intestinal perforation, bleeding, skin infection at the puncture site and pneumothorax.49 The complications related to the catheter are the accidental removal, obstruction and its inadequacy when there is a second loculation, which could require a second drainage catheter.42

270

Recent Advances in Liver Surgery

Stricture

A biliary stricture can be defined as the narrowing of the bile ducts or of a biliary-digestive anastomosis; features that may be associated include intra and extrahepatic bile duct dilatation and presence of stones or sludge in the ducts.11,55,56 Iatrogenic biliary strictures (IBS) can be early or late. Early strictures are usually caused by the primary surgical procedure, because of direct trauma, clipping of the duct, thermal injury and local inflammation due to infection; strictures also may occur as a result of bile leakage and scar formation. Late strictures may develop after months or years and are caused by periductal fibrosis or local ischemia; they are the most frequent complication of liver transplantation.11,12 Strictures, which often start at the hilus and progress to involve the intrahepatic bile ducts, commonly develop within the first 3 months after transplantation; occasionally, ischemic strictures are seen only in the intrahepatic bile ducts.28,29 Strictures also occur during follow-up in about 50% of the patients, who had primary or secondary surgical repair from partial lacerations or total transection of the main duct with end to end reconstruction over a T-tube.18

Imaging

The main clinical findings are pain and jaundice; in addition bilirubinemia and alkaline phosphatase are elevated. However, the diagnosis of a stricture in the early stages of injury is challenging, because clinical and laboratory findings are subtle or even absent.8 In liver transplant patients, hepatic dysfunction may have a variety of causes, so there may be uncertainty regarding the importance of minimal duct dilation and slight narrowing at the anastomosis. In patients with an external biliary drainage (T-tube), it is fast and easy to perform cholangiography in the post-operative period, to assess the condition of the biliary system when a complication is suspected.15,57 In patients in whom a T-tube is not in place, US and MRCP are the best non-invasive methods of imaging the biliary tree;15 CT, which is often used to investigate suspected vascular disease, can also demonstrate associated biliary stricture (Fig. 3A). Direct cholangiography (Fig. 3B; Fig 4A-C) is currently considered the reference standard for diagnosis of biliary strictures, but it has several limitations and is associated with an unacceptably high complication rate in patients for whom the level of clinical suspicion is low. The injection of c.m. may lead to low-grade strictures being overestimated because of overdistention of the ducts. Moreover, the effectiveness of direct cholangiography may be limited in patients with multiple strictures because c.m. cannot pass beyond a high-grade obstruction, so that ducts and strictures beyond such an obstruction cannot be visualized. If the biliary tree is not completely visualized prior surgery (Fig. 4A, B), one or more hepatic segments may be excluded from a biliary-enteric anastomosis (Fig. 4c) and inadequate drainage may lead to cholangitis. Finally, in cases of complete ductal obstruction, PTC cannot visualize the area below the obstruction (Fig. 4B) and ERCP cannot provide a clear view of the biliary tree above the site of obstruction.8 At MRCP, the ductal system—both proximal and distal to the obstruction—is well depicted and the extent of biliary involvement is clearly delineated.55 In addition MRCP is particularly valuable in the evaluation of strictures of biliary-enteric bypass surgery, because endoscopic access is rarely possible and PTC has a high rate of complications. So MRCP can be considered as the primary imaging modality in patients suspected of having biliary strictures; accuracy, sensitivity, specificity, positive predictive value and negative predictive value are 94%, 97%, 74%, 86% and 96%, respectively.55 Since MRCP cannot provide functional information or represent resistance to flow, there is a tendency to overestimate the stricture degree on the basis of the ductal appearance. However, with regard to the use of MRCP as a first-line diagnostic test, the overestimation of a stricture is probably a less serious problem than underestimation: whereas overestimation may lead to an unnecessary referral for direct cholangiography, a false-negative diagnosis may delay appropriate therapy, which increases the risk of cholangitis and, in liver transplant patients, of graft rejection. MRCP also overestimates the stricture length if the duct immediately distal to the stricture has

Percutaneous Treatment of Surgical Bile Duct Injury

271

collapsed; however, an analysis of the source images should help avoid or minimize overestimation.55 Furthermore, only the prossimal boundary of the stricture is relevant for surgical reconstruction, which is the treatment of choice, while MRCP—as said—overestimates its extent.17,29,58 In addition, MRCP can correctly provide other critical information for surgical planning, namely the number of strictures (because cholangitis and further strictures may occur if ducts remain isolated from the biliaryenteric anastomosis) and their locations (because Roux-en-Y choledochojejunostomy is indicated in patients with common bile duct strictures, whereas intrahepatic and hilar strictures are treated with hepaticojejunostomy).55

Percutaneous Treatment

Iatrogenic biliary stricture represents a distinct therapeutic problem due to the high frequency of recurrence after treatment. The initial treatment of choice for IBS is surgical repair. When performed by a competent surgeon, it has a success rate of 77%, with a morbidity of 10%.59 However, alternative treatments may be beneficial in patients at high surgical risk and in whom multiple surgical repairs have failed. Such therapeutic options, which mainly consist of percutaneous balloon dilation and stents placement, are indicated due to the progressive and possibly malignant evolution of this benign disease toward biliary cirrhosis and secondary sclerosing cholangitis, tragic events if one considers that the majority of these strictures are iatrogenic and therefore preventable.4,60-62 Percutaneous balloon dilation has become a viable alternative to the surgical treatment of IBS with a success rate of 76-88% in iatrogenic nonanastomotic strictures and a success rate of 67-73% in anastomotic strictures, due to the considerable fibrotic reaction around the diseased segments.63-65 Standard angioplasty balloon catheters are mainly used for dilation of IBS. The procedure is carried out with anaesthesiological support (sedation and analgesia through the intravenous administration of propofol, fentanyl and midazolam at doses adequate for the patient’s body weight and the length of the procedure). PTC is performed by using a 22G Chiba needle; after performing PTC a peripheral bile duct is catheterised with a 18G needle cannula. Then, with the aid of a catheter support, the steno-occlusion is crossed (Fig. 3B; Fig. 4D-F); a balloon catheter is then positioned on a 0.035 inch superstiff guidewire (Fig. 3C). Usually the diameter of the balloon chosen for a stricture located above the bifurcation is 5-8 mm, in the common bile duct 6-10 mm. As in transluminal angioplasty, comparison with the diameter of adjacent normal segments of bile ducts is advisable. Variable dilation techniques are used, either 3-5 inflations of the balloon at low (4-5 atm) or high (10-20 atm) pressure, varying from a 30 seconds to several minutes, until no residual deformation is seen on the balloon during inflation. Prolonged dilation with inflation of the balloon for 8-12 hours has been advocated.40 After dilation is completed (Fig. 3E, F), a percutaneous biliary drainage catheter is replaced for permanent access, calibration of the stenosis and repeat dilation. Large catheters should be used (8-12F), which can remain in place up to one month. Recurrences also occur after percutaneous balloon dilation and usually result from chronic inflammation or possibly from low stricture compliance because of the presence of an elastic component in the scar tissue. In recurrent strictures, bilioplasty can be repeated and performed with a cutting balloon (Fig. 3D), a noncompliant angioplasty balloon with three or four atherotomes (microsurgical blades) mounted longitudinally on its outer surface, originally introduced for treatment of vascular fibrosis or intimal hyperplasia.61,66-68 Percutaneous placement of plastic or metallic stents represents a semi-permanent solution, because patency of the bile duct lumen is mechanically maintained and elastic recoil and recurrent stenosis are prevented;69,70 the stents should be reserved for patients with recurrent SBI after unsuccessful balloon dilatation.58 Many attempts have been made to define the optimal configuration of biliary stents: they should be easy to insert, removable, should function over an extended period and should induce few complications. With regard to materials used to manufacture stents, biliary endoprostheses

272

Recent Advances in Liver Surgery

Figure 3. Anastomostic stictures in a patient who underwent hepatico-biduct-jejunostomy because of a gallbladder carcinoma. A) Contrast enhanced CT (MPR oblique coronal image) shows dilatation of the biliary ducts (arrows) due to anastomotic stenoses. Legend continued on following page.

Percutaneous Treatment of Surgical Bile Duct Injury

273

Figure 3, continued from previous page. B) Cholangiography, performed after bilateral percutaneous placement of two metallic guides in the jejunal loop, confirms the stenosis of both biliodigestive anastomoses (arrows), with the right one more severe. C) Bilioplasty of both of anastomoses, performed with kissing-balloons (arrows) technique. D) Right bilioplasty completion with cutting-balloon (arrows). E-F) Cholangiography soon after the procedure: satisfactory patency of both anastomoses; the right anastomosis is well visible in figure (E) (black arrows), whereas the left one in figure (F) (white arrows), that was obtained after further injection of c.m. in the left biliary tree.

fall into two broad categories, plastic (teflon, polyethylene or polyurethane) and metallic (stainless steel or nickel-titanium alloy) stents.71 Plastic biliary endoprostheses (PBE) are generally implanted as a palliative treatment in inoperable tumours involving the bile ducts. Less commonly, they are used in IBS especially in strictures involving the duct confluence with dissociation of the biliary hemisystems and in all cases of involvement of the secondary ducts;72,73 in particular, for treatment of strictures at the bifurcation, bilateral transhepatic PBE placement is necessary.74 The main advantage of PBE is that they can be removed and replaced,75 while disadvantages are both the larger delivery system and the risk of occlusion (that can occur after 6 months because of the small inner diameter). Therefore plastic biliary endoprothesis must be exchanged every 6 month or earlier, whenever stent dysfunction is suspected on the basis of symptoms, increase of liver enzymes values and imaging findings.76 As concerns the use of metallic stents for benign strictures, a note of caution is mandatory. A potential advantage of metallic stents is the larger inner diameter than PBE, which ensures a decreased rate of occlusion; however, since blocked metallic stents are very difficult to remove, a variety of non surgical techniques—such as the placement of a second metallic stent within the lumen of the occluded stent, intrastent bilioplasty or percutaneous biliary drainage—has been proposed to relieve their possible obstruction.77 Further, the potential consequences of a metal stent placed across a benign biliary stricture are influenced by the patient’s greater expected survival time and the requirement for longer-term treatment strategies when stent occlusion occurs.78 Complications can be related to delivery procedure or stent function. The most frequent delivery procedure complications are bile leakage or hemorrhage (hemobilia, hemoperitoneum, pseudoaneurysm and sometimes thoracic wall hematoma); pneumoperitoneum is a more rare complication and usually it resolves spontaneously with conservative management. Usually bile leakage and hemorrage are more frequent when PBE is positioned, because of its larger delivery system.79 Migration and occlusion are the most frequently stent function complications. Plastic stents are associated with a dislocation rate of 3-6%, whereas metallic ones rarely dislodge. Plastic stents—as said before—must be exchanged about every 6 months; moreover, the results of primary patency for metallic stents decreased from 75% after 12 months to 25% after 36 months; the secondary patency rates was 100% at 24 months.76 Although the cost of a PBE is lower, the cost-effectiveness is in favour of metallic stents for their longer patency and because they require fewer repeat intervention and readmissions.80 In conclusion, percutaneous balloon dilation should be the first therapeutic choice for treating recurrent IBS, because it will be curative in a large percentage of cases; PBE should be reserved for patient with recurrent biliary strictures after unsuccessful balloon dilatation, while the choice to use a metallic stents must be made on an individualized basis.63-65,69,70,76 At present, percutaneously placed metallic stents are reserved for patients with a life expectancy lower than 2 years.70,75,77

Arteriobiliary or Venousbiliary Fistula (Hemobilia)

The arteriobiliary or venousbiliary fistulas are an uncommon connection between an arterious or venous vessel and a biliary duct; they can cause hemobilia.2 Q uinke described a triad of symptoms and signs associated with hemobilia: upper abdominal pain, upper gastrointestinal hemorrhage and jaundice.48,81

274

Figure 4. Legend on following page.

Recent Advances in Liver Surgery

Percutaneous Treatment of Surgical Bile Duct Injury

275

Figure 4, figure viewed on previous page. Anastomostic stictures in a patient with episodes of cholangitis who underwent cholecystectomy, choledochotomy and Roux hepatico-triduct-jejunostomy because of iatrogenic cystic artery bleeding. A) PTC shows left bile duct dilatation and hepaticojejunal anastomosis stricture. B) PTC the day after: the right biliary ducts are dilated and the hepaticojejunal anastomosis is occluded; the left biliary ducts are not visualized. C-D) After surgical reconstruction of the two hepaticojejunal anastomoses, in which biliary drainages are placed (arrows), PTC shows a persistent dilatation of a bile duct group of the right biliary system (C), due to the occlusion of the third hepaticojejunal anastomosis; after PTC, an external biliary drainage catheter is positioned (d: arrowheads). E-F) After twenty days, the steno-occlusion is crossed (E) and a percutaneous external-internal biliary drainage catheter is placed with the tip in the jejunal loop (F: arrowheads); retrograde opacification of the surgical drainages by the c.m. injected in the jejunal loop (arrows).

The percutaneous liver procedures are the most commonly reported cause of iatrogenic hemobilia. The review of the English language literature carried out by Green from 1996 to 1999, reveals 40% reported cases of iatrogenic hemobilia and the proportion of hemobilia caused by percutaneous procedures alone is 38%.50 The most important percutaneous causes of hemobilia are: endoscopic lithotripsy (10%), biliary stenting (10%), percutaneous biliary drainage (2-10%), angiography (5%), percutaneous transhepatic cholangiography (4%), radiofrequency (0.3%), liver biopsy (0.06-1%).7,40,48 The most important surgical causes of hemobilia are: laparoscopic cholecystectomy (13%), liver transplantation (6%) and biliary surgery (4%);14 for liver transplant recipients the major risk of hemobilia is liver biopsy.82,83 Hemobilia has been also reported following hepaticojejunostomy, choledochoduodenostomy and hepatic lobectomy. Hemobilia is usually caused by an arterobiliary fistula, while it is rare from a venous fistula because of the low value of pressure in the systemic or portal venous system; however, the risk of hemobilia is higher in patients with portal hypertension.84,85 The rate of bleeding is variable: in major hemobilias bleeding is immediately life threatening; in minor hemobilias, although the blood loss is clinically significant, the patient is hemodynamically stable. Bleeding may be so rapid that the blood passes directly into the duodenum, appearing as haematemesis or melaena; when the hemorrage occurs more slowly, blood and bile do not mix owing to their different specific gravities and surface tensions; the resultant clots obstruct the bile ducts.86 In case of hemathemesis, gastroscopy is the first choice investigation: if blood or clots are seen at the papilla of Vater, hemobilia is likely the cause of the haemorrhage. However, as few as 12% of endoscopies may be negative, further investigations may be required.87

Imaging

At abdominal US, in cases of suspected hemobilia, blood clots within the biliary tree and the gallbladder are depicted as nonshadowing echogenicities, whereas substantially sized stones shadow with proper technique. Over time echogenicity tends to decrease, so that the evolution to less reflective masses is useful to support the diagnosis of hemobilia. Sometimes blood filling the gallbladder also may appear as low-level echoes indistinguishable from sludge.88,89 On CT, active bleeding may be seen as pooling of c.m. (Fig. 5A); recent bleeding into the biliary tree and gallbladder may be demonstrated by hyperdense, intraluminal clots and biliary dilation; however, high-density material within the lumen of the gallbladder is seen not only with stones, but also with vicarious excretion of intravenous c.m., biliary sludge and milk of calcium bile: all these entities need to be considered in the differential diagnosis.90 Moreover, US and CT can show various risk factors for developing hemobilia, including aneurysms and pseudo-aneurysms.47 At US, aneurysms and pseudo-aneurysms usually appear as well circumscribed anechoic masses; althought they are not necessarily pulsatile, Doppler US may show flow signals, differentiating them from biloma or cyst; color Doppler can also demonstrate a classical yin-yang flow in the pseudo-aneurysm sac (a pattern with bidirectional color assignment due to turbolent swirling flow). CT—after intravenous c.m. administration—demonstrates the hyperdense true lumen,

276

Recent Advances in Liver Surgery

Figure 5. Hemobilia post percutaneous biliary drainage placement. A) Contrast enhanced CT scan shows a blush of c.m. arising from a right hepatic artery branch (arrow) and a subcapsular hematoma (asterisk); a biliary drainage (arrowheads) is visible. B) Cholangiography obtained throught the biliary drainage during an episode of hemobilia demonstrates clots within a dilated biliary duct (arrows). C) A super selective catheterization of the arterial branch feeding the blush (arrows) is performed with a microcatheter. D) The angiographic control after embolization with microcoils (arrows) does not demonstrate the blush with preservation of the other arterial branches.

whereas thrombotic deposits in the wall of the lesion are depicted as discrete ring-shaped or semilunar hypodensities.91,92 The MR imaging findings indicative of hemobilia are clots—which appear as defects in the gallbladder and bile ducts at MRCP—and hemorrhagic bile, which has the high signal intensity of methemoglobin on fat-suppressed T1-weighted images and a low signal intensity on T2-weighted images.93 In particular, a fluid-fluid level can be observed in the lumen of the gallbladder and extrahepatic bile ducts, where hemorrhagic bile appears as a low-signal intensity area in the lower dependent layer on axial T2-weighted images.94 Cholangiography can be performed, if there is already a percutaneous access or if an endoscopic investigation is performed: blood may be seen refluxing down drainage catheters or at the papilla of Vater and contrast studies may show filling defects in the biliary tree with a variable morphology (string-like defects may occur if the clots have formed a cast of the biliary tree: Fig. 5B).95,96 Angiography is currently employed only before a therapeutic endovascular treatment (Fig. 5C).97,98

Percutaneous Treatment of Surgical Bile Duct Injury

277

Percutaneous Treatment

Transcatheter arterial embolization (TAE) is the first line of intervention to stop bleeding for most causes of hemobilia; previous reviews and retrospective series have shown a success rate of 63-100%; the reported mortality and morbidity rates are lower than those after surgery.99,100 The portal vein should be patent if arterial embolization is to be attempted (but portal thrombosis is not an absolute contraindication) and hepatic sepsis is a relative contraindication; antibiotic prophylaxis is recommended.101,102 The embolization is performed via transfemoral artery cannulation with a 4F or 5F catheter that is placed into the hepatic artery. Superselective catheterization with microcatheter of the bleeding arterial branch is the most important step of the embolization to obtain the best results and to avoid many complications. In order to increase efficacy of the procedure and to reduce complications and costs, it is advisable to combine several materials for embolization. TAE can be performed by injecting gelatine sponge, particles of polyvinyl alcohol, embospheres, trombine, stainless steel coils/microcoils or Amplatzer Vascular Plug until to stop bleeding.92,103,104 The results depends on physician experience, size of the injury and stability of the patient.31,32 The ideal embolic agent would be inexpensive, easy to use, permanent and capable of occluding the injured artery with maximum preservation of hepatic arterial flow. Gelfoam is inexpensive and easy to use; however, it is not permanent and bleeding may recur; moreover, its distribution may be difficult to control and possible diffuse hepatic arterial embolization could occur. Stainless steel coils (Fig. 5D) are permanent occluding agents; they are easy to use but more expensive. Sometimes a “sandwich” technique of coils and Gelfoam may be required for effective occlusion.92,103 In order to obtain complete hemostasis of a ruptured pseudo-aneurysm, microcoils have to be placed in both distal and proximal to the pseudo-aneurysm (endovascular ligature). When a pseudo-aneurysm with or without extravasation of contrast media is identified, a coaxial microcatheter is placed distal to the pseudoaneurysm, followed by placement of microcoils. Subsequently, the coaxial catheter is placed proximal to the pseudo-aneurysm and microcoils are deployed. Arteriography is repeated in order to confirm the exclusion of the pseudo-aneurysm.103 A covered stent placement can be used to treat a pseudo-aneurysm located at the level of large extra-hepatic vessels, especially in patients who have not developed collateral pathways, conserving the continuity of the vascular artery axis; so, not only hemostasis is obtained, but also the manteinance of hepatic blood flow is preserved. Yet the use of such devices is hindered by the tortuosity and the small diameter of the hepatic artery.104 Liver-related complications that occur after TAE are bile leak and/or biloma, hepatic necrosis and perihepatic or intrahepatic abscess.104 It must be stressed that, although 70% of hepatic blood comes from the portal vein, the vitality of the bile ducts depends exclusively on the arterial system. In rare cases TAE may cause biliary wall necrosis with stenosis or leakage as complications; reflux of emboli into the cystic artery may lead to acute cholecystitis, necrosis and perforation of the gallbladder.103 Reflux of emboli into hepatic, pancreatic and splenic arterial branches may cause necrosis and abscesses. Septic complications, such as hepatic abscesses, may be identified by US and CT scan and are usually treated with antibiotics and percutaneous drainage. Most adverse effects are related to physician inexperience, improper material and lack of hospital support.104 Persisting haemorrhage and rebleeding should be treated with a new TAE or surgically.104

Conclusions

With improvements in surgical techniques, there has been a substantial decrease in the incidence of biliary complications of hepato-biliary surgery and liver transplantation. Nevertheless, SBDIs—distinguished in: leak, biloma, stricture and arteriobiliary or venousbiliary fistula—are a serious problem and a major cause of morbidity. The treatment of choice of the bile leak is the percutaneous placement of an external-internal biliary drainage, to transform an uncontrolled fistulous tract in a controlled catheter tract.

278

Recent Advances in Liver Surgery

The appropriate treatment for most of the bilomas is US/CT guided percutaneous drainage, although small-size bilomas may resolve spontaneously. Iatrogenic biliary stricture represents a distinct therapeutic problem due to the high frequency of recurrence after treatment. The initial treatment for IBS is surgical repair; percutaneous balloon dilation and stents placement may be beneficial in patients at high surgical risk, or in whom surgical repairs have failed. In recurrent strictures, bilioplasty can be repeated or performed with a cutting balloon; plastic or self-expanding metallic stents should be reserved for patients with IBS after unsuccessful balloon dilatation; in particular metallic stents should employed in patients with a life expectancy lower than 2 years. As concerns the management of hemobilia, TAE with gelfoam and microcoils is the first line of intervention to stop bleeding; a covered stent can be used only to treat a pseudo-aneurysm located at level of a large extra hepatic vessel. In conclusion, interventional radiology can be considered highly effective and safe for the management of SBDI, showing a low morbidity and practically no mortality.

References

1. Roslyn JJ, Binns GS, Hughes EF et al. Open cholecystectomy: A contemporary analysis of 42,474 patients. Ann Surg 1993; 218:129-137. 2. Deziel DJ, Millikan KW, Economou SG et al. Complications of laparoscopic cholecystectomy: A national survey of 4,292 hospitals and an analysis of 77,604 cases. Am J Surg 1993; 165:9-14. 3. Morgenstern L, Wong L, Berci G. Twelve hundred open cholecystectomies before the laparoscopic era: A standard for comparison. Arch Surg 1992; 127:400-403. 4. Slanetz PJ, Boland GW, Mueller PR. Imaging and interventional radiology in laparoscopic injuries to the gallbladder and biliary system. Radiology 1996; 201:595-603. 5. Richardson MC, Bell G, Fullarton GM. Incidence and nature of bile duct injuries following laparoscopic cholecystectomy: an audit of 5913 cases. West of scotland laparoscopic cholecystectomy audit group. Br J Surg 1996; 83:1356-1360. 6. Andren-Sandberg A, Johansson S, Bengmark S. Accidental lesions of the common bile duct at cholecystectomy. II. Results of treatment. Ann Surg 1985; 201:452-455. 7. Forlee MV, Krige JEJ, Welman CJ et al. Haemobilia after penetrating and blunt liver injury: treatment with selective hepatic artery embolisation. Injury 2004; 35:23-28. 8. Hoeffel C, Hazizi L, Lewin M et al. Normal and pathologic features of the post-operative biliary tract at 3D MR Cholangiopancreatography and MR Imaging. RadioGraphics 2006; 26:1603-1620. 9. Kapoor V, Baron RL, Peterson MS. Bile leaks after surgery. AJR 2004; 182:451-458. 10. Hintze RE, Adler A, Veltzke W et al. Endoscopic management of biliary complications after orthotopic liver transplantation. Hepatogastroenterology 1997; 44:258-262. 11. Colonna JO 2nd, Shaked A, Gomes AS et al. Biliary strictures complicating liver transplantation: incidence, pathogenesis, management and outcome. Ann Surg 1992; 216:344-352. 12. Theilmann L, Küppers B, Kadmon M et al. Biliary tract strictures after orthotopic liver transplantation: diagnosis and management. Endoscopy 1994; 26:517-522. 13. Neuhaus P, Blumhardt G, Bechstein WO et al. Technique and results of biliary reconstruction using side-to-side choledochocholedochostomy in 300 orthotopic liver transplants. Ann Surg 1994; 219:426-434. 14. Greif F, Bronsther OL, Van Thiel DH et al. The incidence, timing and management of biliary tract complications after orthotopic liver transplantation. Ann Surg 1994; 219:40-45. 15. Fulcher AS, Turner MA. Orthotopic liver transplantation: Evaluation with MR cholangiography. Radiology 1999; 211:715-722. 16. Letourneau J, Hunter D, Ascher N et al. Biliary complications after liver transplantation in children. Radiology 1989; 170:1095-1099. 17. Nghiem HV, Tran K, Winter TC III et al. Imaging of complications in liver transplantation. RadioGraphics 1996; 16:825-840. 18. Rauws EA, Gouma DJ. Endoscopic and surgical management of bile duct injury after laparoscopic cholecystectomy. Best Pract Res Clin Gastroenterol 2004; 18:829-846. 19. Tsalis KG, Christoforidis EC, Dimitriadis CA et al. Management of bile duct injury during and after laparoscopic cholecystectomy. Surg Endosc 2003; 17:31-37. 20. Bismuth H. Post-operative strictures of the bile duct. In: Blumgart LH, ed. The Biliary Tract. Edinburgh: Churchill-Livingstone, 1982:209-218. 21. McMahon AJ, Fullarton G, Baxter JN et al. Bile duct injury and bile leakage in laparoscopic cholecystectomy. Br J Surg 1983; 3:307-313.

Percutaneous Treatment of Surgical Bile Duct Injury

279

22. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg 1995; 180:101-125. 23. Bergmann JJGHM, van den Brink, GR Rauws EAJ et al. Treatment of bile duct lesions after laparoscopic cholecystectomy. Gut 1996; 38:141-147. 24. Wu JS, Peng C, Mao XH et al. Bile duct injuries associated with laparoscopic and open cholecystectomy: sixteen-year experience. World J Gastroenterol 2007; 13:2374-2378. 25. Stewart L. Treatment strategies for benign bile duct injury and biliary stricture. In: Poston GJ, Blumgart LH, eds. Surgical Management of Hepatobiliary and Pancreatic Disorders. London: Dunitz, 2003: 315-329. 26. Majeed AW, Johnson A. Pitfalls in cholecystectomy. In: Poston GJ, Blumgart LH, eds. Surgical Management Hepatobiliary and Pancreatic Disorders. London: Dunitz, 2003:301-314. 27. Sanchez-Urdazpal L, Sterioff S, Janes C et al. Increased bile duct complications in AB0 incompatible liver transplant recipient. Transplant Proc 1991; 23:1440-1441. 28. Zajco A, Campbell W, Longsdon G et al. Cholangiographic findings in hepatic artery occlusion after liver transplantation. AJR 1987; 149:485-489. 29. Sanchez-Urdazpal L, Gores G, Ward E et al. Ischemic-type biliary complications after orthotopic liver transplantation. Hepatology 1992; 16:49-53. 30. Aduna M, Larena JA, Martin D et al. Bile duct leaks after laparoscopic cholecystectomy: Value of contrast-enhance MRCP. Abdom Imaging 2005; 30:480-487. 31. Park MS, Kim KW, Yu JS et al. Early biliary complications of laparoscopic cholecystectomy: Evaluation on T2-weighted MR cholangiography in conjunction with mangafodipir trisodium enhanced 3D T1-weighted MR cholangiography. AJR 2004; 183:1559-1566. 32. Vitellas KM, El-Dieb A, Vaswani KK et al. Using contrast enhanced MR cholangiography with IV mangafodipir trisodium (Teslascan) to evaluate bile duct leaks after cholecystectomy: A prospective study of 11 patients. AJR 2002; 179:409-416. 33. Assaban M, Aubé C, Lebigot J et al. Mangafodipir trisodium-enhanced magnetic resonance cholangiography for detection of bile duct leaks. J Radiol 2006; 87:41-47. 34. Kalayci C, Aisen A, Canal D et al. Magnetic resonance cholangiopancreatography documents bile leak site after cholecystectomy in patients with aberrant right hepatic duct where ERCP fails. Gastrointest Endosc 2000; 52:277-281. 35. Fayad LM, Kamel IR, Mitchell DG et al. Functional MR cholangiography: Diagnosis of functional abnormalities of the gallbladder and biliary tree. AJR 2005; 184:1563-1571. 36. Ernst O, Sergent G, Mizrahi D et al. Biliary leaks: Treatment by means of percutaneous transhepatic biliary drainage. Radiology 1999; 211:345-348. 37. Liguory C, Vitale GC, Lefebre JF et al. Endoscopic treatment of post-operative biliary fi stulae. Surgery 1991; 110:779-784. 38. Elmi F, Silverman WB. Nasobiliary tube management of postcholecystectomy bile leaks. J Clin Gastroenterol 2005; 39:441-444. 39. Kaufman SL, Kadir S, Mitchell SE et al. Percutaneous and transhepatic biliary drainage for bile leaks and fistula. AJR 1985; 144:1055-1058. 40. Dondelinger RF, Kurdziel JC. Percutaneous management of benign disease in the bile ducts. In: Dondelinger RF, Rossi P, Kurdziel JC, Wallace S, eds. Interventional Radiology. New York: Th ieme, 1990:213-226. 41. Aytekin C, Boyvat F, Harman A et al. Percutaneous management of anastomotic bile leaks following liver transplantation. Diagn Interv Radiol 2007; 13:101-104. 42. Cozzi G, Severini A, Civelli E et al Percutaneous biliary drainage in the management of postsurgical bile leaks in patients with nondilated intrahepatic bile ducts. Cardiovasc Interv Radiol 2006; 29:380-388. 43. Savader SJ, Trerotola SO, Merine DS et al. Hemobilia after percutaneous transhepatic biliary drainage: treatment with transcatheter embolotherapy. J Vasc Inter Radiol 1992; 3:345-352. 44. L’Herminè C, Ernst O, Delemazyre O et al. Arterial complications of percutaneous biliary drainage. Cardiovasc Intervent Radiol 1996; 19:160-164. 45. Hamlin JA, Friedman M, Stein MG et al. Percutaneous biliary drainage: Complications of 118 consecutive catheterizations. Radiology 1984; 152:343-346. 46. Sciumè C, Geraci G, Pisello F et al “Rendez-vous” technique for palliation of neoplastic jaundice: personal experience. Ann Ital Chir 2004; 75:643-647. 47. Sakamoto I, Iwanga S, Nagaoki K et al. Intrahepatic biloma formation (bile duct necrosis) after transcatheter arterial chemoembolization. AJR 2003; 181:79-87. 48. Green MHA, Duell RM, Johnson CD et al. Haemobilia. Br J Surg 2001; 88:773-786. 49. Savassi-Rocha PR, Almeida SR, Sanches MD et al. Iatrogenic bile duct injuries. Surg Endosc 2003; 17:1356-1361. 50. Moody FG. Bile duct injury during laparoscopic cholecystectomy. Surg Endosc 2000; 14:605-607.

280

Recent Advances in Liver Surgery

51. Olsen DO. Bile duct injuries during laparoscopic cholecystectomy: A decade of experience. J Hepatobil Pancreat Surg 2000; 7:35-39. 52. Do H, Lambiase RE, Deyoe L et al. Percutaneous drainage oh hepatic abscesses: Comparison of results in abscesses with and without intrahepatic biliary communication. AJR 1991; 157:1209-1212. 53. Mueller PR, Ferrucci JT Jr, Simeone JF et al. Detection and drainage of bilomas: Special considerations. AJR 1983; 140:715-720. 54. Christoforidis E, Vasiliadis K, Goulimaris et al. A single center experience in minimally invasive treatment of postcholecystectomy bile leak, complicated with biloma formation. J Surg Res 2007; 141:171-175. 55. Ward J, Sheridan MB, Guthrie JA et al. Bile duct strictures after hepatobiliary surgery: Assessment with MR cholangiography. Radiology 2004; 231:101-108. 56. Terblanche J, Allison HF, Northover JM. An ischemic basis for biliary strictures. Surgery 1983; 94:52-57. 57. Dupuy DE, Costello P. Cross-sectional imaging of liver transplantation. Semin Ultrasound CT MR 1992; 13:399-409. 58. Northover JM, Terblanche J. A new look at the arterial supply of the bile duct in man and its surgical implications. Br J Surg 1979; 66:379-384. 59. Tocchi A, Mazzoni G, Liotta G et al. Management of benign biliary strictures. Arch Surg 2000; 35:153-157. 60. Pitt HA, Miyamoto T, Parapatis K et al. Factors influencing outcome in patients with post-operative biliary strictures. Am J Surg 1982; 144:14-21. 61. Way LW, Bernhoft RA, Thomas MJ. Biliary stricture. Surg Clin North Am 1981; 61:963-972. 62. Warren KW, Mountain JC, Midell Al. Management of strictures of the biliary tract. Surg Clin North Am 1971; 51:711-731. 63. Mueller PR, vanSonnenberg E, Ferrucci JT Jr et al. Biliary stricture dilatation: Multicenter review of clinical management in 73 patients. Radiology 1986; 160:17-22. 64. Moore AV Jr, Illescas FF, Mills SR et al. Percutaneous dilation of benign strictures. Radiology 1987; 163:625-628. 65. Williams HJ Jr, Bender CE, May GR. Benign post-operative biliary strictures: Dilation with fluoroscopic guidance. Radiology 1987; 163:629-634. 66. Carrafiello G, Laganà D, Mangini M et al. Cutting balloon angioplasty for the treatment of haemodyalisis vascular accesses: midterm results. Radiol Med 2006; 111:724-732. 67. Kakani NK, Puckett M, Cooper M et al. Percutaneous transhepatic use of a cutting balloon in the treatment of a benign common bile duct strictures. Cardiovasc Interv Radiol 2006; 29:462-464. 68. Atar E, Bachar GN, Eitan M et al. Peripheral cutting balloon in the management of resistant benign ureteral and biliary strictures: Long term results. Diagn Interv Radiol 2007; 1:39-41. 69. Coons HG. Self-expanding stainless steel biliary stents. Radiology 1989; 170:979-983. 70. Irving JD, Adam A, Dick R et al. Gianturco expandable metallic biliary stents: Results of a European clinical trial. Radiology 1989; 173:321-326. 71. Donelli G, Guaglianone E, Di Rosa R et al. Plastic biliary stent occlusion: Factors involved and possible preventive approach. Clin Med Res 2007; 5:53-60. 72. England RE, Martin DF. Endoscopic and percutaneous intervention in malignant obstructive jaundice. Cardiovasc Intervent Radiol 1996; 19:381-387. 73. Tibble JA, Cairns SR. Role of endoscopic endoprostheses in proximal malignant biliary obstruction. J Hepatobiliary Pancreat Sur 2001; 8:118-123. 74. Nakamura T, Hirai R, Kitagawa M et al. Treatment of common bile duct obstruction by pancreatic cancer using various stents: single center experience. Cardiovasc Intervent Radiol 2002; 25:373-380. 75. Laganà D, Carrafiello G, Mangini M et al. An innovative percutaneous technique for the removal replacement dysfunctioning plastic biliary endoprostheses (PBE) in the management of malignant billiary occlusions. Radiol Med 2007; 112:264-271. 76. Gabelmann A, Hamid H, Brambs HJ et al. Metallic stents in benign biliary strictures: long term effectiveness and interventional management of stent occlusion. AJR 2001; 177:813-817. 77. Siriwardana PH, Siriwardena AK. Systematic appraisal of the role of metallic endobiliary stents in the treatment of benign bile duct stricture. Ann Surg 2005; 242:10-19. 78. Dumonceau JM, Deviere J, Delhaye M et al. Plastic and metal stents for post-operative benign bile ducts strictures: the best and the worst. Gastrointest Endosc 1998; 47:8-17. 79. Amonkar SJ, Laasch HU, Valle JW. Pneumoperitoneum following percutaneous biliary intervention: not necessary a cause for alarm. Cardiovasc Interv Radiol 2007:DOI 10.1007/s00270-007-9252-x. 80. Piñol V, Castells A, Bordas JM et al. Percutaneous self-expanding metal stents versus endoscopic polyethylene endoprostheses for treating malignant biliary obstruction: Randomized clinical trial. Radiology 2002; 225:27-34. 81. Q uinke H. Ein fall von aneurysma der leberarterie. Klin Wochenschr 1871; 8:349-351.

Percutaneous Treatment of Surgical Bile Duct Injury

281

82. Sherman S, Jamidar P, Shaked A et al. Biliary tract complications after orthotopic liver transplantation. Endoscopic approach to diagnosis and therapy. Transplantation 1995; 60:467-470. 83. Manzarbeita C, Jonsson J, Rustgi V et al. Management of hemobilia after liver biopsy in liver transplant recipients. Transplantation 1993; 1545-1547. 84. Sears RJ, Ishitani MB, Bickston SJ. Endoscopic diagnosis and theraphy of a case of bilhemia after percutaneous liver biopsy. Gastrointest Endosc 1997; 46:276-279. 85. Laing FC, Frates MC, Feldstein VA et al. Hemobilia: Sonographic appearances in the gallbladder and biliary tree with emphasis on intracholecystic blood. J Ultrasound Med 1997; 16:537-543. 86. Sandblom P, Mirchovitch V. Minor hemobilia. Clinical significance and pathophysiological background. Ann Surg 1979; 190:254-264. 87. Yoshida J, Donahue PE, Nyhus LM. Hemobilia: Review of recent experience with a wordlwide problem. Am J Gastroenterol 1987; 82:448-453. 88. Marchal G, Fevery J, Snowball S et al. The sonographics aspects of hemobilia. Eur J Radiol 1985; 5:211-215. 89. Chinn DH, Miller EI, Piper N. Hemorrhagic cholecystitis. Sonographic appearance and clinical presentation. J Ultrasound Med 1987; 6:313-317. 90. Mirvis ES, Shanmuganathan K. Imaging of abdominal trauma. In: Mirvis ES, ed. Imaging in Trauma and Critical Care. Philadelphia: Saunders, 2003:444-445. 91. O’Driscoll D, Olliff SP, Olliff JF. Hepatic artery aneurysm. Br J Radiol 1999; 72:1018-1025. 92. Carrafiello G, Laganà D, Recaldini C et al. Combined percutaneous thrombin injection and endovascular treatment of gastroduodenal artery pseudoaneurysm (PAGD): Case report. Emerg Radiol 2007; 14:51-54. 93. Adusumilli S, Siegelman ES. MR imaging of the gallbladder. Magn Reson Imaging Clin N Am 2002; 10:165-184. 94. Watanabe Y, Nagayama M, Okumura A et al. Black-blood T2-weighted SE-EPI imaging of the liver and the biliary tree. Recent Res Devel Radiol 2004; 2:1-16. 95. Shapiro MJ. The role of the radiologist in the management of gastrointestinal bleeding. Gastroenterol Clin North Am 1994; 23:123-181. 96. Orons PD, McAllister JF, Zajco AB. Arteriocholedochal fistula: An unusual cause of hemobilia. Abdom Imaging 1996; 21:30-32. 97. Bloechle C, Izbicki JR, Rashed MY et al. Hemobilia: Presentation, diagnosis and management. Am J Gastroenterol 1994; 89:1537-1540. 98. Basile A, Lupatelli T, Giulietti G et al. Interventional treatment of iatrogenic lesions and hepatic arteries. Radiol Med 2005; 110:88-96. 99. Lygidakis NJ, Okazaki M, Damtson G. Iatrogenic hemobilia: How to approach it. Hepatogastroenterology 1991; 38:454-457. 100. Shibata T, Sagoh T, Ametani F et al. Transcatheter microcoil embolotherapy for ruptured pseudoaneurysm following pancreatic and biliary surgery. Cardiovasc Intervent Radiol 2002; 25:180-185. 101. Richardson A, Simmons K, Gutmann J et al. Hepatic haemobilia: Non-operative management in eight cases. Aust N Z J Surg 1985; 55:447-451. 102. Steiner Z, Brown RA, Jamieson DH et al. Management of hemobilia and persistent biliary fi stula after blunt liver trauma. J Pediatr Surg 1994; 29:1575-1577. 103. Laganà D, Carrafiello G, Mangini M et al. Multimodal approach to endovascular treatment of visceral artery aneurysms and pseudoaneurysms. Eur J Radiol 2006; 59:104-111. 104. Carrafiello G, Laganà D, Ianniello A et al. Bleeding after percutaneous radiofrequency ablation: Successful treatment with transcatheter embolization. Eur J Radiol 2007; 61:351-355.

Chapter 21

Response Evaluation Criteria in Hepatocellular Carcinoma (Moving beyond the RECIST)

Carlo Fugazzola,* Gianpaolo Carrafiello, Chiara Recaldini, Elena Bertolotti, Tamara Cafaro, Maria Gloria Angeretti, Paolo Nicotera and Domenico Lumia

Abstract

T

o assess the clinical success of percutaneous minimally invasive therapies for HCC, conventional anatomical imaging based upon size criteria alone (WHO and RECIST) is not sufficient; therefore, additional criteria provided by new imaging techniques, concerning neoangiogenesis and tumor metabolism, are necessary. In a clinical setting, follow-up is performed by enhanced multiphase CT and/or MR. Dynamic (or perfusion) studies, as well as MR diffusion and MR Spectroscopy are still in a preclinical phase and further studies on largest series are necessary to validate their preliminary results. FDG-PET scan is able to provide valuable information, when CT or MR findings are ambiguous; FDG-PET should be coupled with CT to combine metabolic and morphological data.

Introduction

Imaging studies provide an objective method of quantifying tumor response to a variety of physical and pharmaceutical treatments. “Objective” tumor shrinkage—widely adopted as a standard end-point for selecting new anticancer drugs and as a prospective end-point for clinical trials designed to estimate the benefit of a treatment in a specific group of patients—is amply used in everyday clinical practice to guide clinical decision-making.1 With the development of new minimally invasive therapies for achieve local tumor control of primary liver malignancies, these criteria have turned out to be insufficient for an accurate assessment of the response to treatment, therefore additional criteria beyond the usual morphological-dimensional ones needed to be defined.

Dimensional Criteria

On the initiative of the World Health Organization (WHO), at the beginning of the 1980s, Miller et al2 developed recommendations to standardize criteria for evaluating tumor response to therapy defining terms as response, recurrence, disease-free interval and grading of acute and subacute toxicity. These criteria were based on bidimensional measurement of the tumoral lesions (the product of the longest diameter and that perpendicular to it) and are known as WHO criteria. Because precise instructions about the selection of target lesions (minimum dimensions and number of lesions) and about the modalities that had to be used were not clearly described in the *Corresponding Author: Carlo Fugazzola—Department of Radiology, University of Insubria, Medical School, 21100 Varese, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Response Evaluation Criteria in Hepatocellular Carcinoma

283

WHO guidelines, the assessment of tumor response was poorly reproducible among different investigators.3 Simpler guidelines were proposed in 1999 and they were named RECIST (Response Evaluation Criteria in Solid Tumors) criteria;4 the major proposed change is that RECIST uses unidimensional measurements of the longest diameter (LD) of tumors instead of bidimensional ones. The definition of the complete response (CR) is essentially the same between the two guidelines. The definition of partial response (PR) differs: in fact for PR, WHO requires a 50% decrease in the sum of the products of the perpendicular diameters from baseline value, confirmed at 4 weeks, whereas RECIST requires at least a 30% decrease in the sum of LDs of the target lesions from baseline value, confirmed at 4 weeks. These criteria are almost equivalent if one assumes tumors to be spherical and that the LD and the diameter perpendicular to the LD both decrease by at least 30% (although the latter was not measured by the RECIST). The criteria for progressive disease (PD) also differ between the two guidelines: WHO requires at least a 25% increase of one or more lesions (or the appearance of new lesions), whereas RECIST requires at least a 20% increase in the sum of LDs over the baseline value (or the appearance of new lesions). The WHO requirement of only a 25% increase was criticized by Lavin and Flowerdew,5 who showed that there was a one in four chance of declaring erroneously that PD had occurred when the tumor was unchanged because of the variability in measurements. The RECIST criteria raised the question of whether a simple unidimensional measurement is equivalent to the more complicated bidimensional measurements: James et al4 argue that measuring one dimension is simpler than two; on the other hand, Hilsenbeck and Von Hoff 6 point out that measuring one diameter of not spherical tumors is not really less laborious than measuring two, since multiple measurements are needed to be sure that one takes the maximum diameter. When RECIST (unidimensional) and WHO (bidimensional) criteria were applied to the same patients, recruited in 14 different trials, there was almost no difference in the percentage of responders, whereas there were some differences in the PR rates.3

Limits of Dimensional Criteria

The irregular edges of infiltrating lesions are often difficult to identify and some tumors are impossible to measure: for example, in the case of pulmonary lymphangitis carcinomatosa and ovarian carcinoma seeding into the peritoneal space. Furthermore, there is no consensus on whether necrosis and cystic change should be included when obtaining tumor measurements. Also, it can be difficult to distinguish peritumoral fibrosis from tumor spread; finally, measurement errors in estimating the size of small lesions (<10 mm) often result in misclassification of tumor response. Another limit of dimensional criteria is that lesions with irregular margins can change their shape not homogenously in the three planes, so that any change in size is not reliable. State-of-the-art imaging machines can routinely acquire volumes, but is it real that volumetric measure is more accurate than unidimensional or bidimensional? According to some studies, results are contradictory7 and three-dimensional volume measurements are likely to encounter errors similar to bidimensional or unidimensional measurements.8,9 Another study, instead, showed that volumetric measurements are a better or earlier predictor factor for tumor response.10 Theoretically, three-dimensional measurements are better for irregular lesions and should be more precise when carried out by automatic systems, because a minor intra and inter-operators variability may occur. However, these systems are nowadays available for pulmonary lesions, 11 but not optimised for lesions in organs with poor contrast tissue as the liver. Hilsenbeck and Von Hoff 6 raised the question of the need to overcome the dimensional method and to develop additional criteria to monitor the response to treatment when new selective anticancer drugs that have a cytostatic effect (stop growing) rather than cytotoxic (disappearance of the tumor) are administered. Cytotostatic drugs must be evaluated in a shorter period compared with that of dimensional criteria, in order to identify the agents suitable for further evaluation in larger clinical trials.

284

Recent Advances in Liver Surgery

Besides, the need of a earlier response is connected also with the toxicity and with the high costs of these drugs. However, in the treatment of liver malignancies, non surgical interventional therapies have gained an increasingly important role. Two different approaches are used: (a) the direct percutaneous imaging approach, in which chemical or thermal ways of tissue destruction are used, as in intra-tumor injection of alcohol,12 radiofrequency,13 laser thermal ablation,14 cryoablation,15 micro-waves;16 and (b) the intraarterial approach, in which embolic materials, chemotherapeutic agents, or radioactive agents are injected via a catheter inserted into the branches of hepatic artery, as in transcatheter arterial embolization (TAE),17 chemoembolization (TACE)18 and 90-Yttrium (Y) radioembolization.19 To evaluate the success of these interventional techniques, it is important to confirm complete necrosis of the treated lesion, which would be the equivalent of surgical resection; percutaneous biopsy cannot show the histological characteristics of the whole lesion treated and serum tumors markers are of limited help in assessing tumor response. Therefore, it is necessary to employ imaging modalities that are able to estimate the degree of treatment, the presence of residual disease or recurrence suitable to be treated again with minimally invasive procedures.

Functional Criteria

Functional imaging parameters that reflect tumor vascularization, cell composition and cell metabolism, are considered the earliest signs to show the tumor response to therapy. There are four main modalities for evaluating the biological efficacy of a treatment:20 1. Dynamic (or perfusion) imaging with Computed Tomography (CT), Magnetic Resonance (MR), Ultrasound (US): assessment of tumor microvascularization. 2. MR diffusion imaging: assessment of tumor cellularity. 3. MR spectroscopy: analysis of molecular components of tumors. 4. Positron Emission Tomography (PET): evaluation of tumoral metabolism of 2-Fluoro-deoxy-D-glucose (FDG).

Dynamic (or Perfusion) Imaging

The dynamic imaging can be applied to CT, MR and US with endovenous administration of contrast agents. The principle of dynamic imaging is to follow the biodistribution of a contrast agent inside the tumors. The routine contrast agents used in CT and MR are transported by circulation and, crossing endothelium, diffuse into the interstitial space; they do not enter cells, neither red blood cells. These pharmaco-dynamic features permit to study the vascular changes associated with tumoral growth. As a matter of fact, tumors must establish their own blood supply in order to grow more than 1-2 mm: in a complex process, known as angiogenesis, they produce a range of growth factors resulting in the recruitment of new vessels derived largely from the host vascular system. These new vessels are produced in greater number than one found in normal tissue (i.e., the microvessel density is increased); moreover, the tumor blood vessel walls demonstrate increased permeability to circulating molecules. Therefore, the intravascular phase can provide information about the microvessel density, whereas the extravascular phase can be used to evaluate vascular permeability.21 A first acquisition without contrast agent is performed to establish the site of the lesion to be studied with dynamic imaging; subsequently, after a bolus of intravenous contrast medium, repeated image acquisitions are obtained for a period of 3 minutes, in order to acquire sufficient data to describe transcapillary passage and diffusion into the interstitial compartment. At the beginning, a very elevated temporal resolution is necessary (1 image/second) to assess the arrival of contrast agent during the first passage (perfusion), whereas afterwards less frequent images are obtained to follow slower interstitial diffusion (permeability), also to reduce data volume to analyze and—when using CT20—patient irradiation. Essentially, the arrival (wash-in) and the disappearance (wash-out) of the contrast agent is tracked in a region of interest (ROI), such as the afferent artery and the tumor. The way the enhancement changes with time can be plotted as a time-density

Response Evaluation Criteria in Hepatocellular Carcinoma

285

curve (CT) or a time-signal intensity curve (MR) from which a variety of microvascular features can be extracted with a mathematical system: • Tissue blood flow (ml/min/ml tissue): it represents tumor perfusion and corresponds to the flow of blood per unit of tissue volume; • Vascular permeability (ml/min/ml tissue): it represents the amount of transfer of contrast agent from the blood to the interstitial space per unit of time and unit of tissue volume; • Tissue blood volume (ml/ml tissue): it represents the proportion of vessels containing the injected contrast agent within a volume of tissue; • Interstitial volume (ml/ml tissue): it represents the interstitial volume into which the contrast diffuses; • Mean Transit Time (MTT, expressed in seconds): it represents the mean time required for a molecule to travel across the capillary bed of a tissue—from afferent arteriole to efferent venule—in the absence of extravasation. US is routinely used in oncology to evaluate tumoral response to treatment; however, this imaging modality, also using Doppler techniques, does not allow an accurate analysis of tumor vascularity;22 the use of contrast media has strongly increased the detectability of intra-tumor vessels. Sonographic contrast agents are composed of tiny microbubbles that—differently from CT and MR contrast media—are confined in the intravascular space and thus cannot be used to evaluate vascular permeability. The development of second-generation sonographic contrast agents, which can be scanned using a low mechanical index and the advances in contrast detection technology permit to show the lesional vascularity in real time with the high temporal and spatial resolution offered by gray-scale sonography and to provide a quantitative evaluation of tissue blood flow and tissue blood volume (Fig. 1). In conclusion, functional imaging can be used not only as a useful mean of following-up the effects of treatments on tumors, but also as a predictive factor of success of a therapy.21 Nevertheless, in clinical practice these applications are not so diffuse.23-27

MR Diffusion Imaging

MR diffusion imaging distinguishes water molecules that freely diffuse in tissue from water molecules with restricted diffusion. Intracellular water motion is much more restricted due to the presence of multiple structures (membranes, organelles and cytoskeleton), compared to extracellular water motion; as a result, the diffusion coefficient is considered to be a representation of the relation between intra and extracellular water.28 Viable tumors are highly cellular and these cells have intact membranes that restrict the motion of water molecules and cause a low value of the diffusion coefficient. On the other hand, necrotic cells have increased permeability, allowing for free diffusion of water molecules and an increase in diffusion coefficient value (Fig. 2).29 In preclinical drug studies, using animal tumor models, the use of diffusion MR showed early an evident increase of the apparent diffusion coefficient (ADC)—associated to tumoral necrosis—after antiblastic drugs administration and subsequently a decrease of the ADC—connected with the relapse of the disease confirmed by the histological examination.30 In vivo, on humans, diffusion-weighted MR imaging has been used successfully to assess response to radiation or systemic chemotherapy in patients with brain31 and breast cancer32 and is now under investigation for abdominal applications.33-38

MR Spectroscopy

MR Spectroscopy gives information about tissue molecolar components. Initial applications were in the field of brain tumors, but this technique was used also for others tumours (colon, breast, prostate).39 MR Spectroscopy can virtually be performed on all clinical scanners equipped with the appropriate softwares and coils. MR Spectroscopy doesn’t localize the origin of the signal; for this reason, it must be performed along with traditional imaging to couple morphologic and metabolic information. Hydrogen 1 (1H) and Phosphorus 31 (31P) are the two most frequently used nuclei for

286

Recent Advances in Liver Surgery

Figure 1. CEUS. Perfusion study. A) US: basal B-mode image of a hepatic tumor (arrows). B) US: the same image after contrast agent administration and stationary tissues signal suppression. A ROI is positioned on the target lesion to take out the data about tissue blood volume and tissue blood flow. C) The data are reproduced on a time-enhancement curve in order to obtain the following parameters: • PEAK: maximum value of enhancement; • TTP (time to peak): time from contrast agent arrival to the maximum value of enhancement; • RBV (regional blood volume): proportional to the area under the curve (AUC), calculated using the integral of the curve; • RBF (regional blood flow): ratio of RBV and MTT (medium time transit necessary for a molecule to travel across the capillary bed of the tissue).

biological studies; they are ubiquitous in nature. Based on the surrounding molecular environment, nuclei resonates at slightly different frequencies, allowing evaluation of the molecular components of tissues. Results are displayed on a spectrum showing a series of peaks: the different peaks correspond to different metabolites (creatine, phosphocreatine, choline and lipids) and the height of the peaks is proportional to the metabolic concentration in the sampled tissue. Creatine and phosphocreatine are components of the energy metabolism; choline is involved in membrane synthesis and metabolism. These molecules are involved in the cellular processes linked to cellular turnover and malignant transformation (for instance, tumours shows frequently a high choline rate).20

Response Evaluation Criteria in Hepatocellular Carcinoma

287

Figure 2A-B. MR. Concept of diffusion. A) Restricted diffusion: in the scheme a tissue volume that contains a lot of cells with intact membranes and vessels is presented. Water molecules (arrows) that are in the intracellular, extracellular and intravascular environment, contribute to MR signal. The diffusion is limited, because cell membranes restrict the passage of water molecules and cause a low value of the diffusion coefficient. B) Free diffusion: the tissue volume contains fewer cells with damaged membranes. In this case the relative increase of extracellular environment allows for a greater free diffusion of water molecules; besides damaged cell membranes permit the passage of water from extracellular to intracellular compartment and the diffusion coefficient value increases.

In vivo MR Spectroscopy is quite difficult to perform and it is characterized by poor capability to distinguish the peaks of metabolites due to factors such as the low magnetic field strengths (when compared with in vitro studies), the effects of magnetic susceptibility and patient motion.40 In vivo MR Spectroscopy has been used more with diagnostic aim than to monitor response to the treatment with anti-tumorals;20 as for the liver, in particular, has been used to classify patients with chronic liver diseases,41-42 to monitor response to treatment with interferon and ribavirin41 and to follow up the response to the treatment in tumoral patients.38,43-45

Positron Emission Tomography

Positron Emission Tomography with radiolabeled 18F-2-Fluoro-2-deoxy-D-glucose (FDG-PET) is a nuclear medicine technique able to give metabolic information. 2-Fluoro-2-deoxy-D-glucose labelled with 18Fluorine (ß-emitter) is an analogue of glucose that is captured by cells active from a metabolic point of view. Malignant cells capture huge quantity of FDG due to an intense metabolic activity along with overexpression of transmembrane carriers of glucose; in particular, it was shown that FDG uptake—that is possible to quantify with a parameter called standardized value of uptake (SUV)20—is proportional to proliferation and number of viable cells within a tumor.46 The system can be coupled with a CT as to combine metabolic information (PET) and morphological information with the high spatial resolution of CT (PET-CT); moreover, the combination of the metabolic parameter of PET with the perfusional one of the functional CT gives the power of an advanced characterization of tumour behaviour.47 A large number of studies was published underlining PET utility to evaluate tumor response to therapies; these studies show that metabolic activity of tumors changes earlier than their size; in addition, the very variable methodology used is no much comparable.20 For that reason the European Organization for Research and Treatment of Cancer (EORTC) in 1999 established the guidelines on response evaluation to treatment with FDG-PET, by giving definition of metabolic criteria too (complete or partial metabolic response; progressive or stable disease from the metabolic point of view).46

Contrast Enhancement

Morphological imaging techniques (CT, MR, US), thanks to the possibility of a multiphasic study after contrast administration, are able to evaluate the effectiveness of tumors treatment,

288

Recent Advances in Liver Surgery

Figure 3. HCC nodule with 3 cm diameter at VI hepatic segment. CT. A) Basal scan: an almost isodense lesion, roundish in shape, localized under the capsule. B) Arterial phase: the lesion shows homogeneous hyperdensity compared with surrounding liver tissue, in relation to the rich contrast agent accumulation. C) Portal phase: the lesion becomes hypodense because of initial wash-out of the contrast agent and normal contrast agent accumulation in the healthy surrounding tissue. D) Late phase: the lesion is returns isodense, compared with the surrounding tissue.

in particular of the highly perfused ones, that accumulate the contrast agent avidly during the postcontrastographic early phase (so called arterial phase); in particular, we have to remember that HCC is usually characterized by a conspicuous enhancement in the arterial phase and a more or less rapid wash-out of the contrast agent in the portal phase and in the equilibrium phase (Fig. 3-4).48 The tumor response to treatment is evaluated on the basis of enhancement degree: the absence generally means a success, with a complete tumoral necrosis; the persistence of some foci of enhancement within the lesion means only a partial success, since tumoral viable islets continue to uptake contrast medium. Contrast enhancement, displayed with morphological imaging, is a commonly used criterion to evaluate the HCC response to the treatment, suitable enough to clinical demand; moreover it is hoped that—in the next future—it could be supported by functional and metabolic evaluations, able to give more reliable and earlier information.

Follow-Up of HCCs Treated with TACE

Intraarterial chemotherapy aims to increase the concentration of anticancer drugs within the tumor reducing toxicity to other organs; the use of iodized oil (Lipiodol) in combination with a chemotherapeutic agent (anticancer-in-oil emulsion) further increases the duration of cancer cell

Response Evaluation Criteria in Hepatocellular Carcinoma

289

Figure 4. Two HCC nodules with 1.5 cm diameter at VII hepatic segment. MR, T1 weighted sequences. A) Basal scan: the two lesions (arrows) appear slightly hypointense, compared with the surrounding tissue. B) Arterial phase: the lesions shows a homogeneous hyperintensity compared with the surrounding tissue, due to the rich contrast agent accumulation. C) Portal phase: the lesions persist hyperintense in respect to the surrounding tissue. D) Late phase: the lesions (arrows) appear hypointense in respect to the surrounding tissue.

exposure to the drug; in fact, the iodized oil droplets deposited in the tumor—having no Kuppfer cells—disappear at a slower rate compared with those deposited in the normal liver tissue.49 Arterial embolization creates necrosis by inducing tumor ischemia, since the blood supply for HCC comes from arteries while nontumoral hepatic tissue is mainly supplied by the portal vein. The two procedures can be combined in TACE, that is the treatment of choice of large HCCs or multinodular HCCs.50 The most recently technological development, with the impact of a C-arm CT (that is a combination of a digital subtraction angiography and a CT) allows to evaluate the success of intraarterial procedures immediately at the end of the treatment, before remove the patient from the angiographic table (Fig. 5): the preliminary results, reported by Wallace et al,51 are considered satisfactory because C-arm CT provided additional information that changed the management of the patients in 19% of cases, with an acceptable increase of the procedural time (only 18 minutes).

290

Recent Advances in Liver Surgery

Figure 5. TACE of multifocal HCC. A) Preprocedural angiography: super selective catheterism of left hepatic artery shows three hypervascularized nodules, located at IV segment. B-C) C-arm CT at the end of the treatment with TACE, axial (B) and coronal (C) images: homogeneous accumulation of Lipiodol inside the two greater embolized nodules, sign of a correct treatment (B). The third smaller nodule opacified by Lipiodol, not visible in the axial image, is seen in the coronal plane (C).

Moreover, it is established that the first imaging control (CT, MR) of the effectiveness of the treatment is made usually a month after the treatment. At unenhanced CT, lesion appears as highly hyperattenuating area compared with nontumors liver tissue, from which iodized oil is rapidly washed out. The patterns and the Lipiodol distribution are useful to assessing the TACE therapeutic effects: a complete and homogeneous concentration of Lipiodol is usually associated with a favourable response to treatment; a focal defect of accumulation of iodized oil in the mass suggests the presence of viable cells (Fig. 6A-B).52 In the study of Castrucci et al,53 the presence of homogeneous accumulation of Lipiodol at CT corresponded almost constantly to complete necrosis at histologic evaluation; furthermore, the focal absence of Lipiodol in the lesion is not always expression of persistent disease, because sometimes it corresponds to non vital tissue at histologic evaluation: this fact is due to necrotic tissue portions already present in the tumor before the treatment (Fig. 7A).53 The multiphasic CT study is better, because necrotic tissue on contrast-enhanced CT does not show contrast enhancement (Fig. 7B-C), whereas enhancement is observed in residual tumor (Fig. 6C), in particular in arterial phase; however, it can be difficult to evaluate contrast enhancement in a tumor with partial retention of iodized oil on contrast-enhanced CT because of the beam-hardening artefacts produced by the high attenuation of iodized oil.54

Response Evaluation Criteria in Hepatocellular Carcinoma

291

Figure 6. TACE. CT: inhomogeneous distribution of Lipiodol. A) Before the treatment (arterial phase): hypervascularized HCC nodule at VIII hepatic segment. B) Follow up CT at 1 month after TACE (basal scan): poor and inhomogeneous Lipiodol accumulation in the treated nodule. C) Follow up CT at 1 month after TACE (arterial phase): intense enhancement around the Lipiodol accumulation, corresponding to persistence of viable tumoral tissue.

The RECIST criteria do not correlate with the tumor response to the treatment because, as it was demonstrated by the study of Takayasu et al52 in 41 patients—the rate of tumor size reduction measured on CT is not correlated with the therapeutic effects of TACE: this lack of correlation may be explained because the feeding arteries and sinusoids of HCC are completely embolized and obstructed, with the lesion being totally necrotic; however, the resorption of necrosis—and thus volume restriction—are very slow.52 MR imaging has a specific advantage over CT in the evaluation of the HCC response to TACE: in fact, the influence of the intra-tumoral retention of iodized oil on MR signal intensity is minimal;54 therefore, the identification of persistent neoplastic tissue within the treated tumors may be easier to detect on contrast-enhanced MR images.55 At short-term follow-up, we observe an increase in lesion signal intensity on unenhanced T2-weighted images due to the presence of an intra-lesional hemorrhagic component related to the procedure; at subsequent follow-up, the successfully treated lesions show a hypointensity T2, due to coagulative necrosis; persistence of hyperintensity T2 can be due to a neoplastic focus. Moreover—on the basis of unenhanced exam alone—it is sometimes difficult to distinguish between viable cells and necrotic tissue.54 On postcontrast T1-weighted images, a total lack of

292

Recent Advances in Liver Surgery

Figure 7. TACE. CT: inhomogeneous distribution of Lipiodol. A) Follow up CT at 1 month after TACE (basal scan): roundish hyperdense area with 5 cm diameter, due to a selective Lipiodol accumulation, at II hepatic segment; focal accumulation defects are present at the nodule periphery, in particular on lateral side. B) Follow up CT at 1 month after TACE (arterial phase): the study does not demonstrate enhancement of focal Lipiodol accumulation defects. The lack of enhancement means success of the treatment; the focal Lipiodol absence is due to necrotic tissue portions already present in the tumor before TACE. C) Follow up CT at 6 months after TACE (arterial phase): the lesion, in which focal Lipiodol accumulation defects are still present on lateral side, does not show enhancement and is smaller in size. In the next surrounding tissue a new small hypervascularized HCC (arrow) can be seen.

enhancement is observed in the necrotic lesion, whereas its persistence suggests generally foci of viable tumor. Rarely, however, areas of enhancement are found at the periphery of the nodule and they are correlated with perilesional inflammatory tissue.53,56 TACE does not typically cause an intense reaction at the periphery of the tumor as RFA (see next paragraph), but tissue granulation still remains a potential confounding factor when evaluating MR images,36 since also contrast-enhanced MR is unable to distinguish between viable tumoral cells and reactive granulation tissue.53 Contrast enhanced ultrasound (CEUS) is less accurate than CT and MR;57 it can be useful in selected cases to detect residual or recurrent disease, to complete the treatment of residual disease post-TACE with echo-guided techniques (for example ethanol injection).57 MR diffusion imaging can quantify tumor necrosis after TACE, as demonstrated in a rabbit model58 and in humans.36-38 In particular, Kamel et al37 studied 38 patients affected by HCC before and after TACE: mean tumor ADC increased after TACE by 20%, whereas ADC remained unchanged in nontumorous liver. Diffusion-weighted sequences however, for

Response Evaluation Criteria in Hepatocellular Carcinoma

293

Figure 8. RFA. CT: HCC nodule at IV segment treated successfully. A) CT before the treatment (arterial phase): HCC nodule, with 2.5 cm diameter, at IV hepatic segment with rich contrast agent accumulation. B) Follow up CT at 1 month after RFA (arterial phase): the treated lesion appears hypodense (related to necrosis); the size is apparently smaller than it was before the RFA, in relation to the presence of perilesional hyperdense ring, sign of inflammation. C) Follow up CT at 3 months after RFA (arterial phase): the hypodense area appears greater, due to peripheral inflammation disappearance. Scar retraction of hepatic margin is present. D) Follow up CT at 2 years after RFA (arterial phase): sensible shrinkage of the lesion that persists hypodense. Perihepatic ascites is present.

their lower resolution, can be used on lesion larger than 2 cm; furthermore, they are not useful to evaluate lesions near the hepatic dome, because of magnetic susceptibility effects correlated with the air of lungs; finally these sequences can be obtained only in patients who are able to breath-hold. Also Chen et al38 in their experience studied only large HCC (over 5 cm in diameter) with this technique. Diffusion alone, at the moment, is not sufficient for the assessment of therapeutical response and should be performed together with contrast-enhanced multiphasic sequences.37 An attempt to use MR Spectroscopy in vivo to study metabolite change of HCC before and after TACE was made by Kuo et al;44 eight lesions were evaluated on a 3-Tesla scanner before and two to five days after TACE, showing decrease of choline and increase of lipid concentration after treatment, with a significant decrease of ratio choline-lipids. These findings, confirmed by other Authors,38,43,45 demonstrate that in vivo proton MR spectroscopy is feasible, but at present further studies are necessary to validate the technique on a larger population.38,44 Some studies have demonstrated the value of FDG-PET to monitoring HCC treatment.59-61 In the study of Torizuka et al61 32 HCCs were studied with FDG-PET after TACE to evaluate the residual metabolic activity; the PET results were compared with CT and histological findings. The SUV of viable tumors was significantly higher than one of nonviable tumors; when compared to CT, the PET results showed a better correlation with the histological findings. It is worth remembering that PET has limited spatial resolution and therefore tumors smaller than 5 mm cannot be detected accurately; in addition, respiratory movements of the patients can create artefacts.62

Follow-Up of HCCs Treated with Radiofrequency Ablation

Radiofrequency thermal ablation (RFA) is a percutaneous technique that uses RF waves to induce thermal ablation of hepatic malignancies; this technique has been developed to overcome the limits of percutaneous ethanol injection, particularly in the treatment of hepatic metastases. An alternating current flows from the active electrode to the tissue; ionic agitation is produced and it results in heat production able to cause coagulative necrosis of small tumors.63 With the development of expandable multi-tines needles and high-power generators, volume of necrosis up to 5 cm can be obtained with a single-probe insertion.64

294

Recent Advances in Liver Surgery

Image interpretation immediately after the procedure is challenging; therefore a deep knowledge of time-related changes of the treated area and the surrounding normal parenchyma is important to evaluate the therapeutic response of hepatic tumors treated by RFA.65,66 Multiphase contrast-enhanced CT is the exam mostly used for the follow-up of patients after RFA.67,68 Since the ablative treatment leads to disruption of tumor vascularization, absence of contrast enhancement is considered to be indicative of complete tumor necrosis (Fig. 8A-C); any focal enhancement, usually at the boundary of the ablated lesion, should be considered indicative of residual (whether located along the inner edge: (Fig. 9) or recurrent tumor (located along the outer edge of the ablated lesion).69 At immediate follow-up, a peripheral, generally uniform in thickness, rim enhancement resulting from reactive hyperemia around the treated area—that represents inflammatory reaction to heat injury—may be seen at CT and it usually no more present after two to three weeks (Fig. 10). The finding of a wedge-shaped (or sometimes nodular) area of increased enhancement during the arterial phase next to the treated lesion is to ascribe to a hyperperfusion abnormality due to an artero-venous shunt caused by the treatment; this finding doesn’t cause problems of differential diagnosis with residual or recurrent HCC, because the artero-venous shunt becomes isodense with the surrounding parenchyma in portal and late phase.67 At immediate follow-up, very small air pockets are visible in the ablated area, usually no longer detectable at 1 month control (Fig. 11); these air bubbles are a consequence of tissue necrosis (appreciable also after TACE) or they are introduced along the needle insertion path,67 but they are not indicative of abscess that present extensive air pockets with or without air-fluid levels.65,70 Therefore, it is common opinion that first follow-up exam should be performed at least 4 weeks after the procedure when the findings previously mentioned—especially peripheral enhancement— are usually disappeared.67 Next exams are performed every 3 months—along with α feto-protein dosage—till the end of the first year after the treatment;66 if recurrency or new nodules do not appear, subsequent follow-up is usually performed every 6 months.71 Obviously, in doubtful cases, follow-up may be more frequently performed.66 At first month CT, almost all lesions are increased in size when compared with pretreatment exam;67 this increase is indicative of RFA success, because it is better to extend necrosis to healthy surrounding parenchyma for 5 mm-1 cm (safety margin);67 during subsequent follow-up, lesions show gradual diameter reduction (Fig. 8).65 In particular, a recent study has demonstrated that, when CT images obtained at 48 hours and 15 months after the treatment are compared, there are statistically significant differences between mean diameter at 48 hours and 15 months.69 On the

Figure 9. RFA. CT: postablation tumoral residual tissue. A) CT before the treatment (arterial phase): hypervascularized HCC nodule at IV segment under the diaphragm with 2.5 cm diameter. B) Follow up CT at 1 month after RFA (arterial phase): the lesion appears hypodense (result of the treatment); at the anterior margin (inner edge) a solid tissue, with semilunar morphology and rich contrast agent accumulation, is present, expression of tumoral residual tissue.

Response Evaluation Criteria in Hepatocellular Carcinoma

295

Figure 10. RFA. Early control CT post ablation: “peripheral rim enhancement”. A) CT before the treatment (arterial phase): small HCC nodule hyperdense compared with surrounding tissue. B) Early control CT (2 weeks after RFA, arterial phase): complete necrosis of the lesion, that appears hypodense and reveals an increase in size compared with the pre RFA examination, corresponding to extension of the treatment to healthy surrounding tissue (safe margin); a peripheral enhanced ring is present, due to inflammatory reaction.

other hand, a persistent size increase is usually a sign of neoplastic recurrence; besides, it is associated with hypervascularized peripheral nodules (sometimes absent in metastases).69 In addition, the absence of contrast-enhancement in the ablated lesion at short-term follow-up (within 3 months) does not always indicate successful treatment, since later follow-up studies (at least 12 months) can demonstrate tumor regrowth at the periphery of the ablated lesion.67 On the whole, the absence of enhancement on 12 month imaging follow-up and a progressive size reduction of the ablated lesion means high probability of healing (Fig. 8D).72,73 Unenhanced T1- and T2-weighted MR after RFA reveals markedly heterogeneous signal intensity within the ablated lesion, that is most likely caused by an uneven evolution of the necrotic area and the host response to thermal damage.74 For the evaluation of therapeutic response, the use of a contrast-enhanced study is recommended—as for CT—and moderate hypo-intensity on unenhanced T2-weighted images associated with absence of enhancement on early contrast-enhanced T1-weighted images is reliable for complete tumor necrosis.75 However, contrast-enhanced MR imaging too is unable to distinguish between viable tumoral cells and reactive granulation tissue, that is often noted at the periphery of the tumor, resulting in a vivid enhancement. MR may have an ‘‘edge” over CT in the early detection of local regrowths due the high sensitivity of T2-weighted imaging,75 but this superiority seems to exist in controls after RFA of hypovascular metastases rather than in HCCs. Local failure rates (residual disease or local recurrence) can be high after RFA of hypervascular liver lesions (1.3-50%: Figs. 9, 11, 12);76-79 the ability to detect residual disease in real time immediately after the ablation procedure, in order to retreat the patient in the same session, may reduce the number of these failures. CT or MR are unfeasible while RFA is being performed and must be posticipate at least on the following day; CEUS would be an ideal technique for real-time monitoring of RFA procedures,

296

Recent Advances in Liver Surgery

Figure 11. RFA. Early control CT post-RFA: intralesional “air pocket”. A) Follow-up CT at 1 month after RFA (arterial phase): wide hypodense area due to treatment; two hypervascularized nodules are seen, corresponding to tumoral residues on the lateral and medial side (arrows); a second RFA session is planned for these ones. B) CT the day after the second treatment because of severe abdominal pain (arterial phase): minute air pocket is detected inside the lesion (arrowhead); of the two treated tumoral residues, the medial one still shows enhancement (arrow). C) Follow-up CT at 1 month after RFA (arterial phase): disappearance of the small air bubble; small tumoral residue persists on the medial side (arrow), expression of incomplete treatment.

because ultrasound is the primary method of guiding RFA and could thus be used quickly and efficiently without the patient’s having to be moved.

Response Evaluation Criteria in Hepatocellular Carcinoma

Figure 12. Legend on following page.

297

298

Recent Advances in Liver Surgery

Figure 12, viewed on previous page. RFA. Treatment of tumoral recurrence under US guide. A) Follow up CT at 6 months after RFA (arterial phase): small tumoral hyperdense recurrence at VII segment (arrows), of which a second treatment is planned. B-C) US before RFA: the nodule is poorly visible at basal examination (B: arrows); it is much better recognizable because of its rich enhancement after contrast agent administration (C: arrows). D-E) US immediately after RFA: the lesion is not visualized either at basal examination (D) or after contrast administration (E), since it is hidden by gas, hyperechogenic with a clear posterior acoustic shadow (arrows). F) Follow up CT at 1 month after RFA (arterial phase): the lesion appears hypodense in relation to its complete necrosis.

During the treatment, US can reveal a progressively increasing hyperechogenic cloud corresponding to gas microbubble formation and tissue vaporization appears around the needle that may persist for some minutes; this area of acoustic shadowing, developed around the needle because of gas formation secondary to thermal effects, severely limits sonographic visibility. Conventional colour and power Doppler sonography are too insensitive to detect tumor vascularity reliably; the introduction of contrast sonographic agents has slightly increased performances of Power Doppler;80,81 contrast agents, together with contrast-specific imaging techniques such as pulse inversion have increased sensitivity in detecting residual vascularization (Fig. 12B-C).82,83 Dill-Macky et al84 compared the utility of immediate postprocedural CEUS (within 1 hour after the procedure) with that of delayed enhanced sonography, CT and MR (within 2 weeks to 1 month) in assessing the success of RFA of 22 HCCs. Immediate postprocedural CEUS, despite low sensibility (60%), showed high specificity (94%) and good positive predictive value, so that CEUS can be proposed as a guide for completion of the therapy when residual disease is detected. These benefits, however, must be balanced against the technical difficulties and imaging artefacts that can be encountered soon after the procedure, that are responsible for a minor accuracy in detection of residual disease than either delayed CEUS or CT or MR (Fig. 12D-F). In another recent study,85 CEUS performed within 24 h after RFA showed false negatives (detection of less than 30% of patients with residual disease) as well as false positives, so that CEUS at 24 hours was judged useless in the routine evaluation of the response of percutaneous ablation; probably, gas inside the tumor and posttreatment peritumoral inflammation could explain these insufficient results. On the contrary, in the same series of patients, CEUS at 1 month showed sensitivity of 96.6%, specificity of 90.9% in assessing the therapeutic response after percutaneous treatment when compared with the 1-month CT, considered by the Authors as the gold standard.85 Accordingly, CEUS after 1 month could replace CT scan as imaging modality to define initial

Figure 13A-B. Radioembolization with Y-90. CT (Courtesy of Doctor R. Salem). A) CT before treatment (arterial phase): hypervascularized HCC nodule at left hepatic lobe, with 4 cm diameter. B) Follow up CT at 24 months after a single radioembolization treatment with Y-90 (arterial phase): complete necrosis of the lesion, that appears hypodense and much smaller; retraction of left hepatic lobe is present.

Response Evaluation Criteria in Hepatocellular Carcinoma

299

response to therapy, with the advantage of being less expensive and less time-consuming;86 however, CEUS is not optimal for screening the rest of the liver, where a large proportion of recurrences appear. Screening all the liver with CEUS would require repeated injections of the contrast agents to allow proper examination of all hepatic segments and, for this reason, it is clearly most cost-effective than CT (Fig. 7C). Therefore, CEUS is an useful tool to evaluate response to percutaneous ablation, but CT will still play a major role in the follow-up of those patients.71 To the best of our knowledge, at the moment, there are no specific studies addressing the application of MR diffusion and MR Spectroscopy for the evaluation of response after RFA of HCCs. The literature concerning FDG-PET imaging and RFA for liver primary tumors is very limited. In a preliminary study, Anderson et al87 evaluated 13 patients with 14 hepatic lesions (12 metastases and 2 HCCs) treated with RFA and demonstrated that FDG-PET was superior to anatomic imaging in the surveillance of these patients; similar remarks are reported in a study of Blokhius et al88 concerning 11 patients (only 1 HCC and 10 metastases). A recent study performed on 33 lesions (all HCCs) demonstrated higher sensibility of detection rate of FDG-PET than CT in detecting recurrence at 2-year follow-up (92% against 75%);89 this paper indicates that FDG-PET could detect recurrence earlier than CT; however, further studies are still necessary on larger population to confirm these preliminary results.89

Follow-Up of HCCs Treated with Other Percutaneous Ablative Techniques

Other percutaneous minimally invasive techniques are available for the treatment of primitive hepatic malignancies. Percutaneous ethanol injection has been widely used in the years 80s and 90s, but its major limit—that is high rate of recurrences77,90—induced many centres to leave this procedure for RFA. Laser, micro-waves, cryoablation are more laborious techniques and they haven’t showed real advantages in term of survival.91-94 In addition, when compared with laser and micro-waves, RFA is cheaper and can achieve bigger volume of necrosis with a single probe insertion, simplifying the procedure and reducing the necessary time; cryoablation can achieve wider areas of necrosis but it requires accesses of major diameter, thus raising the possibility of complications.95 Therefore, these techniques are not widely used in routine clinical settings, but only in selected centers; furthermore, criteria for the evaluation of tumor response are not different from the ones used for RFA (Figs. 8-9).70,96 For these reasons these methods are not discussed in details in this chapter.

Follow-Up of HCCs Treated with Radioembolization

Transarterial radiation therapy with 90-Yttrium (Y) incorporated into glass microspheres has been approved by the U.S. Food and Drug Administration97 for the management of unresectable multifocal HCC, at the presence of portal vein thrombosis too. This technique delivers high radiation doses to tumor sparing normal liver and is therefore particularly appealing for patients with HCC and low hepatic reserve because of underlying cirrhosis. The physiologic mode of action would appear to be entirely due to the effects of internal radiation rather than ischemia induced by embolization as it happens in TACE. In fact, adequate tissue perfusion is reported to act synergistically with radiation therapy, as well-oxygenated cells are several-fold more sensitive to the tumoricidal effects of radiation than hypoxic cells.98-99 Also in this setting, size criteria used with CT and MR imaging are not reliable at least up to 3 months after the treatment (Fig. 13),100 a too long period for this category of patients. In a recent paper Keppke et al101 studied with multiphase CT and MR—performed 1 month after the treatment and subsequently at every 2 to 3 month intervals—42 consecutive patients with unresectable HCC treated with 90-Y, evaluating tumor response by means of size criteria, necrosis—similar to those already mentioned for TACE and RFA—and combined criteria (dimensional and necrosis). Enhancing peripheral nodule usually represents residual viable tumor tissue, probably a consequence of an irregular distribution of Y microspheres inside the lesion; sometimes, these lesions can decrease spontaneously and disappear for the slow development of necrosis inside the residual tumor.101-102 “Rim enhancement”, frequent after RFA, can be seen soon also after 90-Y

300

Recent Advances in Liver Surgery

therapy in about one third of cases and eventually disappear with time: this finding corresponds to the presence of granulation tissue related to inflammatory reaction.101 Response rate according to size criteria was underestimated compared with that of necrosis or of combined criteria: necrosis, cystic degeneration, haemorrhage and edema can increase the size of responding tumors; therefore, an increase in lesion size is not sufficient evidence for a diagnosis of progressive disease and the addition of necrosis criteria to size criteria is important for detecting favorable response after the treatment with 90-Y. Moreover, the evaluation of response to treatment was possible earlier with the use of necrosis or combined criteria than dimensional ones (1 month versus 4 months). MR diffusion has been applied for the evaluation of response treatment after 90-Y, albeit in 6 patients only.103 Although the mechanism of necrosis induction by 90-Y is not completely known, tumor disruption is nevertheless preceded by changes in the molecular cell structure that result in changes in local motility of water molecules. As a matter of fact, in this study, a statistically significant change of ADC was reported around 45 days after 90-Y treatment, whereas tumor changes revealed with multiphase MR weren’t statistically significant. This study, although based on a small series, showed the feasibility of MR diffusion; however, since “single-shot echoplanar” technique, usually used for its relative insensibility to movement artefacts, can be limited by significant imaging distorsion, by chemical-shift artefacts and low spatial resolution, further technological developments are necessary to improve image quality of diffusion weighted imaging and spatial resolution.103

Conclusions

For the evaluation of clinical success of percutaneous minimally invasive therapies for HCC, conventional anatomical imaging based upon size criteria alone (WHO and RECIST) is not sufficient; therefore, additional criteria provided by new imaging techniques, concerning neoangiogenesis and tumor metabolism, are necessary. In a clinical setting, follow-up is performed by multiphase CT, using—in ambiguous cases at CT—enhanced MR; CEUS can be used immediately after RFA treatments, in order to carry on in the same session any completion or as guidance for US guided treatment of residual tumor identified with CT or MR. MR diffusion and MR Spectroscopy are still in a preclinical phase and further studies on largest series are necessary to validate their preliminary results; this is even more true for perfusion studies. FDG-PET scan is able to provide valuable complementary information, especially when CT or MR findings are ambiguous; FDG-PET should be coupled with CT to combine functional and morphological information; however, the availability of hybrid equipments (PET-CT) is still poor and it constitutes a limit in the widespread use of this technique in routine clinical settings.

References

1. Therasse P. Measuring the clinical response. What does it mean? Eur J Cancer 2002; 38:1817-1823. 2. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatement. Cancer 1981; 47:207-214. 3. Therasse P, Arbuck SG, Eisenhanuer EA et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205-216. 4. James K, Eisenhauer EA, Christian M et al. Measuring response in solid tumors: unidimensional versus bidimensional measurement. J Natl Cancer Inst 1999; 91:6:523-528. 5. Lavin PT, Flowerdew G. Studies in variation associated with the measurement of solid tumors. Cancer 1980; 46:1286-1290. 6. Hilsenbeck S, Von Hoff DD. Measure once or twice—does it really matter? [editorial]. J Natl Cancer Inst 1999; 91:6:494-495. 7. Tran LN, Brown MS, Goldin JG et al. Comparison of treatment response classification between unidimensional, bidimensional and volumetric measurements of metastatic lung lesions on chest computed tomography. Acad Radiol 2004; 11:1355-1360. 8. Trillet-Lenoir V, Freyer G, Kaemmerlen P et al. Assessment of tumor response to chemotherapy for metastatic colorectal cancer: accuracy of the RECIST criteria. Br J Radiol 2002; 75:903-908. 9. Park JO, Lee SI, Song SY et al. Measuring response in solid tumors: comparison of RECIST and WHO response. Jpn J Clin Oncol 2003; 33:533-537.

Response Evaluation Criteria in Hepatocellular Carcinoma

301

10. Partridge SC, Gibbs JE, Lu Y et al. MRI measurements of breast tumor volume predict response to neoadjuvant chemotherapy and recurrence-free survival. AJR 2005; 184:1774-1781. 11. Bolte H, Janke T, Schafer FK et al. Interobserver-variability of lung nodule volumetry considering different segmentation algorithms and observer training levels. Eur J Radiol 2007; 64:285-295. 12. Lencioni R, Bartolozzi C, Caramella D et al. Treatment of small hepatocellular carcinoma with percutaneous ethanol injection: analysis of prognostic factors in 105 Western patients. Cancer 1995; 76:1737-1746. 13. Rossi S, Di Stasi M, Buscarini E et al. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR 1996; 167:759-768. 14. Pacella CM, Bizzarri G, Magnolfi F et al. Thermal ablation in the treatment of small hepatocellular carcinoma: results in 74 patients. Radiology 2001; 221:712-720. 15. Hinshaw JL, Lee FT. Cryoablation for liver cancer. Tech Vasc Interv Radiol 2007; 10:47-57. 16. Itamoto T, Katayama K, Fukuda S et al. Percutaneous microwave coagulation therapy for primary or recurrent hepatocellular carcinoma: long-term results. Hepatogastroenterology 2001; 48:1401-1405. 17. Yamada R, Sato M, Kawabata M et al. Hepatic artery embolization in 120 patients with unresectable hepatoma. Radiology 1984; 148:397-401. 18. Matsui O, Kadoya M, Yoshikawa J et al. Small hepatocellular carcinoma: treatment with subsegmental transcatheter arterial embolization. Radiology 1993; 188:79-83. 19. Geschwind JF, Salem R, Carr BI et al. Yttrium-90 microspheres for the treatment of hepatocellular carcinoma. Gastroenterology 2004; 127:194-205. 20. Fournier LS, Cuénod CA, Clément O et al. Imaging of response to treatment in oncology. J Radiol 2007; 88:829-843. 21. Miles KA. Functional CT imaging in oncology. Eur Radiol 2003; 13:M134-M138. 22. Cosgrove D. Angiogenesis imaging. Ultrasound. Br J Radiol 2003; 76:S43-S49. 23. Sahani DV, Holalkere NS, Mueller PR et al. Advanced hepatocellular carcinoma: CT perfusion of liver and tumor tissue—initial experience. Radiology 2007; 243:736-743. 24. Bellomi M, Petralia G, Sonzogni A et al. CT perfusion for the monitoring of neoadjuvant chemotherapy and radiation therapy in rectal carcinoma: initial experience. Radiology 2007; 244:486-493. 25. Cianfoni A, Colosimo C, Basile M et al. Brain perfusion CT: principles, technique and clinical applications. Radiol Med 2007; 112:1225-1243. 26. Price SJ. The role of advanced MR imaging in understanding brain tumour pathology. Br J Neurosurg 2007; 21:562-575. 27. Lassau N, Chami L, Benatsou B et al. Dynamic contrast-enhanced ultrasonography (DCE-US) with quantification of tumour perfusion: a new diagnostic tool to evaluate the early effects of antiangiogenic treatment. Eur Radiol Suppl 2007; 17:F89-F98. 28. Le Bihan D. Molecular diff usion, tissue microdynamics and microstructure. NMR Biomed 1995; 8:375-386. 29. Ross BD, Moffat BA, Lawrence TS et al. Evaluation of cancer therapy using diffusion magnetic resonance imaging. Mol Cancer Ther 2003; 2:581-587. 30. Thoeny HC, De Keyzer F, Chen F et al. Diffusion-weighted MR imaging in monitoring the effect of a vascular targeting agent on rhabdomyosarcoma in rats. Radiology 2005; 234:756-764. 31. Mardor Y, Pfeffer R, Spiegelmann R et al. Early detection of response to radiation therapy in patients with brain malignancies using conventional and high b-value diff usion-weighted magnetic resonance imaging. J Clin Oncol 2003; 21:1094-1100. 32. Theilmann RJ, Borders R, Trouard TP et al. Changes in water mobility measured by diffusion MRI predict response of metastatic breast cancer to chemotherapy. Neoplasia 2004; 6:831-837. 33. Chen JH, Tsui EY, Luk SH et al. Diffusion weighted MR imaging of the liver: distinguishing hepatic abscess from cystic or necrotic tumor. Abdom Imaging 2001; 26:161-165. 34. Namimoto T, Yamashita Y, Sumi S et al. Focal liver masses: characterization with diffusion-weighted echo-planar MR imaging. Radiology 1997; 204:739-744. 35. Taouli B, Vilgrain V, Dumont E et al. Evaluation of liver diff usion isotropy and characterization of focal hepatic lesions with two single-shot echo-planar MR imaging sequences: prospective study in 66 patients. Radiology 2003; 226:71-78. 36. Kamel IR, Bluemke DA, Ramsey D et al. Role of diffusion-weighted imaging in estimating tumor necrosis after chemoembolization of hepatocellular carcinoma. AJR 2003; 181:708-710. 37. Kamel IR, Bluemke DA, Eng J et al. The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma. JVIR 2006; 17:505-512. 38. Chen CY, Li CW, Kuo TS et al. Early response of hepatocellular carcinoma to transcatheter arterial chemoembolization: choline levels and MR diff usion constants—initial experience. Radiology 2006; 239:448-456.

302

Recent Advances in Liver Surgery

39. Shah N, Sattar A, Benanti M et al. Magnetic resonance spectroscopy as an imaging tool for cancer: a review of the literature. J Am Osteopath Assoc 2006; 106:23-27. 40. Cox IJ, Sharif A, Cobbold JFL et al. Current and future application of in vitro magnetic resonance spectroscopy in hepatobiliary disease. World J Gastroenterol 2006; 12:4770-4783. 41. Lim AK, Patel N, Hamilton G et al. The relationship of in vivo 31P MR spectroscopy to histology in chronic hepatitis C. Hepatology 2003; 37:788-794. 42. Cho SG, Kim MY, Kim HJ et al. Chronic hepatitis: in vivo proton MR spectroscopic evaluation of the liver and correlation with histopathologic findings. Radiology 2001; 221:740-746. 43. Schilling A, Gewiese B, Berger G et al. Liver tumors: follow-up with P-31 MR spectroscopy after local chemotherapy and chemoembolization. Radiology 1992; 182:887-890. 44. Kuo YT, Li CW, Chen CY et al. In vivo proton magnetic resonance spectroscopy of large focal hepatic lesions and metabolite change of hepatocellular carcinoma before and after transcatheter arterial chemoembolization using 3.0-T MR scanner. J Magn Reson Imaging 2004; 19:598-604. 45. Wu B, Peng WJ, Wang PJ et al. In vivo 1H magnetic resonance spectroscopy in evaluation of hepatocellular carcinoma and its early response to transcatheter arterial chemoembolization. Chin Med Sci J 2006; 21:258-264. 46. Young H, Baum R, Cremerius U et al. Measurement of clinical and subclinical tumor response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 1999; 35:1773-1782. 47. Miles KA, Griffiths MR, Comber L et al. Functional imaging of cancer: combining perfusion CT with FDG-PET. Cancer Imaging 2002; 3:17-18. 48. Jeong YY, Yim NY, Kang HK. Hepatocellular carcinoma in the cirrhotic liver with helical CT and MRI: imaging spectrum and pitfalls of cirrhosis-related nodules. AJR 2005; 185:1024-1032. 49. Nakamura H, Hashimoto T, Oi H et al. Transcatheter oily chemoembolization of hepatocellular carcinoma. Radiology 1989; 170:783-786. 50. Lencioni R, Bartolozzi C. Nonsurgical treatment of hepatocellular carcinoma. Cancer J 1997; 10:17-23. 51. Wallace MJ, Murthy R, Kamat PP et al. Impact of C-arm CT on hepatic arterial interventions for hepatic malignancies. J Vasc Interv Radiol 2007; 18:1500-1507. 52. Takayasu K, Arii S, Matsuo N et al. Comparison of CT findings with resected specimens after chemoembolization with iodized oil for hepatocellular carcinoma. AJR 2000; 175:699-670. 53. Castrucci M, Sironi S, De Cobelli F et al. Plain and gadolinium-DTPA-enhanced MR imaging of hepatocellular carcinoma treated with transarterial chemoembolization. Abdom Imag 1996; 21:488-494. 54. Lim HS, Jeong YY, Kang HK et al. Imaging features of hepatocellular carcinoma after transcatheter arterial chemoembolization and radiofrequency ablation. AJR 2006; 187:341-349. 55. Ito K, Honjo K, Fujita T et al. Therapeutic efficacy of transcatheter arterial chemoembolization for hepatocellular carcinoma: MRI and pathology. J Comput Assist Tomogr 1995; 19:198-203. 56. Bartolozzi C, Lencioni R, Caramella D et al. Hepatocellular carcinoma: CT and MR features after transcatheter arterial embolization and percutaneous ethanol injection. Radiology 1994; 191:123-128. 57. Cioni D, Lencioni R, Bartolozzi C. Therapeutic effect of transcatheter arterial chemoembolization on hepatocellular carcinoma: evaluation with contrast-enhanced harmonic power Doppler ultrasound. Eur Radiol 2000; 10:1570-1575. 58. Geschwind JF, Artemov D, Abraham S et al. Chemoembolization of liver tumor in a rabbit model: assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis. JVIR 2000; 11:1245-1255. 59. Okazumi S, Isono K, Enomoto K et al. Evaluation of liver tumors using fluorine-18-fluorodeoxy-glucose PET: characterization of tumor and assessment of effect of treatment. J Nucl Med 1992; 33:333-339. 60. Nagata Y, Yamamoto K, Hiraoka M et al. Monitoring liver therapy with [F18]FDG positron emission tomography. J Comput Assist Tomogr 1990; 14:370-374. 61. Tourizuka T, Tamaki N, Inokuma T et al. Value of fluorine-18-FDG-PET to monitor hepatocellular carcinoma after interventional therapy. J Nucl Med 1994; 35:1965-1969. 62. von Schulthess GK, Steinert HC, Hany TF. Integrated PET/CT: current applications and future directions. Radiology 2006; 238:405-422. 63. Bartolozzi C, Crocetti L, Cioni D et al. Assessment of therapeutic effect of liver tumor ablation procedures. Hepatogastroenterology 2001; 48:352-358. 64. Solmi L, Nigro G, Roda E. Therapeutic effectiveness of echo-guided percutaneous radiofrequency ablation therapy with a Le Veen electrode in hepatocellular carcinoma. World J Gastroenterol 2006; 21:1098-1104.

Response Evaluation Criteria in Hepatocellular Carcinoma

303

65. Lim HK, Choi D, Lee WJ et al. Hepatocellular carcinoma treated with percutaneous radiofrequency ablation: evaluation with follow-up multiphase helical CT. Radiology 2001; 221:447-454. 66. Liamanond P, Zimmerman P, Raman SS et al. Interpretation of CT and MRI after radiofrequency ablation of hepatic malignancies. AJR 2003; 181:1635-1640. 67. Kim SK, Lim HK, Kim YH et al. Hepatocellular carcinoma treated with percutaneous radiofrequency ablation: spectrum of imaging findings. Radiographics 2003; 23:107-121. 68. Lim HK, Han JK. Hepatocellular carcinoma: evaluation of therapeutic responses to interventional procedures. Abdom Imaging 2002; 27:168-179. 69. Filippone A, Iezzi R, Di Fabio F et al. Multidetector-row computed tomography of focal liver lesions treated by radiofrequency ablation: spectrum of findings at long-term follow-up. J Comput Assist Tomogr 2007; 31:42-52. 70. Mitsuzaki K, Yamashita Y, Nishiharu T et al. CT appearance of hepatic tumors after microwave coagulation therapy. AJR 1998; 171:1397-1403. 71. Colagrande S, La Villa G, Bartolucci M et al. Spiral computed tomography versus ultrasound in the follow-up of cirrhotic patients previously treated for hepatocellular carcinoma: a prospective study. J Hepatol 2003; 39:93-98. 72. Choi H, Loyer ME, DuBrow RA et al. Radiofrequency ablation of liver tumors: assessment of therapeutic response and complications. Radiographics 2001; 21:S41-S54. 73. Chopra S, Dodd DG, Chintapalli KN et al. Tumor recurrence after radiofrequency thermal ablation of hepatic tumors. Spectrum of findings on dual-phase contrast-enhanced CT. AJR 2001; 177:381-387. 74. Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques and diagnostic imaging guidance. AJR 2000; 174:323-331. 75. Dromain C, de Baere T, Elias D et al. Hepatic tumors treated with percutaneous radiofrequency ablation: CT and MR imaging follow-up. Radiology 2002; 223:255-262. 76. Chan RP, Asch M, Kachura J et al. Radiofrequency ablation of malignant hepatic neoplasms. Can Assoc Radiol J 2002; 53:272-278. 77. Lencioni R, Allgaier H, Cioni D et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003; 228:235-240. 78. Bonny C, Abergel A, Gayard P et al. Radiofrequency ablation of hepatocellular carcinoma in patients with cirrhosis. Gastroenterol Clin Biol 2002; 26:735-741. 79. Lin SM, Lin CJ, Lin CC et al. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma <4 cm. Gastroenterology 2004; 127:1714-1723. 80. Choi D, Lim HK, Kim SH et al. Hepatocellular carcinoma treated with percutaneous radiofrequency ablation: usefulness of power Doppler US with a microbubble contrast agent in evaluation therapeutic response—preliminary results. Radiology 2001; 221:447-454. 81. Cioni D, Lencioni R, Rossi S. Radiofrequency thermal ablation of hepatocellular carcinoma using contrast-enhanced harmonic power Doppler sonography to assess treatment outcome. AJR 2001; 177:783-788. 82. Meloni MF, Goldberg SN, Livraghi T et al. Hepatocellular carcinoma treated with radiofrequency ablation: comparison of pulse inversion contrast-enhanced harmonic sonography, contrast-enhanced power Doppler sonography and helical CT. AJR 2001; 177:375-380. 83. Wen YL, Kudo M, Zheng RQ et al. Radiofrequency ablation of hepatocellular carcinoma: therapeutic response using contrast-enhanced coded phase-inversion harmonic sonography. AJR 2003; 181:57-63. 84. Dill-Macky MJ, Asch M, Burns P et al. M. Radiofrequency ablation of hepatocellular carcinoma: predicting success using contrast-enhanced sonography. AJR 2006; 186:S287-S295. 85. Vilana R, Bianchi L, Varela M et al. Is microbubble-enhanced ultrasonography sufficient for assessment of response to percutaneous treatment in patients with early hepatocellular carcinoma? Eur Radiol 2006; 16:2454-2462. 86. Nicolau C, Vilana R, Bianchi L et al. Early-stage hepatocellular carcinoma: the high accuracy of real-time contrast-enhanced ultrasonography in the assessment of response to percutaneous treatment. Eur Radiol 2007; 17:F80-F88. 87. Anderson GS, Brinkmann F, Soulen MC et al. FDG positron emission tomography in the surveillance of hepatic tumors treated with radiofrequency ablation. Clin Nucl Med 2003; 28:192-197. 88. Blokhuis TJ, van der Schaaf MC, van den Tol MP et al. Results of radiofrequency ablation of primary and secondary liver tumors: long-term follow-up with computed tomography and positron emission tomography-18F-deoxyfluoroglucose scanning. Scand J Gatroenterol Suppl 2004; 241:93-97. 89. Paudyal B, Oriuchi N, Paudyal P et al. Early diagnosis of recurrent hepatocellular carcinoma with 18F-FGD PET after radiofrequency ablation therapy. Oncol Rep 2007; 18:1469-1473. 90. Lencioni R, Cioni D, Crocetti L et al. Percutaneous ablation of hepatocellular carcinoma: state-of-the-art. Liver Transpl 2004; 10:S91-S97.

304

Recent Advances in Liver Surgery

91. Vogl TJ, Straub R, Eichler K et al. Malignant liver tumors treated with MR imaging-guided laser-induced thermo-therapy: experience with complications in 899 patients (2520 lesions). Radiology 2002; 225:367-377. 92. Pacella CM, Bizzarri G, Cecconi P et al. Hepatocellular carcinoma: long-term results of combined treatment with laser thermal ablation and trancatheter arterial chemoembolization. Radiology 2001; 219:669-678. 93. Shibata T, Iimuro Y, Yamamoto Y et al. Small hepatocellular carcinoma: comparison of radiofrequency ablation and percutaneous microwave coagulation therapy. Radiology 2002; 223:331-337. 94. Jansen MC, van Hillegersberg R, Chamuleau RA et al. Outcome of regional and local ablative therapies for hepatocellular carcinoma: a collective review. Eur J Surg Oncol 2005; 31:331-347. 95. Hinshaw JL, Lee FT. Cryoablation for liver cancer. Tech Vasc Interv Radiol 2007; 10:47-57. 96. Yoshikawa J, Matsui O, Kodaya M et al. Hepatocellular carcinoma: CT appearance of parenchymal changes after percutaneous ethanol injection therapy. Radiology 1995; 194:107-111. 97. Welsh J. Radiographically identified necrosis after 90Y microsphere brachytherapy: a new standard for oncologic response assessment? AJR 2007; 188:765-767. 98. Harrison L, Chadha M, Hill RJ et al. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 2002; 7:492-508. 99. Harrison L, Blackwell K. Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? Oncologist 2005; 5:S31-S40. 100. Salem R, Lewandoski RJ, Atassi B et al. Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (Therasphere): safety, tumor response and survival. J Vasc Interv Radiol 2005; 16:1627-1639. 101. Keppke AL, Salem R, Reddy D et al. Imaging of hepatocellular carcinoma after treatment with Yttrium-90 microspheres. AJR 2007; 188:768-775. 102. Tsuda M, Majima T, Yamada H. Hepatocellular carcinoma after radiofrequency ablation therapy. Dynamic CT evaluation of treatment. Clin Imaging 2001; 25:409-415. 103. Deng J, Miller FH, Rhee TK et al. Diffusion-weighted MR imaging for determination of hepatocellular carcinoma response to Yttrium-90 radioembolization. J Vasc Interv Radiol 2006; 17:1195-1200.

Chapter 22

One Liver for Two:

Split and Living Donor Liver Transplantation for Adult and Pediatric Patients Bruno Gridelli,* Salvatore Gruttadauria, Angelo Luca, Marco Spada, Riccardo Volpes, Wallis Marsh and Amadeo Marcos

Abstract

T

he dramatic gap between need and availability of grafts for patients on liver transplantation waiting lists has prompted some of the most advanced technical evolutions in transplantation surgery. The knowledge derived from liver surgical anatomy, which has been first applied to liver resection for tumors, has been utilized first to reduce the size of the liver procured from adult cadaver donors and adapt it to children with end-stage liver disease. Subsequently, the division of the cadaver liver between adult and pediatric recipients (split liver) and living donor liver transplantation for children, has further increased the efficient use of liver grafts. Both of these techniques have contributed to almost eliminating pediatric waiting list mortality over the last few years. Adult-to-adult living donor liver transplantation has been implemented more recently, but has quickly become an important component of liver transplant programs worldwide, not only in geographical areas where cadaver organ donation in non-existent or has low rate. Adult-to-adult living donor liver transplantation is challenging both from the ethical and technical point of view for the implications of submitting a healthy individual, the donor, to a complex operation with risks for morbidity and mortality that cannot be completely eliminated. In large centers split liver and living donor liver transplantation for children and adults have excellent patient and graft outcomes and greatly contribute to increase the access to the only life saving procedure for patients with end-stage liver disease.

Introduction

The unbalance between the need and availability of liver grafts has represented a powerful stimulus for the development of innovative surgical techniques to increase the pool of organs for transplantation. Since the very beginning of its history, pediatric recipients have had the highest wait list mortality (up to 30-50%) due to the different epidemiology of end-stage liver disease and brain death in children. The main indications to liver transplantation in children are cholestatic and metabolic liver disease and most of these patients need liver replacement within the first two years of life, when their body weight is often below 10 kg. It is exceedingly rare that children of this age suffer from accidents or spontaneous pathologies causing brain death. In the early 80’s, on the basis of the lessons learned from surgical anatomy applied to oncological surgical resection, livers procured from cadaver donors were resected ex-situ to develop a “reduced-size” left lateral *Corresponding Author: Bruno Gridelli—Mediterranean Institute For Transplantation and Advanced Specialized Therapies, University of Pittsburgh Medical Center in Italy, Palermo, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

306

Recent Advances in Liver Surgery

segment graft (segments II and III) of a size that could be transplanted in small children. The right part of the cadaver donor liver was discarded. Reduced-size liver transplantation provided good outcome in children, at the expense of diverting adult cadaver liver grafts away from adult patients whose waiting lists are several times more populated than the pediatric ones. It has been estimated that 2 out 10.000 newborns need liver transplantation in the pediatric age and that, in about 55% of them, liver replacement has to be performed within the first two years of life. Data on the need in adults are more variable between different geographical areas, being influenced by the epidemiology of the main causes of liver failure and vary between 30 and 80 cases per million inhabitants per year. In a country like Italy with 500,000 newborns per year and a population of 55 millions it can be estimated that the liver transplantation need is of 100 pediatric and of between 1650 and 4400 adult cases per year. The number of patients who are actually wait-listed is also influenced by the several factors that affect the referral process. At the end of the ‘80s, the conflict between pediatric and adult wait lists was addressed by further evolutions in the surgical technique of liver transplantation: split liver transplantation (SLT) and living donor liver transplantation (LDLT) that had the common objective of allowing children transplantation without interfering with the transplantation of adult patients. In 1988, Pichlmayr,1 in Hannover and Strong, in Brisbane, showed for the first time that one liver could support the life of two individuals. Pichlmayr divided the liver from a cadaver donor on the back table into two grafts: the smaller for a child—constituted by the left lateral segment—and the larger—an extended right graft comprising segment I and IV to VIII—for an adult patient. Strong reported the procurement of the left lateral segment from a live donor, the mother, and its transplantation in a child with biliary atresia.2 In the following years, LDLT for children quickly spread around the world because of its excellent outcome and because it represented the only option for countries—like Japan and other Asian countries—with no or minimal cadaver organ donation. SLT, on the contrary, did not gain vast acceptance, as the early results were plagued with technical complications and frequent need for retransplantation. Rogiers, in ’95,3 described the in-situ technique of liver splitting: the division of the liver being performed in the heart beating donor. This technical evolution had a dramatic positive effect on the outcome of SLT and, in countries with high donation rates, almost eliminated the need for pediatric live donor liver transplantation.4 Whereas both of these techniques had a great impact on pediatric wait list mortality, which has become minimal in most countries with advanced liver transplant programs, the shortage of grafts for adults kept growing steadily. In 1994, in Japan the first adult-to-adult LDLT was performed by resecting the right lobe of the liver (segments V to VIII). Soon after, programs of LDLT started in several US and European centers. The number of programs offering the option of LDLT to their patients grew constantly until 2002, when a living donor death in New York reversed the trend. More stringent criteria of donor selection and management were implemented following that case and a smaller number of centers with large experience refined the surgical technique, selection criteria and peri-operative care of both donors and recipients. LDLT for adults has been the most recent and challenging—both from a technical and ethical point of view—evolution of liver transplantation which has contributed to reduce donor shortage.

Living Donor Liver Transplantation: Donor Selection and Outcomes

The first patient who was saved by part of the liver donated by a living donor was a child with biliary atresia who received a left lateral segment from the mother in Australia.2 Following that seminal case, living donor liver transplantation (LDLT) prompted an open debate that recognized the procedure as ethically sound, notwithstanding the risk of death and morbidity for the donor.5 The basic principles of live donation are that the potential donor must be medically fit, genetically or emotionally related to the donor, free from any pressure and material interests (financial

One Liver for Two: Split and Living Donor Liver Transplantation

307

Figure 1. Living donor liver transplantation.

or otherwise). In order to reduce as much as possible the risks associated to donor hepatectomy, extensive, multidisciplinary donor evaluation performed on the basis of specific protocols is mandatory. Medical donor’s evaluation is conducted by a physician who acts as the donor’s advocate having as sole objective the physical and psychological safety of the donor.6 A possible stepwise protocol of living liver donor’s evaluation is reported in Fig. 1. Liver biopsy has the objective of discovering pathological conditions which might pose a risk both to the donor and the recipient; fatty liver infiltration is the most frequent pathological finding that contraindicates donation if more than 30% of hepatocytes show steatosis. In some transplant centers, only potential donors with a body mass index (BMI) greater than 25 undergo liver biopsy, on the assumption that in these individuals only there is a significant presence of steatosis. However, also in individuals with BMI below 25, steatosis in up to 33% of the cases has been reported. Furthermore, liver biopsy can show the presence of other pathological conditions which contraindicate liver donation. At our institution 256 individuals underwent evaluation as potential donors and only 80 qualified and donated part of their liver.7 In Figure 2, the reasons for not acceptance as liver donors are reported. Donor mortality is a rare but catastrophic event which has an incidence between 0.13% (for pediatric donation) and 0.2% (for adult donation). Most operative complications are of minor entity and are managed medically. Biliary complications range from minor leaks from the cut surface to major leaks and strictures requiring endoscopic, radiological or surgical interventions. Donors and their family need to be fully informed of the risks of live donor liver donation. Currently, in experienced centers, live liver donation can be considered a safe procedure. Although long-terms studies on the outcome of liver donation are still lacking, it has been clearly shown that in 4 to 8 weeks liver volume returns to almost its original size with no significant alterations of liver function. Most of the donors return to a normal life in a few weeks.

Split Liver Transplantation: The Sharing of a Cadaver Liver

The technique of liver splitting as it is used today by most centers is performed during organ procurement from heart beating, brain dead donors.8,9 Leaving the hepatic vasculature intact, the

308

Recent Advances in Liver Surgery

Figure 2. Reasons for donor exclusions.

liver parenchyma and left bile duct are transected close to the right side of the falciform ligament. The abdominal organs are then perfused through the aorta with cold preservation solution, the left portal and hepatic veins are dived. The right hepatic artery is transected close to its origin from the common hepatic artery and the left lateral segment is removed. The right part of the liver is then excised with the usual technique used for whole liver procurement.10,11 Only cadaver donors without risk factors (age >60 years, hemodynamic instability and steatosis) are considered for liver splitting. The left lateral segment is almost exclusively transplanted in children. Ideally, the ratio between the body weight of the donor and that of the pediatric recipient should be below 12, otherwise the graft might be too large making abdomen closure problematic. Should that occur, abdominal closure can be temporarily performed using a synthetic mesh and postponing definitive closure.12 The extended right grafts (ERG) can be transplanted in adult patients. ERG are still considered marginal grafts and only used for primary transplantation in stable patients.13 However, single center and multicenter reports have clearly shown that the outcome of adult patients transplanted with whole liver grafts and ERG are not significantly different. In centers with large experience, ERGs have been successfully used both for high risk patients (i.e., fulminant liver failure) and retransplantation.14-16 The surgical technique of ERG transplantation is almost identical to the one used for whole liver transplantation with the only exception of the arterial anastomosis when the celiac trunk is procured with the left lateral segment. In this case, the right hepatic artery of the ERG is anastomosed directly to the recipient right hepatic artery. When this is not technically feasible—as it can happen in retransplantation—a jump graft to the infrarenal aorta, using the cadaver donor iliac artery, can be performed. Until very recently, split liver transplant operations were performed using adult donors only.17-19 With increased experience, also livers from pediatric cadaver donors have been successfully split and transplanted in two pediatric recipients of different body weights and ages.20

One Liver for Two: Split and Living Donor Liver Transplantation

309

Left Lateral Segment Transplantation in Children: Technique and Results

The left lateral segment originating from a split liver procurement operation, or living donor hepatectomy, is composed of segments II and III along with the left hepatic vein, left portal vein branch, left hepatic artery and left branch of the biliary duct system. Left lateral segments procured during liver splitting may have the left hepatic artery in continuity with the main hepatic artery and celiac trunk—in some centers, the main hepatic artery and celiac trunk are given to the ERG. In the recipient, the native liver hepatectomy is performed leaving the vena cava intact. The left lateral segment is then transplanted by anastomosing the left hepatic vein to a triangular opening in the front wall of the vena cava at the junction of the three hepatic veins. The portal vein and hepatic artery are then anastomosed in sequence. The biliary reconstruction is obtained by anastomosing the bile duct to a Roux-en-Y that is often already present in children with biliary atresia who underwent a Kasai operation. Vascular and biliary complications have peculiar characteristics and incidence in pediatric split liver transplantation. Biliary strictures and leaks have cumulative incidences as high as 40%, depending on the experience of the center and on the aggressiveness in diagnosing, in particular, biliary stricture that have the risk, if unrecognized, of causing chronic irreversible damage of the graft.4 Percutaneous transhepatic colangiography should be performed whenever a suspicion of biliary obstruction is present; if biliary stricture is confirmed, balloon dilation of the anastomosis and transhepatic external-internal catheter placement can usually solve the problem. The most typical, although fairly rare, complication of left lateral segment transplantation is stricture at the level of the left hepatic vein to vena cava anastomosis. The outflow impairment induces a Budd-Chiari syndrome with ascites, pleural effusion and hepatic function impairment. Balloon dilation of the venous anastomosis is usually successful in re-establishing good blood flow.21 Both LDLT and split liver transplantation have greatly reduced and in some countries almost eliminated, mortality on the waiting list for children with 5 year survival above 80%.4 It has been suggested that LDLT is preferable to split liver transplantation in children, since the genetic relationship between donor and recipient reduces rejection episodes and children can be transplanted before they develop serious complications of liver disease. However, the evidence of the immunological advantage of LDLT is fragile and outcomes of pediatric split liver transplantation can be as good as the ones of LDLT.4

Live-Donor Hepatectomy: Technical Aspects

Live-donor hepatectomy is a complex operation performed in healthy individuals for purely altruistic reasons and should be performed only by surgeons with large experience in liver surgery and after specific training. Some technical aspects of right donor lobectomy, the most frequent type of liver resection performed for LDLT, will be presented here.22 Careful study of the pre-operative imaging data is of paramount importance to properly plan the surgical procedure. The operation is performed through a bilateral subcostal incision with midline extension up to the xyfoid process (Mercedes incision). The falciform ligament is dived and the supra-hepatic vena cava and right hepatic vein are exposed. The gallbladder is removed and through the cystic duct, a cholangiogram is performed to further confirm the anatomy of the biliary tree. The plane of parenchimal transection, medial to the right hepatic vein, is verified with intraoperative ultrasound. The right lobe is mobilized by dividing the ligaments and the small hepatic veins are divided between ligatures. Larger inferior hepatic veins that need to be preserved are dissected free. The right main hepatic vein is dissected free. The hilar structures are then identified and dissected with extreme care to avoid intimal damage to the hepatic artery and avoid devascularization of the bile duct. At this point the parenchimal transection, just right to the middle hepatic vein, is started. During this phase, central venous pressure is maintained at a pressure below 5 mmHg, to minimize bleeding and therefore avoid non-autologous blood transfusion. The parenchimal transection is performed using electrocautery, ultrasonic dissection and the cone-tipped TissueLink device. When the parenchimal transection is completed, the

310

Recent Advances in Liver Surgery

attention is then returned to the hilum and the right bile duct is divided leaving at least 2 mm on the donor side to allow safe suture to prevent strictures and leaks. The right hepatic artery, portal vein and hepatic vein are clamped and quickly divided. The right graft is removed and brought to the back table, immersed in ice-slush and perfused through the portal vein with cold University of Wisconsin solution. The donor operation is completed by suturing the stumps of the bile duct, hepatic artery, portal and hepatic veins. The falciform ligament of the liver is sutured to the anterior abdominal wall to prevent torsion of the left lobe remnant that could cause result in outflow obstruction. Drains are placed and the abdominal wall is closed. Although donors can be easily extubated in the OR, it is preferrable to keep these patients in the ICU for at least 24-48 hours after the operation to carefully monitor vital parameters and reduce as much as possible the risk for any major complication.

LDLT: Technical Aspects of the Recipient Operation

The recipient operation is usually started when in the donor the surgical exploration and cholangiography have confirmed that the operation is technically feasible without undue risks. The recipient hepatectomy needs to be performed in a way that allows safe implantation of the right lobe graft. In particular, the recipient bile duct is dissected free up to the confluence of the right and left branches that can be both used for anastomosis in case of double right duct branches in the right lobe graft (a variation which is found in about 30% of the cases). Also the hepatic artery and portal vein are dissected up to their right and left branches. The native vena cava is dissected free from the liver by dividing between ligatures or clips the small hepatic veins. The middle and left hepatic veins are cut and sutured, while the right hepatic vein is divided after the vena cava is cross-clamped below and above the liver. We prefer to always use veno-venous by pass in recipients of LDLT to maintain the patients as hemodynamically stable as possible without the need for high central venous pressure maintenance during the anhepatic phase which, upon reperfusion, might damage the graft. The implant of the right lobe liver graft is started with the anastomosis of the right hepatic vein to the recipient vena cava. Extreme care is taken to perform an anastomosis as wide as possible to prevent any outflow obstruction. Any large accessory inferior hepatic vein, draining segments VI and/or VII, are re-implanted with direct anastomosis to the vena cava or, more rarely, with interposition grafts. The right branch of the graft portal vein is anastomosed either to the recipient main portal or to the right portal vein branch. The liver is then reperfused and subsequently the right hepatic artery is anastomosed with interrupted stitch suture. The biliary duct anastomosis is still the “Achilles heel” of LDLT. Whenever possible the right bile duct branch or branches are anastomosed directly to the recipient bile duct or ducts over a T-tube. When this is not feasible, a Roux-en-Y needs to be performed.

Imaging in Planning LDLT and Treatment of Post-Operative Complications

Prior to transplantation, it is important to determine the volumes of the right hepatic lobe that will be donated and of the left remnant hepatic lobe, because sufficient liver parenchyma is necessary to maintain an adequate liver function in both the donor and recipient. The liver volume calculation is performed by multidetector CT scan or MRI using commercially available software (Fig. 3). A minimum of 0.8 of calculated graft volume body weight ratio (GVBWR) is usually recommended as minimum cut-off level to avoid the small-for-size syndrome after partial transplantation. The evaluation of vascular anatomy is a key point to plan the surgery and reduce the risk of operative and post-operative complications. During the last years, MR and CT angiography have replaced the more invasive evaluation with digital subtraction angiography of potential healthy donors (Fig. 4A). CT angiography has higher spatial resolution than MRI angiography but is associated with disadvantages such as exposure to ionizing radiation and nephrotoxic contrast material. CT and MR angiography accurately detect anatomic variants such as replaced or accessory hepatic arteries, common trunk of the right and middle hepatic veins, accessory hepatic veins and anomalies of

One Liver for Two: Split and Living Donor Liver Transplantation

311

Figure 3. Pre operative evaluation in LRLD. The evaluation by Multidetector CT showed that the hepatic volumes were adequate to maintain liver function in both the donor and recipient.

the portal vein such as trifurcations. Vascular anomalies have been described in more than 50% of subjects. Furthermore, the recognition and preservation of vascular supply for the segment IV is mandatory to ensure functioning of this segment. Finally, the stenosis of the celiac trunk in the recipient owing to the arcuate ligament may reduce the hepatic arterial flow and cause graft dysfunction and biliary necrosis after transplantation. MR cholangiopancreatography (MRCP) allows a pre-operative detection of abnormalities and anatomic variants of the biliary tract that may complicate resection (Fig. 4B). The detection of a trifurcation anomaly or a dorso-caudal branch of the right hepatic duct that drains into the left hepatic duct are not uncommon findings. In many centers, MRCP has replaced the endoscopic retrograde cholangiopancreatography (ERCP) for the donors evaluation. Liver biopsy remains the gold standard to confirm the presence of steatosis suggested by other imaging evaluation (Ultrasonography, CT, MRI). In our experience, a severe macrovescicular steatosis is not an uncommon contraindication for liver donation (Fig. 5). Imaging is helpful to evaluate the capacity for regeneration after major hepatic resection. Previous data suggested that in most patients the volume of the remnant liver is restored to some extent within 4-8 weeks (Fig. 6). However, the factors that affect liver regeneration are complex and not completely understood. Imaging, interventional radiology and endoscopy play a key role in the early detection and treatment of the complications that occur as a result of split or living related liver transplantation and reduce morbidity and mortality (Fig. 7). The major complications in donors include hematoma, abscess, bile leakage, liver dysfunction and hepatic artery injury. The major complications in recipients include stenosis of the biliary anastomosis, hepatic artery stenosis or thrombosis, outflow obstruction of the hepatic vein anastomosis, stenosis of the portal vein anastomosis, portal vein thrombosis, bile leakage, abscess, rejection and small-for-size graft syndrome. Surgical complications usually develop within 3 months after transplantation and more frequently occur following complex vascular reconstruction or in presence of hypercoagulable state. Vascular complications are initially detected by Color Doppler sonography (turbulent flow at the stenotic tract, low resistance index, high peak flow velocities, or absence of flow) and subsequently confirmed by CT or MR angiography and/or digital angiography. Interventional radiology procedures including angioplasty, placement of metallic stent or thrombolitic therapy represent an alternative to surgical revision of anastomosis,

312

Recent Advances in Liver Surgery

Figure 4. Pre operative evaluation in LRLD. Multidetector CT angiography did not show anatomic variants in hepatic artery, portal vein and hepatic veins. Of note, the artery for the segment IV arises from the LHA. MRCP showed the right posterior duct draining in LHD.

urgent revascularization with thrombectomy or retransplantion for vascular complications (Fig. 8), whereas the percutaneous or endoscopic retrograde biliary drainage can prevent the need for the surgical revision of biliary anastomosis (Fig. 9).

LDLT: Recipient Outcomes

The use of right lobe grafts for LDLT in children and adults was first reported in the early ‘90s by Japanese surgeons. In 1997, the first case of LDLT in one adult using the right lobe was reported in the USA and subsequently, several American and European centers started programs of adult-to-adult LDLT. In a report of the adult-to-adult liver transplantation (A2ALL) consortium from 9 US centers, the one-year graft survival in 385 recipients was 81%. The main factor influencing the outcome was found to be center’s experience. In centers with a less than 20 cases experience, an 83% higher risk of graft failure (P < 0.0045) was reported. The incidence of biliary complication was 30%. In a study comparing the outcome of 764 patients who underwent LDLT with 1470 matched patients receiving cadaveric grafts, two year patient survival was similar (79% and 80%, respectively); however, graft survival of LDLT was significantly worse than the one of cadaveric grafts (64.4% versus 73.3%). At UPMC, the LDLT program is conducted both in the Pittsburgh and Palermo hospitals (Montefiore hospital and ISMETT, respectively) using the same criteria of donor and recipient selection, surgical technique and post-operative management. One year patient and graft survival are currently above 90% and 80%, respectively. The current practice at UMPC is to offer the option of LDLT to patients whose MELD score indicates that they can benefit from the procedure (>12); in patients with advanced liver failure and MELD scores above 30, LDLT is probably not

One Liver for Two: Split and Living Donor Liver Transplantation

313

Figure 5. Pre-operative evaluation in LRLD. Liver biopsy showed severe (>30%) macrovescicular steatosis. Severe steatosis is not one uncommon contraindication for liver resection.

Figure 6. Post operative evaluation. One month after LRLT the hepatic volume increased in donor (left lobe +70%) as well in recipient (right lobe +105%).

314

Recent Advances in Liver Surgery

Figure 7. Post operative evaluation after partial liver transplantation. Multidetector CT angiography showed patent hepatic artery and portal vein. Ultrasonography showed normal resistance index in hepatic artery and hepatopetal flow in portal vein.

the best option. Although right lobe grafts procured from living donors have not suffered any of the damages associated with brain death, the volume of functioning parenchyma that they provide is sub-optimal and the risk of primary nonfunction or delayed graft function high.

The Small-For-Size Syndrome

The history of partial liver transplantation has its roots in the need to provide small grafts for children. This goal has been successfully obtained both by split liver and LDLT for children.

Figure 8. Post operative evaluation after partial liver transplantation. a) MDCT angiography with 3D reconstructions showed a severe stenosis at the hepatic artery anastomosis, b) angioplasty was performed using 4-mm balloon catheter, c) a final arteriogram showed good caliber of the anastomosis with a trans-stenotic gradient decreased to 5 mmHg.

One Liver for Two: Split and Living Donor Liver Transplantation

315

When LDLT moved in the adult patients’ arena, it became quickly evident that the problem to overcome was exactly the opposite. In adults, the weight of the liver is about 2% of the body weight. Since the weight of the right lobe is about 60% of the total liver weight, it is clear that by procuring a right lobe from an adult and then transplanting it in an adult of about the same size, the graft-to-recipient weight ratio (GRWR) is often below the physiologic ratio. Early reports from LDLT series indicated that a GRWR below 0.8 is associated with lower patient survival rates. Ascites, cholestasis, poor coagulation, eventually progressing to overt liver failure are the clinical manifestations of what is currently called “small-for-size syndrome” (SFSS).23 In order to better understand the causes and consequences of SFSS, we need to briefly recall some concepts of hepatic blood flow. The liver has a double vascular inflow through the portal vein and hepatic artery. The total blood flow tends to remain fairly constant, in relation with liver volume and the portal and arterial flows vary in opposite direction to maintain the total blood flow stable. The transplantation of a smaller than “ideal” liver graft, exposes the graft itself to a higher portal blood flow. The portal hyper-perfusion causes vasoconstriction of the intra-hepatic branches of the hepatic artery and a relative out-flow obstruction. The latter manifests itself with liver congestion and ascites, one of the early manifestations of SFSS. The hepatic artery flow reduction induces

Figure 9. Post operative evaluation after partial liver transplantation. CT scan showed perihepatic fluid collection. The PTC confirmed the biliary leakage; a 6.6 F biliary catheter was placed for internal-external biliary drainage. Two months later there was the complete resolution of biliary leakage and the catheter was removed.

316

Recent Advances in Liver Surgery

ischemic damage to the liver and, in particular, to the biliary system whose blood flow is totally dependent on the arterial blood. The alterations of hepatic blood flow have a negative impact on the progression of liver regeneration that always follows LDLT, therefore impairing liver function with varying degrees of severity. Furthermore, the biliary system ischemic damage can cause biliary sepsis and probably favors the occurrence of the biliary reconstruction complications that plague the post-operative course of LDLT. There is growing evidence that, however, the occurrence of SFSS is not only linked to the GRWR but also to the severity of portal hypertension. Patients with higher portal pressure will need larger grafts to reduce the risk of SFSS or interventions to reduce portal hypertension. Beta-blocker administration, temporary porto-caval shunts and splenic artery ligation or embolization have been proposed to reduce portal pressure in the post-operative period of LDLT to mitigate the consequence of transplanting liver grafts smaller than ideal.24 It is clear that the pre-operative planning of LDLT therefore needs to take into account several elements both in the donor and the recipient that can factor in the genesis of SFSS.

LDLT: Special Considerations

Adult-to-adult liver transplantation is helping to significantly reduce the gap between need and availability of grafts. Living donors not only benefit their recipients but also make cadaveric liver graft available to other recipients. The main drawback of LDLT is the mortality and morbidity risk of the living donors, healthy individuals undergoing major surgery for altruistic motivations. Any institution undertaking a program of LDLT needs to pay extreme attention at donor safety and motivation. Even the suspect of financial, or materialistic, motivation and any major damage to the health of the donor can have very negative consequences on transplantation at large and the institution carrying out the LDLT program. It has been suggested that in recipients of LDLT, the recurrence of HCV occurs more frequently, possibly as an effect of liver regeneration on viral replication. Recent data seem to indicate the opposite, but certainly more research is needed. LDLT would be the ideal situation to try and eradicate HCV infection in the peri-operative phase, should more effective anti-viral drugs became available. Hepatocellular carcinoma (HCC) is one of the most frequent indications to LDLT. The option of liver transplantation is offered to patients whose HCC is within the scientifically accepted criteria. The Milan criteria (one single nodule below 5 cm in diameter and not more than three nodule below 3 cm in diameter each) are still the most commonly used internationally, although other criteria are being evaluated and proposed to expand the population of HCC patients who can be wait listed for transplantation. A higher incidence of HCC recurrence in recipients of LDLT matched for cancer stage to recipients of cadaveric livers has been reported by a few centers.25,26 It has been hypothesized that liver regeneration and low waiting time—which prevents the identification of patients with fast progressing tumors—could be causative factors. In spite of these reports, LDLT is still considered an excellent therapeutic option for patients with HCC since it allows transplantation before the tumor progresses outside of the currently accepted criteria.

Conclusions and Future Perspectives

Split liver and LDLT are the most significant technical evolutions of liver transplantation which, over the last decade, have contributed to dramatically reduce pediatric wait list mortality and the gap between need and availability of liver grafts for adult patients. To further improve the outcome of these complex operations, refinements in the surgical technique and better comprehension of the interrelations between liver regeneration and portal hypertension will be needed. Immunosuppressive therapy toxicity is one of the major problems of organ transplantation which affect patient and graft survival. LDLT, with its attendant possible scheduling of the operation, gives the best possible theoretical conditions to treat patients in the pre-operative period in order to induce immunologic tolerance and eliminate the need for long-life anti-rejection drugs.

One Liver for Two: Split and Living Donor Liver Transplantation

317

It is a common clinical observation that in a substantial number of patients, the spontaneous— due to noncompliance—or planned withdrawal of immunosuppresive drugs (to treat posttransplantation immunosuppression-related complications) does not always results in liver rejection. Thomas Starzl has indicated that the passenger leukocites, which are cotransplanted with any solid organ, migrate to the recipients’ immune system that becomes micro-chimeric and promote acceptance of the transplanted organ (tolerance).27 In order to induce this natural phenomenon that is currently happening in an unpredictable and nonreproducible fashion, several approaches have been proposed. In general, they consist of administering lymphoid depleting drugs and donor’s leukocytes before transplantation to induce microchimerism in the recipient. Although more clinical research in this area is needed, there is a growing body of evidence to suggest that, particularly in living donor transplantation, this approach has the potential to effectively induce tolerance.

References

1. Pilchmayr R, Ringe B, Gubernatis G et al. Transplantation of a donor liver to 2 recipients (splitting transplantation)—a new method in the further development of segmental liver transplantation. Archiv fur Chirurgie 1988; 373(2):127-130. 2. Strong RW, Lynch SV, Ong TH et al. Successful liver transplantation from a living donor to her son. N Engl J Med 1990; 322(21):1505-1507. 3. Rogiers X, Malago M, Habib N et al. In situ splitting of the liver in the heart-beating cadaveric organ donor for transplantation in two recipients. Transplantation 1995; 59(8):1081-1083. 4. Gridelli B, Spada M, Petz W et al. Split-liver transplantation eliminates the need for living-donor liver transplantation in children with end-stage cholestatic liver disease. Transplantation 2003; 75(8):1197-1203. 5. Singer PA, Siegler M, Whitington PF et al. Ethics of liver transplantation with living donors. N Engl J Med 1989; 321(9):620-622. 6. Barr ML, Belghiti J, Villamil FG et al. A report of the Vancouver Forum on the care of the live organ donor: lung, liver, pancreas and intestine data and medical guidelines. Transplantation 2006; 81(10):1373-1385. 7. Gruttadauria S, Marsh JW, Cintorino D et al. Adult to adult living-related liver transplant: report on an initial experience in Italy. Dig Liver Dis 2007; 39(4):342-350. 8. Deshpande RR, Bowles MJ, Vilca-Melendez H et al. Results of split liver transplantation in children. Ann Surg 2002; 236(2):248-253. 9. Yersiz H, Renz JF, Farmer DG et al. One hundred in situ split-liver transplantations: a single-center experience. Ann Surg 2003; 238(4):496-505; discussion 506. 10. Rogiers X, Malago M, Gawad K et al. In situ splitting of cadaveric livers. The ultimate expansion of a limited donor pool. Ann Surg 1996; 224(3):331-339; discussion 339-341. 11. Spada M, Gridelli B, Colledan M et al. Extensive use of split liver for pediatric liver transplantation: a single-center experience. Liver Transpl 2000; 6(4):415-428. 12. Shun A, Thompson JF, Dorney SF et al. Temporary wound closure with expanded polytetrafluoroethylene in pediatric liver transplantation. Clin Transplant 1992; 6(4):315-317. 13. Cardillo M, De Fazio N, Pedotti P et al. Split and whole liver transplantation outcomes: a comparative cohort study. Liver Transpl 2006; 12(3):402-410. 14. Wilms C, Walter J, Kaptein M et al. Long-term outcome of split liver transplantation using right extended grafts in adulthood: A matched pair analysis. Ann Surg 2006; 244(6):865-872; discussion 872-863. 15. Merion RM, Rush SH, Dykstra DM et al. Predicted lifetimes for adult and pediatric split liver versus adult whole liver transplant recipients. Am J Transplant 2004; 4(11):1792-1797. 16. Spada M, Cescon M, Aluffi A et al. Use of extended right grafts from in situ split livers in adult liver transplantation: a comparison with whole-liver transplants. Transplant Proc 2005; 37(2):1164-1166. 17. Zamir G, Olthoff KM, Desai N et al. Toward further expansion of the organ pool for adult liver recipients: splitting the cadaveric liver into right and left lobes. Transplantation 2002; 74(12):1757-1761. 18. Humar A, Ramcharan T, Sielaff TD et al. Split liver transplantation for two adult recipients: an initial experience. Am J Transplant 2001; 1(4):366-372. 19. Colledan M, Andorno E, Valente U et al. A new splitting technique for liver grafts. Lancet 1999; 353(9166):1763. 20. Cescon M, Spada M, Colledan M et al. Feasibility and limits of split liver transplantation from pediatric donors: an italian multicenter experience. Ann Surg 2006; 244(5):805-814. 21. Miraglia R, Luca A, Marrone G et al. Percutaneous transhepatic venous angioplasty in a two-yr-old patient with hepatic vein stenosis after partial liver transplantation. Pediatr Transplant 2007; 11(2):222-224.

318

Recent Advances in Liver Surgery

22. Sharma V, Tan H, Marsh W et al. Technical aspects of live-donor hepatectomy. Living Donor Transplantation 2007; Ch. 15:169-183. 23. Dahm F, Georgiev P, Clavien PA. Small-for-size syndrome after partial liver transplantation: definition, mechanisms of disease and clinical implications. Am J Transplant 2005; 5(11):2605-2610. 24. Gruttadauria S, Mandala L, Miraglia R et al. Successful treatment of small-for-size syndrome in adult-to-adult living-related liver transplantation: single center series. Clin Transplant 2007; 21(6):761-766. 25. Fisher RA, Kulik LM, Freise CE et al. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am J Transplant 2007; 7(6):1601-1608. 26. Chao SD, Roberts JP, Farr M et al. Short waitlist time does not adversely impact outcome following liver transplantation for hepatocellular carcinoma. Am J Transplant 2007; 7(6):1594-1600. 27. Starzl TE, Demetris AJ. Transplantation tolerance, microchimerism and the two-way paradigm. Theor Med Bioeth 1998; 19(5):441-455.

Chapter 23

Radiological Intervention for Treatment of Complications after Liver Transplantation Giovanni Gandini,* Maria Carla Cassinis, Dorico Righi, Andrea Doriguzzi-Breatta, Maria Cristina Martina and Maria Antonella Ruffino

Abstract

O

rthotopic liver transplantation (OLT) is a widely accepted treatment for end-stage chronic liver disease and severe liver failure. Despite improvement in survival due to advances in surgical technique, organ preservation technology and immunosuppressive strategies, there are significant complications after liver transplantation. They include vascular, arterial and venous and biliary complications, infections, liver abscesses, fluid collections, haematomas, recurrent tumors, lymphoproliferative disorders. Vascular complications, such as arterial stenosis and venous trombosis are associated with a higher risk of graft disfunction and biliary complications remain a significant cause of morbidity and mortality after OLT. Early detection of these complications and adequate treatment is crucial in order to prevent loss of graft and improves graft and patient survival. Ultrasound (US) and Color Doppler Ultrasound (CDUS) are the first-line post OLT examination and are able to demonstrate vascular abnormalities, hepatic parenchyma and bile ducts. Multidector CT (MDCT) with CT angiography (CTA) is a safe, accurate, non invasive method of evaluating vascular and non vascular complications (bilomas, liver abscesses, tumors). Magnetic Resonance Cholangiography (MRC) is an excellent non invasive diagnostic tool, alternative to direct cholangiography, for the evaluation of the biliary tract abnormalities. In the recent years, interventional radiology has gained worldwide acceptance for the management of post OLT complications and plays a significative role especially in the treatment of biliary complications, including biliary strictures (anastomotic or non anastomotic site), leakage and obstruction, that occur in 10% to 25% of cases. In the treatment of vascular complications the percutaneous approach includes angioplasty, thrombolisys, embolization, but is limited to selected patients, while in most cases surgical re-intervention is preferred. On the other hand in case of biliary complications the percutaneous approach is performed before surgery, since it is less traumatic and better accepted by this population of patients already stressed by transplant intervention and prolonged pharmacological therapies. Percutaneous treatment is particularly recommended when the complications involve most of the biliary system and when the only surgical option could be retransplantation. *Corresponding Author: Giovanni Gandini—Department of Radiology, University of Turin, San Giovanni Battista Hospital, via Genova 3, 10126-Turin-Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

320

Recent Advances in Liver Surgery

In the management of intrahepatic biliary complications, percutaneous approach is safer than the endoscopic treatment for sterility and outcomes. Furthemore percutaneous approach, unlike the endoscopic one, can be performed in all cases, in presence of bilio-enteric anastomoses and when biliary ducts are not dilated. Percutaneous treatment should be performed by skilled interventional radiologists, in interventional radiological rooms where is available a wide choice of sophisticated and dedicated material and instruments. Furthermore strict co-operation among gastroenterologists, surgeons and radiologists is mandatory for the optimal management of these complications in order to avoid irreversible graft damage.

Introduction

Orthotopic liver transplantation (OLT) is now widely accepted as the gold-standard treatment of advanced chronic liver disease, acute liver failure and selected cases of hepatocarcinoma. Despite the improvements of immunosuppressive therapy and surgery of the last ten years with 1- and 5-year, survival rates of 87 and 74 %1-2 respectively, the complications onset is still frequent.3 Post OLT complications can be divided in early and late. The early appear within the first three months: they are primary graft nonfunction, acute rejection, technical and functional problems due to vascular and biliary complications. They are associated with increased risk of mortality. Late complications appear after three months from transplant and include chronic infections, vascular and biliary anastomotic strictures, recurrence of primary disease and tumors or limphoproliferative disorders.4 The improvement in surgical techniques more and more sophisticated as those performed in case of living donor transplantation and split liver or pediatric liver transplantation, increases the number of transplanted patients as well as the incidence of biliary and vascular complications. An early diagnosis of hepatic artery thrombosis, biliary fistulas, abscesses and haemorrhage and their early treatment are crucial in order to achieve the revascularization and prevent damage to the graft, avoiding another transplant. Imaging and interventional radiology (IR) are fundamental in patient monitoring during the first days after OLT as well as for the follow up with these aims: a. early diagnosis of vascular and biliary complications; b. differential diagnosis from acute rejection, one of the most serious complications, that shows similar clinical signs and symptoms; c. diagnosis of infections or abscesses related to immunosuppressive therapy; d. to rule out tumors or disease recurrence; e. to offer an alternative solution to more invasive surgery allowing to maintain the graft function and increasing the patient survival without precluding surgical re-intervention. The imaging techniques normally employed are Ultrasound (US) and Color-Doppler Ultrasound (CDUS), Multidetector CT (MDCT) and CT Angiography (CTA), Magnetic Resonance (MR), MR Cholangiography (MRC) and MR Angiography (MRA). CTA and MRC have replaced the invasive Digital Subtraction Angiography (DSA) and direct colangiography such as Endoscopic Retrograde Cholangiopancreatography (ERCP) or Percutaneous Transhepatic Cholangiography (PTC), now performed with therapeutic purpose. Tube-T cholangiography, on the other hand, is the examination of choice in patients with suspected biliary strictures in the early post OLT phase when the T-tube is still in place. However if T-tube is not present (removed or not employed) direct cholangiography can be performed only by ERCP or PTC.3 US and Color Doppler Ultrasound are the first-line examinations in immediate post OLT patients, carried out at patient’s bedside, in order to study vascular anastomosis, parenchyma, biliary system dilatation, bilomas and haematomas. CDUS shows high accuracy in detecting vascular complications, with rates of 92% and 85% in the diagnosis of the hepatic artery thrombosis and stenosis, respectively. Nevertheless, US is not reliable for the early diagnosis of biliary complications, since normal ultrasound findings cannot exclude the presence of sludge or leakage.3

Radiological Intervention for Treatment of Complications after Liver Transplantation

321

Multidetector CT is now the gold standard imaging technique, replacing DSA, to evaluate vascular complications. CT angiography, particularly with the development of multidetector technology and 2D-3D reconstructions, such as Multiplanar Reconstruction (MPR), Maximum Intensity Projection (MIP) and Volume Rendering (VR), allows high quality images of vascular anatomy and complications with an accuracy rate of more than 93%.3,5 Furthermore, thanks to its high spatial resolution, MDCT depicts fluid collections (abscesses or haematomas), recurrence of the primary disease and onset of post-OLT lymphoproliferative disease. MR angiography is a valide alternative to CTA in young and/or iodine contrast allergic patients; despite Literature refers a high sensitivity (86%) in detecting arterial complications6 MRA is limited by a high false positive rate due to artefacts caused by the presence of metallic clips that limit the correct grading of the hepatic artery stenosis. MR cholangiography is recognized as the only imaging technique that shows biliary anastomosis (hepaticojejunal or choledocho-choledocho anastomosis) in a non invasive way. In the suspicion of biliary complications, after tube-T removal, MRC allows to demonstrate: (a) anastomotic dehiscence, (b) perianastomotic collections, (c) strictures site and length, (d) biliary sludge or stones and offers important information for the following treatment. Besides MR with the use hepato-specific contrast agents can provide functional information: a physiological transit of the contrast agent in the duodenum (within 15 minutes) allows to show not only anastomotic patency without stenosis or obstruction, but also complications as Oddi sphincter disfunction caused by surgical manipulation.4 Limitation of MRC is its low spatial resolution, which can lead to miss mild strictures or to overestimate possible strictures, when a signal void occurs in the biliary tree.

Vascular Complications

Vascular complications have been reported in approximately 9% of patients with liver trasplant and involve, with different incidence, arterial vessels (6%), cava and hepatic veins (2, 5%) and portal vein (1%).3,4 Complications can be early (haemorrhages, strictures and thrombosis) and late (strictures, thrombosis and aneurysms). Haemorrhages from anastomotic dehiscence represent a surgical emergency and need reintervention. Among vascular complications, those involving the hepatic artery (thrombosis and stenosis) are the most serious: they represent one of the most important cause of death after OLT and retransplantation is inevitable in 75% of patients with hepatic artery thrombosis. In these cases second transplantation has a mortality rate of 30%. Venous complications are less severe than arterial and occurr rarely; among these, thrombosis of the portal vein is the most important.

a) Vascular Arterial Complications

Vascular arterial complications include thrombosis, stenosis and pseudoaneurysms of the hepatic artery and arterio—portal fistula.

Hepatic Artery Th rombosis

Thrombosis of the hepatic artery can be early or delayed, but usually it arises within the first three months from transplantation. Surgical anastomosis is the most common site, the main cause are technical problems (size discrepancy between the artery of the graft and the recipient, difficult anastomosis, complex anatomy, prolonged ischemic time). Thrombosis of the hepatic artery is associated with high mortality rate (50-58%). Although the risk of massive hepatic necrosis is rare thanks to the US follow-up during postsurgical surveillance, ischemia can cause abscesses, bilomas or liver haematomas. The treatment of choice is surgical with revascularization achieved by Thrombectomy and anastomotic revision; complete artery thrombosis requires retransplant. Percutaneous treatment of the hepatic artery thrombosis is thrombolysis. Before the fibrinolytic treatment, a selective hepatic angiography, with non traumatic sliding and flexible coaxial micro-catheter (2.7-3 F), must be performed. Then, after super-selective catheterisms, fibrinolysis

322

Recent Advances in Liver Surgery

can start connecting the catheter to an infusional pump. Usually, drugs used are urokinase and r-TPA: urokinase (50.000 UI/hour for 24-48 hours followed by a 2 days systemic administration of heparin) is employed in case of sub-acute hepatic ischemia with low cytolisis markers that allows an interval of at least 24 hours to verify the treatment efficacy. The r-TPA (0,025 mg/kg bolus followed by infusion of 6-8 mg/kg during 4 hours) is the drug of choice in patients with acute ischemia and high graft loss risk, but it cannot be used during the immediate post OLT due to the high bleeding risk. During the infusion of thrombolitic drug, it is recommended to control the efficacy of the treatment with angiography performed by micro-catheter, 12-24 hours after the infusion beginnig, if urokinase is used, or 4 hours if the r-TPA is employed. In the second case fibrinogen monitoring with every hour sampling is essential, since values <150 mg/dl require the interruption of the treatment. Despite the high risk of anastomosis bleeding, some authors suggest to combine fibrinolytic treatment with metallic stents placement in order to assure vessel patency in the medium term (18-25 months) avoiding retransplantation. Although the experience of the authors is limited to a few cases, serious complications are not reported.7 However, there is no consensus on the use of metallic stents that would be justified only when thrombosis is associated to a stenosis treatable with angioplasty.

Hepatic Artery Stenosis

Hepatic artery stenosis is normally observed within the first three months after OLT at the anastomotic site, but it can be localized in non-anastomotic site like coeliac trunk and intrahepatic arteries.4 If untreated, significant stenosis may lead to thrombosis, hepatic ischaemia, biliary strictures, sepsis and graft loss. Common causes of hepatic artery stenosis are surgical intimal traumatisms, that lead to fibrosis, and hepatic rejection. Non-anastomotic stenosis of the coeliac trunk are due to pre-existing atherosclerotic lesions or to artery impingement by the diaphragmatic pillar or arcuate ligament; also they can be due to excessive arterial length. Non anastomotic intrahepatic stenosis result from rejection and are infrequent, but serious because they lead to massive necrosis, graft loss and retransplantation. Percutaneous treatment of hepatic artery stenosis consists of percutaneous transluminal angioplasty (PTA) with small size (2-4 mm) and length (2-4 cm) balloon catheters. The artery stricture must be passed delicately in order to avoid anastomosis damage and vessel dissection. For this purpose it is advisable to use micro-catheters and metallic guidewire (0,014-0,018 inches of diameter) on which extremely thin and sliding balloon catheter (internal lumen: 4F) can be loaded. Once positioned across the stricture, the balloon is gradually inflated until stenosis releases (Fig. 1). The technical success rate reported in the literature is about 80-100%. Complications rate is 9%; they include spasms, dissections, pseudoaneurysm and breakage.8 The restenosis rate is about 30-60%. When PTA is unsatisfactory, in order to reduce recurrence and prolong vessel patency, the use of metallic stents, able to preserve the vessel dilation, has been proposed. Given the small size of the vessels and brevity of stenosis, coronary stents, possibly “drug-eluting” type, are recommended, to prevent intra-stent restenosis. The stents’ patency average reported in the Literature is longer than 1 year.4

Hepatic Artery Pseudoaneurysms

Pseudoaneurysms are a rare complication (0.7-2%) and can be divided into extra-hepatic and intra-hepatic. Extrahepatic pseudoaneurysms, caused by sepsis, surgical or PTA complications at the anastomosis site, are the most frequent. Early detection is crucial to avoid a high mortality (69%). Intrahepatic pseudoaneurysms are rare in comparison to the extrahepatic ones and are often iatrogenic, subsequent to liver biopsy or PTC, with or without concomitant infection. A variety of options exists to prevent life-threatening haemorrhage including surgical, endovascular and percutaneous approaches.

Radiological Intervention for Treatment of Complications after Liver Transplantation

323

Figure 1. Early stenosis of hepatic artery anastomosis. a) Multidetector CT-angiography with MIP reconstructions shows short, but severe anastomotic stenosis of the hepatic artery. b) Digital angiography provides similar depiction of the hepatic artery stenosis. c) Percutaneous Transluminal Angioplasty (PTA) is performed by appropriate size Grüntzig balloon catheter inserted and inflated across the stenosis. d) Final digital angiography shows good outcome of PTA and restored arterial diameter.

The site, proximal or distal and the morphology of the pseudoaneurysm (presence or absence of neck) are very important factors influencing the endovascular treatment, when surgery is unsuitable or has a high risk. Percutaneous treatment of distal pseudoaneurysm with or without neck, consists of endovascular embolization of the afferent branch and/or the aneurysmal sac, with metallic micro coils and embolizing permanent material (Cyanoacrylates, Polyvinil alcohol), alone or in association. In the proximal pseudo-aneurysm with a neck the embolization of the aneurysmal sac with metallic coils is recommended, because it is mandatory to preserve the distal flow. In the proximal pseudo-aneurysm without neck, to avoid the distal spread of embolizing fragments, it is recommended to insert a covered metallic stent in order to exclude definitively the aneurysmal sac from the arterial circulation. This technique is not lacking risks since in these immunodepressed patients the suprainfection of the treated pseudo-aneurysm cannot be excluded. Direct percutaneous thrombin injection is another proposed treatment when there is a high risk of thrombotization using an endovascular technique.10

Intrahepatic Arterio-Portal Fistulas

Intrahepatic arterio-portal fistulas represent a relatively frequent complication after biopsy procedures. The diagnosis can be easily established with CDUS and CTA. Usually this complications have spontaneous resolution. Large, persistent and high flow fistulas can be treated by endovascular

324

Recent Advances in Liver Surgery

super-selective embolization of arterial afferent vessel using micro-catheter and micro-coils in order to avoid iatrogenic ischemic damages.2

b) Vascular Venous Complications

Vascular venous complications involve portal vein, inferior vena cava or hepatic veins.

Vena Porta Complications

These are rather unusual (1-3%) and include thrombosis or stenosis of the portal vein and more frequently involve the anastomosis. Common causes are: mismatch between the size of anastomosed vessels, previous portal thrombosis, blood coagulation disorders. The appearance of signs of portal hypertension such as ascites, splenomegaly or varices suggestes a portal complication. The CDUS and CTA diagnose portal thrombosis in the majority of the cases. The endovascular treatment, as for arterial thrombosis, consists in thrombolysis followed, if necessary, by stent placement In portal vein stenosis, less frequent than thrombosis, the CDUS shows a high speed turbulent flow, but the certain diagnosis is confirmed by evidence, through transhepatic or jugular catheterism, of trans-stenotic pressure gradient superior to 5 mm Hg.4 The endovascular treatment of portal stenosis consists in percutaneous catheterism of an intrahepatic branch, usually through right intercostal approach. When coagulation disorders coexist, it is advisable a transjugular access reaching the right portal branch through the right hepatic vein, performing a technique similar to the one followed in case of TIPS (Transjugular intrahepatic porto-systemic shunt). Follows the treatment of the portal stenosis with PTA, performed through the expansion of a balloon catheter of a diameter included between 8-14 mm, according to the size of graft and native portal branches. When the result is insufficient, PTA is completed with the placement of a stent of appropriate size in the portal anastomoses (Fig. 2). The right percutaneous approach, better than transepigastric approach on left bile ducts, as more aligned to the portal axis, permits the placement of greater size metallic stents, especially the covered type that have very low flexibility. The immediate technical success rate described in literature is about 70%, instead Funaki e coll.9 evidence restenosis after PTA alone in 50% of patients after only six months, on the other hand the stents patency is excellent with a rate of 100% at 47 months follow-up.

Vena Cava and Hepatic Veins Complications

These are very rare, usually anastomotic and related to technical reasons ( different size between graft and patient vessels, hepatomegaly compression and “piggy back” anastomosis torsion). In the stenosis of the vena cava, CDUS shows a turbulent flow with speed increased of 3-4 times in the stenotic site, but the certain diagnosis has to be obtained with cavography that allows to measure a trans-stenotic gradient pressure >5-6 mm Hg and to differentiate the stenosis from size mismatch.4,10 Cava anastomotic stenosis can be treated with PTA through large sized balloon catheters (up to 25 mm) with an immediate technical success rate of 80% (Fig. 3); the stent placement can guarantee a longer term patency, but compromises the possibility of a retrasplant. Instead the stent placement is necessary when the stenosis is caused by anastomosis torsion since PTA alone cannot avoid the anastomosis retorsion that occurs immediately after the dilation.

Biliary Complications

Biliary complications represent one of the main causes of mortality and morbidity after OLT. In major transplant centers the reported incidence of biliary complications varies from 10% to 26%11 with associated mortality rate of 0-19% and retransplantation rates of 6-12.5%.12 In recent years interventional radiology has gained worldwide acceptance for the treatment of these complications and can be considered an effective alternative to surgical treatment due to minimal

Radiological Intervention for Treatment of Complications after Liver Transplantation

325

Figure 2. Anastomotic portal vein stenosis. a) Multidetector CT angiography with MIP reconstructions of the portal phase acquisition shows a critical portal vein narrowing at the anastomotic site with poststenotic dilation. b) Portography obtained after percutaneous portal catheterism trought direct transheptic puncture of the right portal branch confirms the anastomotic stenosis. c) Across the stenosis is inserted a metallic stent moulded by a large Grüntzig balloon catheter (14 mm of diameter). d) Final portography shows satisfactory outcome with the restored portal vein diameter at anastomotic site.

invasiveness, low complications and high success rates, emphasizing the role of early treatment of these patients.12 Moreover interventional procedures, that in the last few years have made important technological progress, are better accepted by these patients stressed by prolonged therapies before and after OLT. Therefore surgical management should be limited to few cases of failure of percutaneous treatment.11 The endoscopic management13 is less traumatic in comparison to the radiological one, but potentially more dangerous in relation to a high risk of septic complications (retrograde contamination of the biliary tree, pancreatitis, aerobilia) and to a long-term risk of cholangitis due to intestinal reflux post sphincterotomy. The surgical techniques employed for biliary tract reconstruction are choledochococholedochostomy and Roux-en-Y hepatico-jejunostomy, the latter reserved for intrinsic damaged biliary tree and difficult anastomoses.12 Post OLT biliary complications include early complications arising during the first three months and late complications after first year or rarely after few years. Early complications are more frequent than the late ones and virtually have a technical origin related to an ischemic necrosis of the bile duct or an unsatisfactory anastomosis. The incidence of late complications is clearly associated to arteria thrombosis in 85% of cases.2

326

Recent Advances in Liver Surgery

Figure 3. Anastomotic caval stenosis. a) Inferior cavography shows severe anastomotic stenosis with 14 mm/Hg transtenotic pressure gradient. b) PTA was performed with a 18 mm angioplasty balloon. c) Final control suggests good morphological outcome with transtenotic gradient reduction (5 mm/Hg).

The major biliary complications are: • fistulas: usually early, represent the most common complication in patients with choledococholedochostomy; they are most often located to tube-T site, while occur rarely (1%) at the Roux-en-Y hepatico-jejunostomy; • obstructions: develop usually in the first month post-OLT and are related to technical causes, presence of biliary debris, sludge, stones and biliary casts or to extrinsic compression; • stenosis: can have an ischemic origin or result from cicatricial biliary strictures or arise post cholangitis. Frequently appear later, sometimes years after the transplant. When early they are more frequently anastomotic. Late stenosis can be anastomotic, ilar or intrahepatic; anastomotic strictures are solitary and short, while hilar or intrahepatic are extensive, developing from the ilum into the intrahepatic biliary ducts. Biliary stenosis are the most frequent complication and require multiple treatments since, in particular the ischemic ones, have high recurrence.14 Less frequent biliary complications are intrahepatic fluid collections and abscesses. Percutaneous procedures in transplanted patients are the same employed for nontransplanted. However for the critical patient conditions, immunosuppressive therapy and above all for the complexity of these complications, often involving more biliary ducts without biliary ducts dilation, the treatment should be performed by expert interventional radiologists, in interventional radiological rooms where a wide choice of sophisticated and dedicated materials and instruments are available. Percutaneous transhepatic cholangiography (PTC) represents the preliminary modality to confirm the diagnosis, place a temporary percutaneous transhepatic biliary drainage (PTBD), external or internal and perform therapeutic manoeuvres as stones removal, percutaneous bilioplasty (PTB) and fluid collections or abscesses drainage. The treatment of the biliary fistulas requires an internal-external (7-10 F) drainage catheter inserted into the biliary tree across the fistula, in order to obtain a complete exclusion of the bile leak. The catheter can be removed only when cholangiography shows the complete healing of the fistula (Fig. 4). Percutaneous treatment success rate reported in the literature is 62.5% within 2-3 months, while for the endoscopic approach, only when can be performed, with placement of naso-biliary tube or stent, the success rate is of 95%.13

Radiological Intervention for Treatment of Complications after Liver Transplantation

327

Figure 4. Hepatico-jejunal anastomoses biliary fistula. a) Chiba needle percutaneous transhepatic cholangiography shows non dilated intrahepatic bile ducts and a large anastomotic fistula with subhepatic leakage of contrast medium. b) Following a preliminary PTC and the bile duct catheterism, an internal-external biliary drainage was placed across the fistula and removed only after leak resolution. c) PTC performed six days later shows the complete recovery of the biliary fistula.

In presence of concomitant fluid collection (biloma) US or CT-guided percutaneous catheter drainage is the treatment of choice and is essential to prevent sepsis. The biliary stenosis are treated by percutaneous transhepatic bilioplasty employing high pressure balloon catheters 4-16 mm in diameter (the smaller for intrahepatic ducts and the larger for extrahepatic branches) placed across the strictures and inflated until the stenosis resolution. Cholangiography must be performed to assess the result of the stricture dilation. After bilioplasty an internal-external biliary drainage catheter (8-10 F) is left in site (10 days-3 months) to prevent recurrences, that are more frequent in anastomotic stenosis than in intrahepatic strictures. In case of recurrence repeated bilioplasty are requested. Despite several Authors have recommended the employment of plastic or metallic stents for anastomotic strictures,12 after bilioplasty we prefer to leave in site an internal-external drainage. It allows the safeguard of the treated segment, to perform cholangiography and, eventually, another dilation in case of early recurrence (10 days-3 months) avoiding a new percutaneous access. We believe that the employment of metallic stents should be proposed carefully, since they can obstruct and may complicate a subsequent surgical treatment as they become embedded in the bile duct wall.11 Percutaneous approach is the first-line treatment in intrahepatic stenosis (Fig. 5) and all sites stenosis in hepatico-jejunal anastomoses (Fig. 6), while endoscopic technique is the treatment of choice for extrahepatic strictures in choledocho-choledocho anastomoses. However, in our experience, the percutaneous approach is preferred also in end-to-end anastomoses strictures. This way Vater’s papilla is preserved, avoiding retrograde duodenal reflux in the biliary tree. In literature success rate for percutaneous treatment is about 90% with biliary patency at 6 years of 70% and 20% recurrence rate at 1 year.4 In particular the long term patency after PTB is negatively influenced by recurrences of sclerosing cholangitis or ischemic strictures. The endoscopic approach to anastomotic strictures has a reported success rate ranging between 67-91%.13 An abscess associated with biliary complications always needs treatment with US or CT-guided percutaneous drainage; the catheter can be removed only after evidence of complete healing of the lesion at the US or CT examination. Frequently debris, sludge or stones complicate stenotic lesions; in these cases after bilioplasty it is essential to perform percutaneous lithotripsy removing bile duct stones by occlusion balloon

328

Recent Advances in Liver Surgery

Figure 5. Intrahepatic ischemic stricture. a) PTC shows an ischemic stenosis at the origin of bile ducts for the VI and VII hepatic segments, due to an inadvertent section of the tributary artery with extrahepatic origin. Also the confluence of the ducts for the VI and VII hepatic segment is involved by the repair process that causes the separation of the bile ducts. b) First bilioplasty is performed with balloon catheter inflated at the confluence of the bile ducts for the VI and VII hepatic segment. c) Second bilioplasty, in the same sessions, is performed with balloon catheter inflated at the origin of the two ducts. d) Final colangiography shows the good result of the bilioplasty and complete restoration of the diameter of the bile ducts.

and high-frequency pulsed hydro jet. It is mandatory to leave an internal- external biliary drainage for cholangiography follow-up surveillance. The complete biliary “cleansing” is almost always achieved by these easy manoeuvres, without need of more complex treatments as contact or shock-wave lithotripsy. Percutaneous approach is not complication-free: haemobilia, bleeding, cholangitis, biliary fistula, bile duct and duodenal perforation are described in literature and overall complication rate ranging between 8-30%.15 Anyway the risk of bleeding, haemobilia, pancreatitis and duodenal perforation is much higher with endoscopic procedures than with percutaneous technique.3,11 Between October 1990 and May 2006 a total of 1516 liver transplants have been performed in 1417 patients at San Giovanni Battista Hospital of Turin. In our series, biliary complications occured in 218/1417 patients (15.4%), 28 needed surgical treatment ( 8/28 re-OLT), 8 are asymptomatic and till now in follow-up.

Radiological Intervention for Treatment of Complications after Liver Transplantation

329

Figure 6. Hepatico-jejunal anastomoses ischemic stenosis. a) Percutaneous transhepatic cholangiography performed through right intercostal approach shows a bilio-digestive anastomosis ischemic stricture, which involves the origin of the right paramedian and the lateral biliary ducts. The left biliary ducts are not opacified. b) Percutaneous transhepatic cholangiography obtained through transepigastric approach on bile duct for segment III, shows a stricture of the left main bile duct at the origin. c) Three balloon catheters were positioned across right and left bile ducts stenosis and contemporary inflated performing balloon dilation (kissing balloon technique). d) Final cholangiography shows an optimal outcome of the procedure with restored diameter of the right and left ducts with flow of contrast medium into the jejunal loop.

The strictures treated by interventional procedures were 112 (with a minimum follow-up of 12 months, media 49.5 months); 66/112 underwent a single procedure, 21/112 needed two treatments and 6/112 more than two. The surgical treatment of the stenosis was performed in 12 patients: 8 required duct-to-duct anastomosis conversion to bilio-digestive anastomosis and 4 surgical bilio-digestive anastomosis reassessment. Re OLT was necessary in 4 patients. Seventy cases presented bile fistulas; 48 cases had a spontaneous resolution or underwent surgery. Bile leaks were managed with percutaneous treatment in 22 cases, 19/22 with complete resolution (86%). In this series of patients we had just 4 major complications (<3%): 3 haematomas (2 had spontaneous healing, 1 needed surgical treatment) and a massive bleeding of a bilio-digestive anastomosis stenosis after PTB; this case was treated by endovascular embolization of the hepatic artery with complete resolution.

330

Recent Advances in Liver Surgery

Our experience suggests that the percutaneous approach is the choice treatment in most of post-OLT biliary complications, reserving surgery only in cases of failure. The very low number of retransplanted patients (4) is significant of the therapeutic efficacy of this technique. Even in case of failure of the percutaneous treatment, the diagnostic support of a direct cholangiography and the presence of a biliary drainage, according to our experience, are helpful. In particular the biliary drainage allows to perform surgery in elective conditions and protect the anastomosis improving the outcome of surgery.

Conclusions

Orthotopic liver transplantation (OLT) is now widely accepted as the gold-standard treatment of end-stage liver disease with 1 year survival rate about 90% and 10 years predicted survival of 70%. Despite advances in surgical technique and post operative care, morbidity after liver transplantation remains a serious problem. The early diagnosis and appropriate treatment of vascular and biliary complications are crucial to prevent irreversible damage to the graft. Interventional radiology plays an important role in the management of vascular and especially of biliary complications and represents an effective therapeutic alternative to surgical intervention with a high rate of success. Because of critical patient conditions and biliary lesions features, the treatment should be performed only by skilled interventional radiologists with long experience and training with transplanted patients. New future improvements will come from refinement of diagnostic imaging equipment and from the employment of more sophisticated materials and instruments (catheters, stents). In more distant future MR-guided interventional radiology procedures may allow dose reduction not only for patients, but also for radiologists.

References

1. Jain A, Reyes J, Kashyap R, Dodson SF et al. Long term survival after liver transplantation in 4,000 consecutive patients at single center. Ann Surg 2000; 232(4):490-500. 2. Denis A, Chevallier P, Doenz F et al. Interventional radiology in the management of complications after liver transplantation. Eur Radiol 2004; 14:431-439. 3. Boraschi P, Donati F. Complications for orthotopic liver transplantation: Imaging findings. Abdom Imaging 2004; 29(2):189-202. 4. Golfieri R, Giampalma E, Fusco F et al. Orthotopic liver transplantation (OLT): Contribution of imaging and interventional radiology in preparing the transplantation and imaging complications. Part 2: post-OLT complications and their treatment. Radiol Med 2005; 110(5-6):433-481. 5. Brancatelli G, Katyal S, Federle MP et al. Three-dimensional multislice helical computed tomography with the volume rendering technique in the detection of vascular complications after liver transplantation. Transplantation 2002; 73:237-242. 6. Glockner JF, Forauer AR, Salomon H. Three- dimensional gadolinium- enhanced MR angiography of vascular complications after liver transplantation. AJR 2000; 174:1447-1453. 7. Cotroneo AR, Di Stasi C, Cina A et al. Stent placement in four patients with hepatic artery stenosis or trombosis after liver transplantation. J Vasc Interv Radiol 2002; 13(6):619-623. 8. Vignali C, Cioni R, Petruzzi P et al. Role of interventional radiology in the management of vascular complications after liver transplantation. Transpl Proc 2004; 36:552-554. 9. Funaki B, Rosenblum JD, Leef JA et al. Percutaneous treatment of portal venous stenosis in children and adolescens with segmental hepatic transplant: Long terms results. Radiology 2000; 215:147-151. 10. Tibballs J. Interventional radiology in liver transplantation. Imaging 2002; 14:329-339. 11. Righi D, Cesarani F, Muraro E et al. Role of interventional radiology in the treatment of biliary strictures following orthotopic liver transplantation. Cardiovasc Intervent Radiol 2002; 25:30-35. 12. Thethy S, Thomson BNJ. Management of biliary tract complications after orthotopic liver transplantation. Clin Transplant 2004; 18:647-653. 13. Londoño MC, Balderramo D, Cardenas A. Management of biliary complications after orthotopic liver transplantation: the role of endoscopy. World J Gastroenterol 2008; 14(4):493-497. 14. Michael EJ, Wall W, Wall M. Management of biliary problems after liver transplantation. Liver Transpl 2001; 11(Suppl 1):S46-S52. 15. Civelli EM, Meroni R, Cozzi G et al. The role of interventional radiology in biliary complications after orthotopic liver transplantation: A single-center experience. Eur Radiol 2004; 14:579-582.

Chapter 24

Hepatocyte Transplantation:

A New Approach to Treat Liver Disorders Javed Akhter,* Loreena A Johnson and David L Morris

Abstract

A

s demand for liver transplantation increases, hepatocyte transplantation will play an increasingly important role in the clinic. Clinically, hepatocyte transplantation has already shown its potential as a bridging adjunct to the standard clinical practice of Orthotopic Liver Transplantation (OLT). However, it also has the potential to treat liver-based metabolic disorders, acute liver failure and perhaps replace OLT in severe and end-stage chronic liver disease. In this chapter we examine some of the benefits and potential issues with hepatocyte transplantation, look at the current pre clinical and clinical research currently underway.

Introduction

While Orthotopic Liver Transplantation (OLT) continues to be the gold standard for many hepatic disease states, there remains a major limitation; the shortage of suitable donor organs. As a consequence, a wide variety of alternative strategies are being studied. These include partial liver transplantation, split liver procedure (where the liver is shared between an adult and paediatric subject), bio-artificial liver devices (BAL’s) and human foetal stem cells. Unfortunately, quite apart from technical, ethical and moral issues, the number of suitable donors still fundamentally limits the impact of these alternatives. Hepatocyte transplantation (HTX) is another strategy that has potential as a supportive treatment regime and in some cases, an alternative to OLT for a variety of disorders. Possibilities include acquired liver disorders, acute (e.g., fulminant) and chronic liver failure (e.g., cirrhosis); genetic disorders such as Wilson’s disease); metabolic deficiency states (e.g., Crigler Najjar syndrome); coagulation disorders such as protein C and S deficiency and immune disorders such as hereditary angioedema.1 A wide range of possible hepatocyte sources are under investigation including xenogenic (porcine) immortalised human cell lines and stem cells (foetal and adult) as well as allogenic and heterogenic human sources. Of these alternatives all except allogenic and heterogenic do not suffer supply problems but have different issues including the danger of transmutation and potential transfer of undesirable elements. To date research has shown that hepatocyte transplantation can support liver function in times of hepatic insufficiency and effectively ‘bridge’ patients to OLT.2 With the advent of new techniques in cryopreservation3,4 and proliferation, HTX also has the potential to treat multiple patients from a single donor and to use healthy hepatocyte cells from other nontraditional sources such as liver margins resected during HCC removal. Finally, HTX costs about one tenth that of OLT2 with the advantage of being repeatable, lower morbidity and does not preclude OLT at a later date if required. *Corresponding Author: Javed Akhter—Department of surgery, St George Hospital, 3rd floor Pitney Building, Gray St. Kogarah, Sydney, New South Wales 2217, Australia. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

332

Recent Advances in Liver Surgery

The contraindications are relatively minimal and can be divided into two; donor related and recipient related. Livers with HIV or hepatic viruses can not be used and studies have indicated that hepatocytes from steatotic livers are of unusable quantity and quality. Recipients must also be evaluated carefully, particularly patients with portal hypertension and chronic liver disease since transplantation carries with it a risk of portal vein thrombosis. Clinically, scenarios such as active sepsis, metastatic malignancies, cholangio-carcinoma and AIDS also require careful review as they may have too short a survival expectation to justify the risk of transplantation. Possibly the most clinically relevant contraindication is the problem of immunologic rejection requiring chronic immunosuppression. Patients who are already critically ill and weakened may not be able to cope with an immunosuppression regime. Hepatocytes are normally infused in batches over a longer period of time and a single bolus injection of steroid as given before the whole liver transplantation is unlikely to be effective in this situation. It has been suggested that until further clinical experience is gained in hepatocyte transplantation, immuno-suppression should be maintained in much the same way as for OLT, with steroid boluses repeated at each hepatocyte infusion to reach tacrolimus blood levels of 5-7 ug/ml.5 There are several possibilities being investigated that may help overcome this issue. Hepatocytes themselves do not express major histo-compatibility complex class II antigen and very weekly the class I antigen6 and thus do not appear to contribute to the reaction. It is the biliary and endothelial cells still remaining in the hepatocyte preparations that are usually responsible. A more stringent protocol to isolate and purify hepatocytes may reduce or totally alleviate the need of immunosuppression. Ostrowsaka et al7 demonstrated that no acute rejection in engrafted purified or cryopreserved hepatocytes was noted up to 21 days after transplantation in a mouse model while inoculated crude hepatocytes rapidly declined.7 Other alternatives include the use of encapsulated donor hepatocytes; a preparative protocol which will be discussed later. In this chapter the clinical indicators, potential hepatocyte sources and current research into human hepatocyte isolation and transplantation will be examined.

A Brief History of Animal Hepatocyte Transplantation Research

The scientific foundation for clinical hepatocyte transplantation has been firmly laid over the last 40 years of experimental animal research. In 1963, Nose et al8 published the results of an artificial liver using various canine liver tissue preparations (homogenate, fresh liver slices, freeze-dried granules of liver tissue). In conjunction with haemodialysis, they found that the canine hepatocytes had beneficial effects on glucose homeostasis, hyperlactemia and hyperammonemia. Matas et al9 in 1976 demonstrated that allo-transplantation of normal hepatocytes and the autotransplantation of genetically modified hepatocytes could correct metabolic defects and Matsummura tested a suspension of isolated viable hepatocytes in a similar setting of haemodialysis.10 Animal studies showed that the hepatocytes become engrafted in the liver and function normally, correcting a variety of metabolic disorders even when they accounted for only 1-5% of the total hepatocyte mass.11 This low percentage of hepatocytes number is unlikely to correct any metabolic deficiencies permanently unless a significant liver repopulation occurs. However it did indicate that short-term function support was possible. In one study of urokinase plasminogen activator deficiency in mice, massive liver repopulation was noted with normal and /or corrected hepatocytes12 but this appears to be the exception rather than the rule. To verify that it was the donor hepatocytes that were creating the improvements direct identification of the transplanted hepatocytes was essential. In animal research this issue was resolved by the use of specific animal models.13,14 These included Nagase analbuminemic rats (minuscule serum albumin levels as compared with normal animals), DPPIV-deficient rats (dipeptidyl peptidase IV). Alternatively donor hepatocyte cells were engineered to secrete unique reporters such as hepatitis B surface antigen, human alpha-1-antitrypsin,15-17 the lentivirus vector reporter gene or green fluorescent protein (GFP). Table 1 presents some of the animal models currently used for liver cell therapy research.

333

Hepatocyte Transplantation

Table 1. Animal models currently used for liver cell therapy research Animal Designation

Origin/Manipulation

Disease Produced

Ref

DPPIV-rat

Natural mutation (rat)

None

DPPIV-mouse

Gene knockout

FAH mouse

Gene knockout

Tyrosinemia type 1

12

Gunn rat

Spontaneous mutation

Crigler-Najjar syndrome

18

13 13

LEC rat

Spontaneous mutation

Wilson’s disease

19

P-glycoprotein (mdr2) mouse

Gene knockout

Biliary phospholipids transport defect

20

Spf-ash mouse

Spontaneous

Ornithine transcarbamylase 21 deficiency

Watanabe heritable Spontaneous mutation hyperlipidemic rabbit (WHHL)

Familial hypercholesterolemia

22

Nagase an-albuminemia rat (NAR)

Spontaneous mutation

Analbuminemia

23

Mice, rats, rabbits, pigs, dogs

Acetaminophen, carbon tetrachloride, D-galactosamine, other chemical, subtotal partial hepatectomy

Acute liver failure

24,25, 26,27, 28

Rats

Repeated carbon tetrachloride

Liver cirrhosis

29

FVII-deficient mice

Gene replacement; FVII gene exons 2-8 with neomycin phosphotransferase (neo) gene

FVIII-deficient mice

Gene knockout

126

Heamophilia A

127

Transplantation of hepatocytes in animals has shown reconstitution of defective hepatic enzymes in metabolic models, improved survival rate in acute hepatic failure and improved liver function in cirrhotic rats. It has laid the foundation for clinical hepatocyte transplantation in humans and continues to provide useful models for preclinical research. However, animal experimentation does have its limitations as it does not reflect clinical reality. Such models have the advantage of a limitless hepatocyte supply for transplantation and ability to alter and modify as required to enable direct identification and monitoring of the donor hepatocytes.

Clinical Sources of Hepatocytes

The main source of human hepatocytes for the clinic and research setting remains livers discarded for liver transplantation. Unfortunately, this results in less than optimal hepatocytes. Baccarani et al30 from an analysis of a nationwide study found that organ rejection is generally a result of steatosis in excess of 30% and the consequence is a reduced hepatocyte yield, decreased viability and reduced hepatocyte engraftment. Other sources currently under investigation include livers from nonheart-beating donors (NHBDs). These are being assessed but there is as yet no clinical data on the quality and suitability of the organs.

334

Recent Advances in Liver Surgery

This chronic shortage of suitable liver donors is an inducement to explore every option and potential hepatocytes sources do exist in addition to the traditional liver transplant donors. The hepatocyte sources described below are potentially the most promising and while no one source will ever be able to meet the growing demand, combinations of these supplemental sources in conjunction with the current hepatocyte source should greatly alleviate the clinical and research shortage.

Split-Liver

Reduction procedures are used for liver transplantation into children with the resulting liver fragments normally discarded.31 Barbich et al32 utilized seven such human fragments for hepatocyte isolation achieving a mean cell viability of 61.17 + 27.43% and a cell yield range between 0.13 and 38 × 106 cell/g of tissue (median value: 14.73 × 106 cells/g of tissue) from a graft weight range between 55 and 1000 g (median value: 145.6 g). Mitry et al33 have proposed the retrieval of the liver segment IV with or without the caudate lobe from split-liver procedures. This is potentially a good source of high quality hepatocytes for transplantation although still limited by the number of transplantations being performed.

Foetal Hepatocytes

Foetal hepatocytes are an ideal source for donor hepatocytes because of their high proliferative and engraftment potential. Foetal hepatocytes when transplanted into hepatectomized rats were able to go through approximately 10 cell divisions while adult hepatocytes under similar conditions under go only one to two cell divisions.34 Transplantation of human foetal hepatocytes has been claimed to result in clinical improvement of patients including reduced immune response issues as compared to xenogenic hepatocytes.35,36 However, ethical issues in many countries preclude this option and are unlikely to be resolved in the near future.

Stem Cells

Since Peterson et al37 showed that hepatocytes could be derived from bone marrow stem cells many workers have confirmed that pluripotent stem cells reside in the bone marrow.37-39 Lagasse et al38 injected intravenously adult bone marrow cells in a fatal hereditary tyrosinemia mouse model and reported survival and restoration of liver functions. Many researchers have reported that stem/progenitor cells from bone marrow, embryo and placental amnion can be expanded into hepatocyte—like cells in the presence of growth factors. These cells express markers such as albumin, tryptophane dioxygenase, tyrosine amino transferase and even some drug metabolizing enzymes found in fully differentiated cells.40,41 There are some clear advantages in this approach as cells could be matched to HLA if required. However, it is yet to be determined that hepatocyte-like cells derived from these sources will express the full hepatic functions and whether differentiated hepatocytes can be produced in sufficient number for clinical transplantation programs. Resident hepatic stem/progenitor cells have been identified in small numbers and implicated in liver tissue repair, when hepatocyte and bile duct replication capacity is exhausted or experimentally inhibited.42 However it is unclear whether sufficient numbers of such stem cells can be secured to be clinically relevant and there is the further issue of potential accumulated malignancy within the these stem cell as these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development.43

Immortalized Hepatocyte Cell Lines

Immortalised hepatocyte cell lines eliminate the difficulties inherent in primary hepatocyte cultures and could provide an unending supply of hepatocytes for research and clinical transplantation. Kobayashi et al44 successfully immortalized primary hepatocytes by transformation with the Simian virus large tumour antigen DNA (SV40LT). These immortalized cells retained the expression of albumin, transferrin, hemopexin and glucose -6-phosphate and were not tumorigenic in the animal model. Wege et al45 transformed human foetal hepatocytes with telomerase reverse transcriptase

Hepatocyte Transplantation

335

(hTERT) and found that the hepatocytes were able to divide past 30-35 doubling times while retaining most hepatic functions. Additionally, the hepatocytes were able to maintain contact inhibition and did not show anchorage independent growth or tumorigenicity in animal model. While in principal immortalized hepatocyte cell lines appear to be an ideal source there are major concerns regarding their long-term safety. These include the possibility of accumulated malignant transformation as well as ethical issues regarding the original source and uncertainty of the full long-term therapeutic potential of these cells.

Xenogenic Hepatocytes

Porcine hepatocytes have been considered for use in extracorporeal bio-artificial devices (BAL) and hepatocytes transplantation for bridge liver transplant.46,47 Its success has been limited due to hyper-acute immune response and transferring retroviruses from the recipient. Recently, Nagata et al48 demonstrated that porcine hepatocytes were equally effective as syngenic rat hepatocytes when transplanted into spleens of cirrhotic rats with liver failure and the xenografts were better tolerated than expected by the host immune responses. The rats retained the ability to reject allogenic skin grafts and showed an immune response to rat hepatocytes but surprisingly not with the porcine hepatocytes. Whether this is the case with pig-to-human xeno-transplantation is unknown and given the recent emergence of retro viral transfer issues, is likely to remain so.

Hepatocytes from Resected Livers

Attempts have also been made to isolate hepatocytes from tissue taken during partial hepatectomy operation mostly for tumour resection49 and from liver biopsies.50 Perfusion of biopsies is quite difficult due to size variations and the paucity of visible vessels available for catheterization.51 David et al49 proposed a nonperfusion method to isolate hepatocytes from nonwedge liver biopsies with useful, if small, quantities of quality hepatocytes being isolated. Separation and isolation of healthy hepatocytes from the liver margins resected for colorectal cancer has also been proposed (Figs. 1, 2).52 This alternative is currently under investigation and includes cell separation and molecular detection techniques to purge malignant cells from the healthy hepatocytes and ensure allogenic transplantation safety. With the acceptance of partial hepatectomy as standard treatment for liver metastases, such a source would be available to centres

Figure 1. Cannulation of resected liver.

336

Recent Advances in Liver Surgery

Figure 2. Hepatocytes grown for 24 hrs in culture medium.

not directly involved with whole organ procurement, thereby increasing the clinical availability of hepatocyte transplantation to a much larger patient pool.

Isolation, Functionality and Preservation of Hepatocytes

Transplantation of liver fragments ectopically has been performed many times53,54 but the transplanted liver tissue either degenerated or disappeared within days or weeks. Another approach was needed. Mechanical isolation of hepatocytes from liver tissue appeared and continues to be the most promising; however, there are many clinical issues which still need to be resolved. Between surgical removal of the liver piece to the isolation process, hepatocytes are exposed to a number of variables that can potentially affect final hepatocyte functional ability and viability. The surgical technique of resection for example, necessitates restriction of blood supply to the organ leading to warm ischemia and hypoxia of the affected portion of the liver and thus potentially reducing the viability of hepatocytes. A protocol that preserves the liver and minimizes the damage to hepatocytes is therefore essential. Over the years, many researchers have attempted to optimize a hepatocyte isolation protocol and dozens of different protocols exist. Unfortunately, consensus on a single isolation protocol for use in all laboratories has yet to be agreed upon, creating difficulties in qualitative and quantitative comparison of different studies outcomes. The European Centre for Validation of Alternative Methods (ECVAM) has instigated studies to standardize the protocols for the use of human hepatocytes and their functionality55 and a selection of recommendations from the ECVAM multi-laboratory study is listed in Table 2. Alexandre et al56 performed a detailed study of resected liver biopsies (surgical waste after hepatectomy) from 149 patients and found that age, sex, disease, previous chemotherapy, alcohol or tobacco consumption had no apparent affect on hepatocytes yields. However >10% steatosis

337

Hepatocyte Transplantation

Table 2. Criteria for tissue origin, collection, transport and hepatocyte isolation Criteria

Recommendation

Hepatocyte Source

Surgical liver biopsies from patients with benign livers diseases or liver cancer Required with a preservative medium if transport time is > than 60 mins Acceptable 2-4 cannulae 20-40 ml/min/cannulae <20 mins

Flushing in theatre Use of glue No. of cannulae Flow rate Digestion time with collagenase (pwdr)

and warm ischaemia longer than 30 minutes was found to significantly decrease digestion and thus reduce the yield of hepatocytes. Caruana et al57suggested that the resected liver should be flushed immediately with ice-cold University of Wisconsin (UW) solution and then transported to the laboratory on ice in the same buffer. They found that liver pieces not washed and preserved in UW solution were poorly digested by collagenase, probably due to blockage of the hepatic microcirculation by blood cells from either coagulation or swelling of the hypoxic liver cells, trapping red blood cells in the sinusoids. The authors concluded that good UW perfusion to clear blood from the liver tissue before cold storage, careful attention to cannulation and ligation techniques of subsidiary ‘leaking vessels’ was important for successful collagenase digestion. The ECVAM multi laboratory study further confirmed that cold ischaemia up to 5 hours did not influence viable hepatocyte yield substantially increasing the available time for processing and transportation of hepatocytes. Research into mechanical isolation of hepatocytes started in the early 1940s but cell viability remained poor58 until Berry and Friend in 1969, demonstrated a protocol involving a two-step collagenase perfusion method.59 This protocol has become the basis of all current hepatocyte isolation protocols and is outlined in Figure 3. Modifications of this enzymatic technique in terms of collagenase concentration and perfusion rate have dramatically improved the isolation and viability of human hepatocytes for clinical application60-62 although there is as yet, no agreement on the most appropriate protocol for all instances.

Hepatocyte Viability and Function

For clinical transplantation hepatocytes should have a viability >60% with an absence of microbiological contamination.63 However, viability is not the only indicator for hepatocyte health; it does not for example, indicate the functionality of the hepatocytes. Once again there is a lack of common protocol and in most studies estimation of biochemical functions is limited and usually carried out only on a few cell batches. Yet functional variation of hepatocytes occurs not only between donors as a result of genetic polymorphism, liver diseases and premedication, but also as a result of the hepatocyte preparation conditions. The time between liver resection and dissociation, duration of warm ischemia and cold ischemia for example, can modify the functionality of the hepatocytes regardless of their in situ capacity.64,65 Thus there is a need to fully evaluate the metabolic capacities of isolated human hepatocytes in culture and after transplantation.62,41 Such information provides information as to the quality of the hepatocytes, assists calculations of the percentage mass of cells needed for optimal transplantation results and the probable long-term outcome of the engrafted cells. This in turn translates into an improved probability of a successful outcome for the procedure and the patient. Albumin (Fig. 4), urea synthesis (Fig. 5) and the status of the cytochrome P450 are perhaps the most commonly used function tests for the drug metabolizing capacity of the hepatocytes. For example, Nakazawa et al66 used CYp3A4-mediated metabolism of testosterone to 6-b-hydroxy metabolite

338

Recent Advances in Liver Surgery

Figure 3. Two step liver perfusion technique.

or de-ethylation of Ethoxyresorufin (EROD) to measure CYP1A activity as a quality control test for their hepatocyte transplantation studies. So there is a clinical necessity to reach a consensus on which of the metabolic capacities of the isolated human hepatocytes needs to be evaluated both before and after transplantation.29,36 At this time, complete function testing of hepatocytes can take 4-5 days which is impracticable where fresh hepatocytes are to be used for transplantation. Despite extensive research over the last 30 years, our understanding of the changes and factors effecting hepatocyte functionality and viability is far from complete. The question yet to be answered is; which of these tests are necessary to establish the functional capacity of the hepatocytes?

Preservation of Isolated Hepatocytes

Cryopreservation of hepatocytes has the potential to alleviate the shortage of donor livers by enabling preservation and banking of hepatocytes that would otherwise be lost. Various cryopreservation protocols successfully used in animal experiments 67-69 have been applied to human hepatocytes.3,70-73 The results indicated only partial success with losses of 60-65% hepatocyte viability and a highly variable attachment rate (5-90%).44,71,69,73 For example, Hengstler et al74 reported that hepatocytes of human, monkey, dog, rat and mouse isolated and cryopreserved by their standard protocol, varied by at least 80% in viability. Metabolic capacity of cryopreserved hepatocytes as determined by testosterone hydroxylation, 7-ethoxyresorufin-O-de-ethylase (EROD), 7-ethoxycoumarin O-diethyl’s (ECOD), glutathione S-transferees, UDP-gluronosyl transferase and epoxide hydrolase activities were at least 60% that of freshly isolated cells. They recommended carbogen equilibration during isolation of hepatocytes and before cryopreservation, to maintain the functional capacity of the hepatocytes. Guillouzo et al75 in a study on human hepatocytes from five donors, compared cryopreserved cells to their unfrozen counterparts after 44 hours of culture. They found that in most cases phenacetin de-ethylase activity was decreased in cryopreserved cells whereas procainamide N-acetylation, paracetamol sulfoconjugation and glucuronidation were increased compared to the unfrozen cells. It was also noted by Alexandre et al69 that albumin synthesis was approximately 2-fold lower

Hepatocyte Transplantation

339

Figure 4. Albumin synthesis by hepatocytes isolated from resected liver.

in thawed culture hepatocytes compared to freshly isolated hepatocytes (FIH) and further, that there was some variability in cytochrome P-450 (CYP) phase I and phase II enzymes in freshly isolated hepatocytes compared to cryopreserved hepatocytes. Recently Cho et al76 showed that a viability of 65-75% could be obtained with thawed human hepatocytes. The cells were attached to culture dishes and proliferated after stimulation with hepatocyte growth factor (hHGF). Hepatocytes were then transplanted into NOD-SCID mice, where the cells engrafted into the peritoneal cavity and the liver parenchyma. Functional assays found that the engrafted hepatocytes retained hepatic function. Conflicting findings regarding hepatocyte viability following prolonged storage time are common throughout the research literature. Most researchers report a considerable loss of viability and some loss of functionality of hepatocytes after cryopreservation.77 However, it has also been claimed that there was unaltered viability and attachment rates on the culture dish of hepatocytes preserved for up to 4 years.3 Recently, Fisher et al78 found that hepatocyte viability decreased significantly within 60 min after thawing and the same study also noted that hepatocytes isolated from normal donor livers had normal biological functions and less cellular damage/necrosis compared to those isolated from fatty liver donors (40-50% steatosis). There are also various claims that controlled rate freezing is better than the normal freezing protocol of 80˚C (2hrs) followed by liquid nitrogen.79 Guillouzo et al80 in their review concluded that there are no advantages in complex freezing methods over the commonly used two-step method. Once again, there are as many claims for a particular protocol, as there is against it. Adams et al81 used University of Wisconsin solution, foetal bovine serum and dimethyl sulfoxide (DMSO) to cryopreserve primary human hepatocytes and reported >90% viability and metabolic activity was preserved up to 8 months. Similarly, Jamal et al4 showed that mouse hepatocytes were still capable of clonal replication when transplanted in a mouse model after 32 months of cryopreservation. There is no doubt that there are clear advantages of hepatocyte banking namely, hepatocytes can be used on demand, can be batched and function tested and can be pooled to treat a number

340

Recent Advances in Liver Surgery

Figure 5. Urea synthesis by hepatocytes isolated from resected liver.

of patients. However the apparent conflict of results and conditions across studies as indicated above, serves to highlight the work still required to optimize the cryopreservation process.18,19 Despite these problems, Baccarani et al30 have started a nation wide liver collection and hepatocyte banking facility in Italy for the purpose of cell therapy and research. Indeed due to the shortage of fresh hepatocytes, cryopreserved hepatocytes have already been used in various human clinical trials with the results indicated in Table 3. Obviously there are many problems that need to be addressed and one of the most difficult seems to be in achieving a universally acceptable cryopreservation protocol within the research community. An international panel of experts in 1999, recognized that ‘research should continue to improve the cryopreservation procedures …’82 until a universal framework for cryopreservation was agreed. At this stage, there seems little likelihood of such a universal protocol being agreed upon within the next decade. Without such a framework, issues such as cyto-toxicity, hepatocyte apoptosis and retention of comparable function in cryopreserved hepatocytes, become almost irresolvable.

Engraftment and Proliferation Adjuncts Extracellular Matrix

As indicated above Hepatocytes die within few days after transplanting to various heterotopic sites. This is mainly due to the lack of appropriate extracellular matrix component (ECM) needed for the cell attachment. In the intact liver, hepatocytes are in close contact with each other three dimensionally and extracellular matrix (ECM) proteins present in the Disse’s space also attach to hepatocytes.83 The liver ECM actually comprises less than 3% of the relative area in normal liver and consists mostly of various collagen proteins the most abundant being type I, III, IV and V. However the ECM also provides the various macromolecules that comprise the liver scaffold thus the placement of extracellular matrix components at the site of transplantation could act as an anchor for the hepatocytes, encouraging attachment and increasing survival. Results from animal

Hepatocyte Transplantation

341

experiments have been encouraging; indicating that attachment, vascularisation and a return of some therapeutic function is possible.84-86 There is growing interest in synthetic and biodegradable polymeric biomaterials for liver tissue engineering. Various artificial liver systems have been investigated including hydrogel microspheres, hollow fibers and macroporous polymer scaffolds.87,88 Among the polymeric materials used for the artificial liver support system, polyethersufone membranes are the most notable for their characteristics of stability and biocompatibility.89 However, to prolong the survival of transplanted hepatocytes ECM alone is not sufficient. The hepatocytes must be stimulated to attach to both the matrix and to one another to improve the efficiency of hepatocyte survival. For example it has been shown that the addition of RGD amino acid sequence (arginine-glycine-aspartic acid) which is present in binding domains of most extracellular matrix (ECM) proteins (e.g., fibronectin, vitronectin and collagen)90,91 stimulates cell adhesion on synthetic surfaces. Most of the cell receptors involved in such cell interactions belong to the integrin family of adhesion molecules, providing signals for cell proliferation, differentiation and migration.91 Pinkes et al92 have shown that hepatocytes survival depends on β1-integrin mediated attachment of hepatocyte to hepatic extracellular matrix. In this study, pretreatment of hepatocytes with anti β1-integrin antibodies resulted in reduction of cell attachment to laminin, fibronectin, collagen 1 and collagen IV as well as a reduction in survival, demonstrating the importance of extracellular matrix for their survival. Ajioka et al93 transfected the vascular endothelial growth factor gene (VEGF) into transplanted hepatocytes and found that the hepatocytes formed large colonies with vascular networks around the transplant. Recently, Shani-Peretz et al94 reported that hVEGF165 enhances the presence of transplanted hepatocytes within portal vessels after transplantation into rats. The authors suggested that transplanted hepatocytes first stick to each other in the portal radicles and later become included in the liver parenchyma as groups of organized cells in a process stimulated by VEGF. There is no doubt that there are yet more growth factors and other molecules which may aid the process of engraftment and eventually, proliferation of the transplanted hepatocytes. This is of interest not only for transplantation into human patients, but also in the transplantation and establishment of functioning hepatocytes in Bio Artificial devices (BAL’s). Such devices are of particular interest in Acute liver failure (FHF); a clinical syndrome associated with sudden severe impairment or loss of hepatocyte function and usually resulting in encephalopathy within 3-8 weeks.2 There is a 75-90% mortality rate in patients with acute FHF who do not receive OLT. But in less extensive hepatic necrosis, 40% survival rate has been reported95 indicating that if the cause of liver failure can be reversed, the patients who do survive (without transplantation) fully recover and have a normal life expectancy. Thus in FHF patients, temporary liver device support systems could be used to bridge until a liver becomes available for transplantation. Furthermore, it could significantly improve the survival of patients who are either too sick for surgery, metastatic cancer or concurrent alcoholism. However, it too suffers from the same issues; long term engraftment and proliferation of a clinically significant number of the donor hepatocytes.

Encapsulation

The microencapsulating technique initiated by Lim and Sun96 brought new hope for artificial liver and hepatocyte transplantation. Encapsulation of hepatocytes is developed in order to transplant and immuno-isolate these cells to human immune system. During the hepatocyte encapsulation process the cells are retained in a semi-permeable membrane that both protects them from attack by the host immune system and maintains their survival and metabolic functions by allowing the bidirectional diffusion of oxygen, nutrients and cellular products. For example, sodium alginate is extensively used as one of the synthetic ECMs. Hepatocytes encapsulated in alginate capsule produce a very high density cell culture system with mechanical support to the cells as well as immuno-protection after implantation. Alginate capsule by itself does not attract hepatocyte adhesion, due to highly hydrated anionic surface of the alginate material.97 Since

342

Recent Advances in Liver Surgery

cell anchorage is required for the survival and function of most mammalian cells, alginate is usually modified with an Arg-Gly-Asp (RGD) containing peptide to facilitate anchorage to the matrix.98 Micro-encapsulation also protects immobilized cells from damage during handling.84 Numerous animal studies have demonstrated the efficiency of encapsulated hepatocytes to immuno-isolate hepatocytes in various liver failure models.99-101 Mai et al102 used cryopreserved and noncryopreserved encapsulated (encapsulated in 400 um of alginate-poly-L-lysin) human immortalized hepatocytes in a mouse fulminant liver failure model and found survival rates were increased to 50-55% as compared to control of 20-30%. It was interesting to note in this study that intraperitoneal delivery of non-encapsulated fresh hepatocytes did not improve survival of mice with FLF, indicating a rapid loss of transplanted cells due to innate or humoral rejection mechanisms. Encapsulated hepatocytes have not yet been used in human trials nevertheless; animal trials have been extremely encouraging.

Hepatocyte Cellular Mass Required for Transplantation

An average liver contains approximately 2.8 × 1011 hepatocytes, occupying almost 80% of the total liver volume. However, it should be remembered that the total number of hepatocytes in a human liver has only been estimated. Calculations of available cells from a given transplant section is still vague although convention stipulates 4 × 109 hepatocytes per kilogram of body weight.103 Experimentally, 2.4 × 106 hepatocytes per gram of liver can be transplanted safely from a living donor, suggesting that it would not be possible to transplant more than approximately 10% of functional liver mass into a recipient liver.104 The therapeutic mass of hepatocytes actually required to restore adequate liver function in a patient, is likely to be dependant on disease state. Animal studies have indicated that transplanted hepatocytes can correct a variety of metabolic disorders even when they account for only 1-5% of the total hepatocyte mass.11 However this mass is significantly less than that thought to be required for the treatment of either chronic or acute liver failure. Both fulminant and chronic liver failure will probably require replacement of more than 10% of functional hepatocytes. As indicated above, this is not possible into the liver or spleen, but in such cases ectopic sites such as the peritoneal cavity, may provide an alternative site for hepatocyte transplantation. The required mass of cells to correct a single enzymatic biochemical defect is likely to be significantly less than for treatment of either chronic or acute liver failure. It is suggested that provision of only 1-5% of liver mass by transplantation may be sufficient to restore adequate liver functional activity.53-55 The reason for this is twofold. First, the liver has a natural ability to perform its function with only a third remaining. This is often seen in patients after a massive hepatic resection for tumour removal. Secondly, increased enzymic induction; Transplanted competent cells will exhibit higher specific activities for the missing enzymes.

Routes of Hepatocyte Implantation

Direct transplantation of hepatocytes into the liver is via infusion through the intraportal or intrasplenic route because it offers an ideal place for cell engraftment.105 It has been demonstrated through animal studies that hepatocytes translocate from the portal pedicle into the space of Disse by disrupting the sinusoidal endothelium and within 20 hours, the donor hepatocytes can join with adjacent host hepatocytes.105 Hepatocytes also engraft well when injected into the splenic pulp. Here they are entrapped in the sinusoids and vascular spaces106 and can proliferate, replacing approximately 40% of the splenic pulp (called splenic hepatisation) as well as retaining synthetic, metabolic and biliary transport function.61 Unfortunately there is a major limiting factor in using either the intrasplenic or intraportal route; the number of hepatocytes, which can be used without causing the complications previously discussed. Further there is a lack of sustained survival of the transplanted hepatocytes in the recipient liver parenchyma. Different solutions currently being investigated to encourage hepatocyte attachment, proliferation and survival include ectopic hepatocyte transplantation,

Reference

Cause of Liver Disease

Type of Transplanted Hepatocytes

LC (n = 9), CH (n = 1)

Freshly isolated autologous hepatocytes

Number of Hepatocytes Transplanted

Route of Transplantation Outcome

1.7 × 107-6.0 × 108 Intraportal

1 patient survived >10 months

Habibullah et al35 FHF (n = 7) Pooled blood group-matched human foetal hepatocytes

6 × 107/kg

Intraperitoneal

Patients (n = 2) with Grade III encephalopathy Survived; but with grade IV Only 1 recovered

Strom et al2,62

7.5 × 106-1.7 × 108

Intraportal

With FHF, 6 bridged to OLT; 1 recovered; 4 died.

Mito et al118

Soriano et al109

FHF (n = 11),

Hepatocytes cryopreserved for 1.5 weeks-8 months

LC (n = 2), Ch (n = 1)

(n = 5) or 48-h cultured hepatocytes (n = 1)

FHF (n = 3) Cryopreserved hepatocytes (duration?)

Hepatocyte Transplantation

Table 3. Clinical trials related to human hepatocyte transplantation in acute liver failure patients

All died with LC and Ch. 4 × 107-4 × 109

Intrasplenic

Two patients died One patient recovered

119,120

Bilir et al

FHF (n = 5),

Hepatocytes cryopreserved for 1-8 months

LC (n = 3)

NA

Fisher et al121

FHF (n = 1) Not available

3 × 10

9

Intraportal

All alive 4 years later

NA 8.8 × 108

4 FHF patients survived <12 days then died but one died <72 h

Intraportal

Fully recovered

LC: liver cirrhosis; Ch: chronic hepatitis; FHF: fulminant hepatic failure; NA: Not available.

343

344

Recent Advances in Liver Surgery

inclusion of extracellular matrix elements, encapsulation and proliferative stimulants and these will be discussed below. Finally, there are post transplantation problems which have been observed when utilizing either the intraportal or intrasplenic route to infuse hepatocytes. In the case of intraportal infusion, portal vein thrombosis, portal hypertension and pulmonary embolism91 are all major complications that have been noted. Intrasplenic transplantation has also resulted in similar complications. However, portal hypertension usually resolve within hours after the procedure107 and measures can be taken to reduce these complications as for example hepatic artery ligation to decrease the sinusoidal blood flow prior to hepatocytes infusion or the slow infusion of hepatocytes over a longer period has been tried.108,109 In one clinical trial 7.5 × 109 hepatocytes were transplanted through the portal vein over a 15 h period.103 No fatalities from these complications have been reported to date. Ectopic hepatocyte transplantation is defined as a transplantation site for hepatocytes other than the liver or spleen. It can potentially provide more space to transplant a greater number of isolated hepatocytes. Moreover, it has been shown to produce fewer complications than transplantation through the intraportal route. For example, Yokoyama recently showed that by preparing subcutaneous space in advance with fibroblast growth factor (bFGF) a potent angiogenic factor and providing a polyethylene terephthalate matrix, transplanted rat and mouse hepatocytes survived from 4-8 months. Hepatocytes retained their albumin synthetic and drug metabolizing capacity in this engineered subcutaneous cavity. Furthermore, the authors were able to transplant ten times the usual number of hepatocytes into the subcutaneous cavity as could be done by liver inoculation.110 Researchers have transplanted hepatocytes into several ectopic sites, including the intraperitoneal cavity,111 pancreas,112 mesenteric leaves,113 intrapulmonary artery,114 lung parenchyma,115 under the kidney capsule116 and interscapular fat pads.117 Unfortunately the transplanted hepatocytes appear to survive only for a very short time. The precise reasons are unclear but it is thought that transplantation of inadequate donor cell engraftment mass and lack of neovascularization are significant factors. To overcome these issues, the addition of different types of matrix, growth factors such as vascular endothelial growth factor gene (VEGF) and proliferative stimulants are being trialled.

Human Hepatocyte Transplantation Experience

More than 60 clinical cases have been treated with hepatocyte transplantation to either bridge patients to OLT or to improve hepatic metabolic deficiencies. The first human hepatocyte transplantation was attempted by Mito et al118 in 1993. Patients with chronic liver disease received infusions of autologous hepatocytes into the spleen, which could still be detected between 1 month and I year (radionucleotide scanning) post transplantation. Although successful as a potential protocol, no clinical improvement was noted. Attention shifted to hepatocyte transplantation for acute liver failure. There are two potential advantages to such a treatment regime; First, prolongation of survival that could bridge patients to OLT. Secondly, OLT could be avoided altogether if cell transplantation could permit regeneration of the native liver. Habibullah et al22 were the first to report single infusion transplantation of human foetal hepatocytes into the peritoneal cavity of seven patients with advanced encephalopathy (Grades III and IV). This study reported an improvement in survival from 33% to 48% (after foetal hepatocyte transplant) in 7 patients with matched retrospective controls. A summary of hepatocyte transplantation in acute liver failure patients is given in Table 3. Additionally, Strom2 reviewed the results of hepatocyte transplantation into 18 patients diagnosed with acute liver failure from a number of clinical trials in America. Complete recovery without organ transplantation occurred in two, 6 were bridged to OLT (within 1-10 days) and the remaining 10 patients died between 18 hours and 52 days after the first hepatocyte transplantation. A case of spontaneous recovery of the liver was reported by Fisher et al122 in a 37-year-old woman with FHF who was infused with 8.8 × 108 allogenic hepatocytes into the liver through a catheter placed into the portal vein. This patient fully recovered, with a rapid fall in serum ammonia levels and was discharged from the hospital after two weeks. Habibullah et al35 also reported that two of their FHF patients with Grade 3 encephalopathy fully recovered without requiring subsequent liver transplantation.

Reference

Liver Disease

Hepatocytes Type

Hepatocyte Number

Route

Grossman et al5 FH (n = 5)

Hepatocytes transfected with human LDL receptor cDNA

1 × 109-3 × 109

Intraperitoneal No improvement

Strom et al2

hAAT (n = 2)

Hepatocytes cryopreserved for 1.5 weeks-8 months

2.2 × 106

Intraportal

OLT 2-4 days cirrhosis at time of cells infusion

Strom et al62

OCT (n = 1)

Cryopreserved hepatocytes

0.7 × 109-1 × 109

Intraportal

Dead (43 days); normal ammonia level within 48 h HT

CJ (n = 1)

Freshly isolated hepatocytes

7.5 × 109

Intraportal

OLT (3.5 years)

Horslen et al

OCT (n = 1)

Fresh and cryopreserved

1.5-4.5 × 109

Intraportal

OLT (6 month) Normal protein intake after HT

Muraca et al123

GSD Ia (n = 1)

Fresh hepatocytes

2 × 109

Intraportal

Well (3 years); tolerate 7 h fasting

Sokal et al124

Refsum Disease (n = 1) Cryopreserved and fresh

Fox et al103 122

Dhawan et al125 Factor VII Deficiency defect PFIC2, CJ, OCT (n = 6)

Cryopreserved and fresh

Outcome

1.1 × 109 (fresh) 0.9-1.96 × 109 Intraportal (Cryopreserved)

Well (1 year); pipecholic acid <60%

1.09 × 109 2.18 × 109

Improvement but OLT after 7-14 months.

Intraportal

Hepatocyte Transplantation

Table 4. Hepatocyte transplantation in patients with inborn errors of metabolism

FH: homozygous familial hypercholesterolemia; hAAT: α1-antitrypsin deficiency; OCT: ornithinine transcarbamylase; CJ: Crigler-Najjar syndrome I; GSD Ia: glycogen storage disease.

345

346

Recent Advances in Liver Surgery

For metabolic deficiencies OLT has been recommended only if the genetic defect is located exclusively in the liver and associated with the onset of end-stage or FHF disease. The greatest advantage of hepatocyte transplantation for metabolic deficiencies potentially, is that the cells can be genetically manipulated ex vivo. However, the clinical use of hepatocyte transplantation is currently limited to support for the inborn errors of metabolism mainly because there are acceptable therapeutic alternatives for many metabolic diseases. For example, dietary restrictions and specific metabolic supplements are typically used to manage cytoplasmic urea cycle defects, tyrosinaemia and glycogen storage diseases and the problem is usually not severe enough to necessitate liver transplantation. The first attempt to use hepatocyte transplantation for metabolic disease in humans was in four children with familial hypercholesterolemia, a defect in which the low-density lipoprotein (LDL) receptor is deficient.5 In this study autologous hepatocytes were successfully transfected in vitro with a retroviral vector carrying the human LDL receptor gene and latter re-infused into the patient. Although there was evidence of cell engraftment, no significant metabolic improvement was seen. To date 14 patients have undergone isolated hepatocyte transplantation for metabolic diseases, the details of which are displayed in Table 4. Given the diversity of disease and hepatocyte sources and the number of patients, no final conclusion can be drawn as to the overall success of hepatocyte transplantation for metabolic diseases. However the outcomes are suggestive that isolated hepatocytes have the potential to treat patients with specific inborn errors of metabolism. It is difficult to know, given the wide variety of protocols used, whether hepatocyte transplantation was of actual benefit to any of the patients. Without clearly defined parameters such as patient selection or standardized clinical and laboratory protocols, any attempt at statistical comparison can only lead to false conclusions. There is simply not enough known to be able to show unequivocally the clinical benefits of hepatocyte transplant to patients with these disorders. It can be inferred however, that hepatocyte transplantation has the potential to be a clinically viable alternative to OLT for such disorders and with standardisation of protocols and statistically relevant clinical trials, the clinical benefits and limitations should become clear. However, research and trials can only proceed when a reliable supply of quality hepatocytes can be assured. The use of autologous, syngeneic, allogenic and xenogenic hepatocytes have all been demonstrated to be effective when used for hepatocyte transplantation.34,47,101 However, for hepatocyte transplantation to be successful whether in artificial support systems (such as biological artificial livers) or in pharmacotoxicological research, good quality human hepatocytes are essential.2,46

Conclusions

The limited numbers of hepatocyte transplantation clinical trials in man has indicated the safety and feasibility of hepatocyte transplantation but has yet to demonstrate whether it can take its place as a viable therapeutic alternative to OLT. Significant functional liver repopulation must be reliably achieved and there is still much to be learned before the appropriate therapeutic mass and engraftment parameters are optimised to enable this. Unfortunately the limiting factor for hepatocyte transplantation research is the same as that for the clinic; the availability of quality human hepatocytes. It is clear from the work so far, that the quality of the hepatocytes is paramount for successful transplantation.5,118 Ultimately, an unlimited supply of cells may be established through the creation of immortalized hepatocyte banks or use of stem cells to generate hepatocytes.40,41 However, these strategies are still in developmental infancy. Alternatives are needed now to continue the research needed to establish the safety and efficacy of hepatocyte transplantation, its appropriate uses and the development of clinical protocols. Therefore it is essential to look beyond the traditional sources of hepatocytes and to explore all the alternatives such as those discussed here. Many have their own distinctive set of problems that need to be resolved before they can be used clinically; for example, resection techniques of liver for benign disease or nontumour portions of liver resected for cancer and development of protocols that can monitor and adequately remove tumour cells before transplantation,52 is essential.

Hepatocyte Transplantation

347

The proviso for clinical use is whether a consensus can be reached with regards a universal protocol for the selection, collection, storage and reimplantation of hepatocytes. In addition, research into isolated hepatocytes from resected livers could provide the stimulus for development into cell based BAL (biological artificial livers) devices. Improved long and mid-term preservation and storage protocols of hepatocytes will further extend the pool of quality hepatocytes available for the laboratory. Why continue with hepatocyte transplantation research? Despite the obvious problems, hepatocyte transplantation has several potential therapeutic advantages over OLT. In economic terms, the cost of hepatocyte transplantation is considerably less than that of OLT. Thus multiple hepatocyte transplantation could be performed in the same patient in a cost effective manner.2 Harvested hepatocytes from a single donor could be cryopreserved and banked for future use30 thereby increasing the potential number of patients that could be successfully treated from a single donor and significantly reducing the waiting list for OLT where whole organ transplantation is not suitable. Further, recent trials have shown it possible to genetically manipulate isolated hepatocytes ex vivo. This enables targeting of inborn liver metabolic deficiencies before retransplantation of the manipulated autologous hepatocytes back into the patient, eliminating the need for immuno-suppression. The potential scope of hepatocyte transplantation is undeniable. New possible therapeutic avenues are being continually discovered; so many in fact that there is little in the way of co-ordinated research for immediate use in the clinic. Increased availability of quality human hepatocytes should redress this problem, promoting research interest and increasing the number and size of trials that can be undertaken. The data generated in turn, will help to define and refine clinical protocols and demonstrate the potential uses and therapeutic value of hepatocyte transplantation. The appearance of hepatocyte transplantation as a clinical option within the next decade could become a reality.

References

1. Mazaris EM, Roussos CT, Papalois VE. Hepatocyte transplantation: a review of worldwide clinical developments and experiences. Exp Clin Transplant 2005; 3:306–315. 2. Strom SC, Chowdhury JR, Fox IJ. Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis 1999; 19:39-48. 3. Chesno C Guyomard C, Fautrel A et al. Viability and function in primary culture of adult hepatocytes from various animal species and human beings after cryopreservation. Hepatology 1993; 18:406-414. 4. Jamal HZ, Weglarz TC, Sandgren EP. Cryopreserved mouse hepatocytes retain regenerative capacity in vivo. Gastroenterology 2000; 118:390-394. 5. Grossman M, Rader DJ, Muller DW et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolemia. Nat Med 1995; 1:1148-1154. 6. Burlina AB. Hepatocyte transplantation for inborn error of metabolism. J Inherit Metab Dis 2004; 27:373-383. 7. Ostrowsaka A, Karrer FM, Bilir BM. Histological identification of purified and cryopreserved allogenic hepatocytes following transplantation in a murine model without host immunosuppression. Transpl Int 1999; 12:188-194. 8. Nose Y, Mikami J, Kasai Y et al. An experimental artificial liver utilizing extracorporeal metabolism with sliced or granulated canine liver. ASAIO Trans 1963; 9:358-362. 9. Matas AJ, Sutherland DE, Steffes MW et al. Hepatocellular transplantation for metabolic deficiencies: Decrease of plasma bilirubin in Gunn rats. Science 1976; 192:892-894. 10. Matsumura KN. Method and device for purifying blood. US Patent N0. 3734851, US Patent Offi ce, Washington DC, 1973; 11. Gupta S, Bhargava KB, Novikoff PM. Hepatocyte transplantation: emerging insights into mechanisms of liver repopulation and their relevance to potential therapies. J Hepatology 1973; 30:162-170. 12. Overturf K, Al-Dhalimy M, Tanguay R et al. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinemia type 1. Nat genet 1996; 12:266-273. 13. Rajvanshi P, Kerr A, Bhargava KK et al. Studies of liver repopulation using the dipeptidyl peptidase IV-deficient rat and other rodent recipients: cell size and structure relationships regulate capacity for increased transplanted hepatocyte mass in the liver lobule. Hepatology 1996; 23:482. 14. Oertel M, Rosencrantz R, Chen YQ. Repopulation of rat liver by foetal hepatoblasts and adult hepatocytes transduced ex vivo with lentiviral vectors. Hepatology 2003; 37:994-1005.

348

Recent Advances in Liver Surgery

15. Rozga J, Holzman M, Moscioni AD et al. Repeated intraportal hepatocyte transplantation in analbuminemic rats. Cell Transplant 1995; 4:237-243. 16. Gupta S, Chowdhury NR, Jagtiani R et al. A novel system for transplantation of isolated hepatocytes utilizing HBs Ag-producing transgenic donor cells. Transplantation 1990; 50:472-475. 17. Ponder KP, Gupta S, Leland F et al. Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation. Proc Natl Acad Sci USA 1991; 88:1217-1221. 18. Groth CG, Arborgh B, Bjorken C et al. Correction of hyperbilirubinemia in the glucoronyltransferae deficient rats by intraportal hepatocyte transplantation. Transplant Proc 1977; 9:313-316. 19. Yoshida Y, Tokusashi Y, Lee GH et al. Intrahepatic transplantation of normal hepatocytes prevents Wilson’s disease in Long—Evans cinnamon rats. Gastroenterol 1996; 11:1654-1660. 20. De Vree JM, Ottenhoff R, Bosma PJ et al. Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis. Gastroenterol 2000; 119:1720-1730. 21. Michel JL, Rabier D, Rambaud C et al. Intrasplenic transplantation of hepatocytes in spf-ash mice with congenital ornithine transcarbamylase deficiency. Chirurgie 1993; 119:666-671. 22. Wiederkehr JC, Pollak R. Hepatocyte transplantation for the low-density lipoprotein receptor-deficient state. A study in the Watanabe rabbit. Transplantation 1990; 50:466-471. 23. Sugiyama K, Emori T, Nagase S. Synthesis and secretion of plasma proteins by isolated hepatocytes of analbuminemic rats. J Biochem 1982; 92:775-779. 24. Gagandeep S, Sokhi R, Slehria S et al. Hepatocyte transplantation improves survival in mice with liver toxicity induced by hepatic over expression of Mad 1 transcription factor. Mol Ther 2000; 1:358-365. 25. Nakamura J, Okamoto T, Schumacher IK et al. Treatment of surgically induced acute liver failure by transplantation of conditionally immortalized hepatocytes. Transplantation 1997; 63:1541-1547. 26. Sutherland DE, Numata M, Matas AJ et al. Hepatocellular transplantation in acute liver failure. Surgery 1997; 82:124-132. 27. Arkadopoulos N, Chen SC, Khalili TM et al. Transplantation of hepatocytes for prevention of intracranial hypertension in pigs with ischemic liver failure. Cell transplant 1998; 7:357-363. 28. Sommer BG, Sutherland DE, Simmons RL et al. Hepatocellular transplantation for experimental ischemic acute liver failure in dogs. J Surg Res 1980; 29:319-325. 29. Kobayashi N, Ito M, Nakamura J et al. Treatment of carbon tetrachloride and Phenobarbital-induced chronic liver failure with intrasplenic hepatocyte transplantation. Cell transplant 2000; 9:671-673. 30. Baccarani U, Sanna A, Cariani A et al. Isolation of human hepatocytes from livers rejected for liver transplantation on a national basis: Results of a 2 year experience. Liver Transplant 2003; 9:506-512. 31. Bismuth H, Houssin D. Reduced-sized orthotopic liver graft in hepatic transplantation in children. Surgery 1984; 95:367-370. 32. Barbich M, Lorenti A, Hidalgo A et al. Culture and characterization of human hepatocytes obtained after graft reduction for liver transplantation: A reliable source of cells for a bioartificial liver. Artif Organs 2004; 28:676-682. 33. Mitry RR, Dhawan A, Hughes RD et al. One liver, three recipients: segment IV from split-liver procedures as a source of hepatocytes for cell transplantation. Transplantation 2004; 77:1614-1616. 34. Sandhu JS, Petkov PM, Debeva MD et al. Stem cell properties and repopulation of the rat liver by foetal liver epithelial progenitor cell. Am J Pathol 2001; 159:1323-1334. 35. Habibullah CM, Syed IH, Qamar A et al. Human foetal hepatocyte transplantation in patients with fulminant hepatic failure. Transplantation 1994; 27:951-952. 36. Khan AA, Habeeb A, Parveen N et al. Peritoneal transplantation of human foetal hepatocytes for the treatment of acute fatty liver of pregnancy: a case report. Top Gastroenterol 2004; 25:141-143. 37. Petersen BE, Bowen WC, Patrene KD et al. Bone marrow as a potential source of hepatic oval cells. Science 1999; 284:1168-1170. 38. Lagase E, Connors H, Al-Dhalimy M et al. Purified hematopoietic cells can differentiate into hepatocytes in vivo. Nature Med 2000; 6:1229-1234. 39. Oh SH, Miyazaki M, Kouchi H et al. Hepatocyte growth factor induces differentiation of adult bone marrow cells into hepatocyte lineage, in vitro. Biochem Biophys Res Comm 2000; 279:500-504. 40. Yamada T, Yoshikawa M, Kanada S et al. In vitro differentiation of embryonic cells into hepatocyte-like cells identified by cellular uptake of indocyanine green. Stem Cells 2002; 20:146-154. 41. Miki T, Cai H, Lehmann T et al. Production of hepatocytes from human amniotic cell. Hepatology 2002; 36:20. 42. Sharma AD, Cantz T, Manns MP et al. The role of stem cells in physiology, pathology and therapy of the liver. Stem Cell Rev 2006; 1:51-58. 43. Alison MR. Liver stem cells: implications for hepatocarcinogenesis. Stem Cell Rev 2005; 253-260. 44. Kobayashi N, Fujiwara T, Westerman KA et al. Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes. Science 2000; 287:1258-1262.

Hepatocyte Transplantation

349

45. Wege H, Le HT, Chui MS et al. Telomerase reconstitution immortalizes human foetal hepatocytes without disrupting their differentiation potential. Gastroenterology 2003; 124:432-444. 46. Donini A, Baccarani U, Risaliti A et al. In vitro functional assessment of a porcine hepatocyte based bioartificial liver. Transplant Proceeding 2001; 33:3477-3479. 47. Demetriou AA, Brown RS Jr, Busuttil RW et al. Prospective, randomized, multi-centre, controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg 2004; 239:660-667. 48. Nagata H, Ito M, Cai J et al. Treatment of cirrhosis and liver failure in rats by hepatocyte xenotransplantation. Gastroenterology 2003; 124:422-431. 49. David P, Viollon C, Alexandre E et al. Metabolic capacities in cultured human hepatocytes obtained from nonwedge small liver biopsies. Human and Expt Toxicol 1998; 17:544-553. 50. Ballet F, Bouma M, Wang S et al. Isolation, culture and characterization of adult human hepatocytes from surgical liver biopsies. Hepatology 1984; 4:849-854. 51. Guguen-Gillouzo C, Campion JP, Brissot P et al. High yield preparation of isolated human adult hepatocytes by enzymatic perfusion of the liver. Cell Biol Int Rep 1982; 6:625-628. 52. Haghighi KS, Woon WWL, Akhter J et al. A new source of hepatocyte for transplantation. Transplant Proc 2004; 36:2466-2468. 53. Cameron GR, Oakley CL. Transplantation of liver. J Pathol Bacteriol 1934; 38:17-28. 54. Seneviratne RD. Transplantation of a lobe of the liver in the rat. J Pathol Bacteriol 1955; 70:271-283. 55. Richert L, Alexandre E, LIoyd T et al. Tissue collection, transport and isolation procedures required to optimize human hepatocyte isolation from waste liver surgical resections. A multi-laboratory study. Liver International 2004; 24:371-378. 56. Alexandre E, Cahn M, Abadie-Viollon C et al. Influence of pre, intra- and post-operative parameters of donor liver on the outcome of isolated human hepatocytes. Cell and Tissue Banking 2002; 3:223-233. 57. Caruana M, Battle T, Fuller B et al. Isolation of human hepatocytes after hepatic warm and cold ischemia: A practical approach using University of Wisconsin Solution. Cryobiology 1999; 38:165-168. 58. Schneider WC, Potter VR. The assay of animal tissues for respiratory enzymes. II Succinic dehydrogenase and cytochrome oxidase. J Biol Chem 1943; 149:217. 59. Berry MN, Friend DS. High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol 1969; 43:506-520. 60. Seglen PO. Preparation of isolated rat liver cells. Methods Cell Biol 1976; 13:29-83. 61. Strom SC, Jirtle RL, Jones RS et al. Isolation, culture and transplantation of human hepatocytes. J Natl Cancer Inst 1982; 68:771-778. 62. Strom SC, Fisher RA, Rubinstein WS et al. Transplantation of human hepatocytes. Transplant Proc 1997; 29:2103-2106. 63. Hughes RD, Mitry RR, Dhawan A. Hepatocytes transplantation for metabolic liver disease: UK experience. JR Soc Med 2005; 98:341-345. 64. Loretz LJ, Li AP, Flye MW et al. Optimization of cryopreservation procedures for rat and human hepatocytes. Xenobiotica 1989; 19:489-498. 65. Chesne C, Guyomard C, Fautrel A et al. Viability and function in primary culture of adult hepatocytes from various animal species and human beings after cryopreservation. Hepatology 1993; 18:406-414. 66. Nakazawa F, Cai H, Miki T et al. Human hepatocyte isolation from cadaver donor liver. In: Gupta S, Jansen PLM, Klempnauer J, Manns MP, eds. Hepatocyte Transplantation. Falk Symposium 126, London, Kluwer Academic Publishers, 2002: 67. Adams RM, Wang M, Crane AM et al. Effective cryopreservation and long-term storage of primary human hepatocytes with recovery of viability, differentiation and replicative potential. Cell Transplant 1995; 4:579-586. 68. Coundouris JA, Grant MH, Engeset J et al. Cryopreservation of human adult hepatocytes for use in drug metabolism and toxicity studies. Xenobiotica 1993; 23:1399-1409. 69. de Sousa G, Dou M, Barbe D et al. Freshly isolated or cryopreserved human hepatocytes in primary culture: influence of drug metabolism on hepatotoxicity. Toxicol in Vitro 1991; 5:483-486. 70. Rijntjes PJ, Moshage HJ, van Gemert PJ et al. Cryopreservation of adult human hepatocytes. The influence of deep freezing storage on the viability, cell seeding, survival, fine structures and albumin synthesis in primary cultures. J Hepatol 1986; 3:7-18. 71. Ruegg CE, Silber PM, Mughal RA. Cytochrome P-450 induction and conjugated metabolism in primary human hepatocytes after cryopreservation. In Vitro Toxicol 1997; 10:217-222. 72. Chesne C, Guillouzo A. Cryopreservation of isolated rat hepatocytes: a critical evaluation of freezing and thawing conditions. Cryobiology 1988; 25:323-330. 73. Ostrowska A, Bode CD, Pruss J et al. Investigation of functional and morphological integrity of freshly isolated and cryopreserved human hepatocytes. Cell and Tissue Banking 2000; 1:55-68.

350

Recent Advances in Liver Surgery

74. Hengstler JG, Utesch D, Steinberg P et al. Cryopreserved primary hepatocytes as a constantly available in vitro model for the evaluation of human and animal drug metabolism and enzyme induction. Drug Metab Rev 2000; 32:81-118. 75. Guillouzo A, Rialland L, Fautrel A et al. Survival and function of isolated hepatocytes after cryopreservation. Chemico-Biol Interactions 1991; 121:7-16. 76. Cho JJ, Joseph B, Sappal BS et al. Analysis of the functional integrity of cryopreserved human liver cells including xenografting in immunodeficient mice to address suitability for clinical applications. Liver International 2004; 24:361-370. 77. Koebe HG, Dunn JC, Tonner M et al. A new approach to the cryopreservation of hepatocytes in a sandwich culture configuration. Cryobiol 1990; 27:576-584. 78. Fisher RA, Bu D, Thompson M et al. Optimization of conditions for clinical human hepatocyte infusion. Cell Transplant 2004; 13:677-689. 79. LIoyd TDR, Orr S, Skett P et al. Cryopreservation of hepatocytes: a review of current methods for banking. Cell and Tissue Banking 2003; 4:3-15. 80. Guillouzo A, Rialland L, Fautrel A et al. Survival and function of isolated hepatocytes after cryopreservation. Chemico-Biol Interactions 1991; 121:7-16. 81. Adams RM, Wang M, Crane AM et al. Effective cryopreservation and long-term storage of primary human hepatocytes with recovery of viability, differentiation and replicative potential. Cell Transplant 1995; 4:579-586. 82. Li Ap, Gorycki PD, Hengstler JG et al. Present status of the application of cryopreserved hepatocytes in the evaluation of xenobiotics: consensus of an international expert panel. Chemico-Biological Interactions 1999; 121:117-123. 83. Zeisberg M, Kramer K, Sindhi N et al. De-differentiation of primary human hepatocytes depends on the composition of specialized liver basement membrane. Mol Cell Biochem 2006; 283:181-189. 84. Ambrosino G, Varotto S, basso SMM et al. Hepatocyte transplantation in the treatment of acute liver failure: microencapsulated hepatocytes versus hepatocytes attached to an autologous biomatrix. Cell Transplant 2003; 12:43-49. 85. Ohashi K, Meuse L, Schwall R et al. Sustained survival of human hepatocytes in mice: a model for in vivo infection with human hepatitis B and hepatitis delta viruses. Nat Med 2001; 6:327-331. 86. De Bartolo L, Catapano G, Della Volpe C et al. The effect of surface roughness of microporous membranes on the kinetics of oxygen consumption and ammonia elimination by adherent hepatocytes. J Biomater Sci-Polym Edn 1999; 10:641-655. 87. Dixit V, Piskin E, Arthur M et al. Hepatocyte immobilization on PHEMA microcarriers and its biologically modified forms. Cell Transplantation 1992; 1:391-399. 88. Xu Q, Sun X, Qiu Y et al. The optimal hepatocyte density for a hollow-fibre bioartificial liver. Ann Clinical and Lab Science 2004; 34:87-93. 89. De Bartolo L, Morelli S, Rende M et al. New modified polyetheretherketone membrane for liver cell culture in biohybrid systems: adhesion and specific functions of isolated hepatocytes. Biomaterial 2004; 25:3621-3629. 90. Hersel U, Dahmen C. RGD modified polymers: biomaterials for stimulated cell adhesion and beyond. Biomaterials 2003; 24:4385-4415. 91. Hynes RO. Integrins: versatility, modulation and signalling in cell adhesion. Cell 1992; 69:11-25. 92. Pinkse GGM, Voorhoeve MP, Noteborn M et al. Hepatocyte survival depends on B1-integrin-mediated attachment of hepatocytes to hepatic extracellular matrix. Liver Int 2004; 24:218-226. 93. Ajioka I, Akaike T, Watanabe Y. Expression of vascular endothelial growth factor promotes colonization, vascularization and growth of transplanted hepatic tissues in the mouse. Hepatol 1999; 29:396-402. 94. Shani-Peretz H, Tsiperson V, Shoshani G et al. HVEFG165 increases survival of transplanted hepatocytes within portal radicles: suggested mechanism for early cell engraftment. Cell Transplant 2005; 14:49-57. 95. Court FG, Wemyss-Holden SA, Dennison AR et al. Bioartificial liver support devices: historical perspectives. ANZ J Surg 2003; 73:739-748. 96. Lim F, Sun AM. Microencapsulated islets as bio-artificial endocrine pancreas. Science 1980; 210:908-910. 97. Glicklis R, Shapiro L, Agbaria R et al. Hepatocyte behaviour within three-dimensional porous aliginate scaffolds. Biotechnol Bioengineering 2000; 67:344-353. 98. Smetana K Jr. Cell biology of hydrogels. Biomaterials 1993; 14:1046-1050. 99. Dixit V, Darvasi R, Arthur M et al. Restoration of liver function in Gunn rats without immunosuppression using transplanted microencapsulated hepatocytes. Hepatology 1990; 12:1342-1349. 100. Hamazaki K, Doi Y, Koide N. Microencapsulated multicellular steroid of rat hepatocytes transplanted intraperitoneally after 90% hepatectomy. Hepatogastroenterol 2002; 49:1514-1516.

Hepatocyte Transplantation

351

101. Matas AJ, Sutherland DE, Steffes MW et al. Hepatocellular transplantation for metabolic deficiencies: Decrease of plasma bilirubin in Gunn rats. Science 1976; 192:892-894. 102. Mai G, Huy NT, Morel J et al. Treatment of fulminant liver failure by transplantation of microencapsulated primary or immortalized xenogenic hepatocytes. Transplantation proc 2005; 37:527-529. 103. Fox IJ, Chowdhury JR, Kaufman SS et al. Treatment of the Crigler-Najjar syndrome type 1 with hepatocyte transplantation. N Engl J Med 1998; 338:1422-1426. 104. Selden C, Hodgson H. Cellular therapies for liver replacement. Transplant Immunol 2004; 12:273-288. 105. Gupta S, Rajvanshi P, Sokhi R et al. Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium. Hepatol 1999; 29:509-519. 106. Mito M, Ebata H, Kusano M et al. Morphology and function of isolated hepatocytes transplanted into rat spleen. Transplant 1979; 28:499-505. 107. Grossman M, Rader DJ, Muller DW et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolemia. Nat Med 1995; 1:1148-1154. 108. Rajvanshi P, Kerr A, Bhargava KK et al. Efficacy and safety of repeated hepatocyte transplantation for significant liver repopulation in rodents. Gasteroenterology 1996; 111:1092-1102. 109. Soriano HE, Wood RP, Kang DC et al. Hepatocellular transplantation in children with fulminant liver failure. Hepatol 1997; 26:239A. 110. Yokoyama T, Ohashi K, Kuge H et al. In vivo engineering of metabolically active hepatic tissue in a neovascularised subcutaneous cavity. Am J Transplant 2005; 6:50-59. 111. Demetriou AA, Levenson SM, Novikoff PM et al. Survival, organization and function of microcarrier-attached hepatocytes transplanted in rats. Proc Natl Acad Sci USA 1986; 83:7475-7479. 112. Jaffe V, Darby H, Selden C et al. The growth of transplanted liver cells within the pancreas. Transplantation 1988; 45:497-498. 113. Sano K, Cusick RA, Lee H et al. Regenerative signals for heterotopic hepatocyte transplantation. Transplant Proc 1996; 28:1857-1858. 114. Selden C, Gypta S, Johnstone R et al. The pulmonary vascular bed as a site for implantation of isolated liver cells in inbred rats. Transplantation 1984; 38:81-83. 115. Then P, Sandbichler P, Erhart R et al. Hepatocyte transplantation into lung for treatment of acute hepatic failure in the rat. Transplant Proc 1991; 23:892-893. 116. Ricordi C, Lacy PE, Callery MP et al. Trophic factors from pancreatic islets in combined hepatocyte-islet allografts enhance hepatocellular survival. Surgery 1989; 105:218-223. 117. Jirtle RL, Biles C, Michalopoulos G. Morphologic and histochemical analysis of hepatocytes transplanted into syngeneic hosts. Am J Pathol 1980; 101:115-126. 118. Mito M, Kusano M, Kawaura Y. Hepatocyte transplantation in man. Transplant Proc 1992; 24:3052-3053. 119. Bilir BM, Guinette D, Karrer DA et al. Hepatocyte transplantation in acute liver failure. Liver Transpl 2000; 6:32-40. 120. Bilir B, Durham JD, Krystal J et al. Transjugular intra-portal transplantation of cryopreserved human hepatocytes in a patient with acute liver failure. Hepatol 1996; 24:308A. 121. Fisher RA, Bu D, Thompson M et al. Defining hepatocellular chimerism in a liver failure patient bridged with hepatocyte infusion. Transplantation 2000; 69:303-307. 122. Horslen SP, Fox IJ. Hepatocyte transplantation. Transplantation 2004; 77:1481-1466. 123. Muraca M, Gerunda G, Neri D et al. Hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet 2002; 359:317-318. 124. Sokal E, Smets F, Bourgois A et al. Hepatocyte transplantation in a 4-year old girl with peroxisomal biogenesis disease: technique, safety and metabolic follow-up. Transplantation 2003; 76:735-738. 125. Dhawan A, Mitry RR, Hughes RD et al. Hepatocyte transplantation for inherited factor VII deficiency. Transplantation 2004; 78(12):1812-1814. 126. Rosen ED, Chan JC, Idusogie E et al. Mice lacking factor VII develop normally but suffer fatal perinatal bleeding. Nature 1997; 390:290-294. 127. Kumaran V, Benetn D, Follenzi A et al. Transplantation of endothelial cells corrects the phenotypes in haemophilia A mice. J Thromb Haemost 2005; 3:2022-2031.

Chapter 25

Liver Transplantation in HIV-Infected Individuals Paolo Antonio Grossi*

Abstract

S

everal recent reports have shown that end-stage liver disease is the leading cause of death among HIV-infected persons in the highly active antiretroviral therapy (HAART) era. Until a few years ago, HIV infection was an exclusion criteria for organ transplantation. One major concern was that administering iatrogenic immunosuppression to an already immunocompromised individual would lead to an increased risk of opportunistic infections and acceleration of HIV-related disease. However, more recently, because of the significant increase in life expectancy of HIV-infected persons treated with HAART, liver, kidney, kidney-pancreas, heart and lung transplantation have been introduced in this patients population in several centers around the world. Despite the limited number of transplanted patients worldwide and the shortness of the follow-up of a great number of them, ongoing studies confirm that the short term results are comparable with those observed in non HIV-infected liver transplant (OLT) recipients. It would seem that at this point, there is no medical justification to withhold organs from patients whose HIV infection is well controlled, as their cumulative survival does not dramatically differ from the non-HIV population. The challenges involved with the care of these patients require a joint effort by a multidisciplinary team.

Introduction

AIDS-related morbidity and mortality in human immunodeficiency virus (HIV)-infected patients continue to decrease as a result of the introduction of highly active antiretroviral therapy (HAART) and prophylaxis for traditional opportunistic infections. HIV-infected patients now harbor hope for a prolonged AIDS-free survival.1-5 However, HIV-infected individuals are frequently co-infected with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) due to shared routes of transmission. Chronic liver disease, has emerged as a leading cause of morbidity and mortality among persons living with HIV. Several studies suggest that HIV disease modifies the natural history of chronic HCV infection leading to an accelerated course of progression from chronic active hepatitis to cirrhosis, end-stage liver disease and death.6-7 In addition, there is an increasing awareness of the potential toxic effects associated with prolonged HAART. Although some adverse effects (e.g., lactic acidosis) are currently rarely observed owing to avoidance of specific drug combinations,8 long-term toxic effects possibly resulting from mitochondrial toxicity, type 2 diabetes mellitus and cardiovascular disease have now emerged.9-12

*Paolo Antonio Grossi—Department of Clinical Medicine, University of Insubria, 21100 Varese, Italy. Email: [email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

Liver Transplantation in HIV-Infected Individuals

353

For patients with end stage liver disease liver transplantation is the only viable option. Patients with HIV infection have generally been excluded from consideration for organ transplantation. One major concern was that administering iatrogenic immunosuppression to an already immunocompromised individual would lead to an increased risk of opportunistic infection and acceleration of HIV-related disease. Prior to the advent of HAART, very poor outcomes and numerous complications after OLT were reported.13-16 Other arguments against OLT for the HIV population included the scarcity of organs, ethical concerns regarding organ allocation and the fear of decreased public support.17-18 However, HIV infection may now be considered a chronic disease and not an absolute exclusion to transplantation. For people with HIV experiencing organ failure, transplantation needs to be an option.19-21 Ongoing pilot programs in the United States and Europe are currently evaluating the efficacy and safety of liver and kidney transplantation in HIV-positive individuals. Limited published data that described good short-term outcomes after OLT for patients with HIV infection, demand a revision of the attitudes that have excluded these patients from transplantation.22-29 It would seem that at this point, there is no medical justification to withhold organs from patients whose HIV disease is well controlled, as their cumulative survival does not dramatically differ from the non-HIV population. The challenges involved with the care of these patients require a joint effort by a multidisciplinary team. This chapter will attempt to describe the current clinical strategies and the outcomes after liver transplantation in the HIV-positive recipients.

The Need: Liver Disease in HIV-Infected Individuals

The prevalence of end-stage liver disease in HIV-infected patients continues to increase as a result of HCV and HBV co-infection reported at 22-33% and 9% respectively.30-33 There are in fact data to support that progression of liver disease mediated by viral hepatitis is exacerbated in people with HIV as compared to people who are HIV negative and monoinfected with HBV or HCV.34 Hepatocellular carcinoma also appear to be more aggressive in this patient’s population.35 Although HAART clearly has prolonged survival, it has done so at the cost of many new and unusual drug-induced toxicities: lipodystrophy, diabetes, dyslipidemia and direct hepatotoxic injury. Nucleoside analogue toxicity can cause fulminant hepatic failure with lactic acidosis and massive hepatic steatosis and nevirapine can cause significant hepatotoxicity and even death.36-37

Referral for Transplant Evaluation and Selection Criteria

In general, referral for liver transplantation follows the same criteria established for all potential candidates. In patients with chronic liver disease and cirrhosis the main indications for liver transplantation are: • decompensated liver disease with ascites, encephalopathy (important to exclude HIV-related dementia) or problematic varices; • poor synthetic function, e.g., albumin <30 g/l, INR >1.5 and elevated serum bilirubin e.g., >50 mmol/L; • hepatocellular carcinoma detected during regular tumour surveillance (recommended at least 6 monthly in all patients with cirrhosis). The selection criteria for HCC are normally what are referred to as the Milan criteria.38 These are: no more than three tumour nodules, no nodule greater than 5 cm in diameter, absence of macroscopic portal vein invasion. The criteria for proceeding with transplantation in the HIV-positive patient continue to evolve and are slowly being liberalized. Following the first experiences it was immediately clear that given the potential clinical scenarios, e.g., past opportunistic infections, persistently detectable HIV viral load, antiretroviral therapy intolerance due to liver dysfunction and an unknown durability of immunologic recovery, it should have been critical to begin prospective clinical trials to determine the safety and efficacy of transplantation in HIV-infected individuals with end-stage liver disease. The absolute CD4+ T-cell count continues to be used as a reflection of the intact immune system. For patients with end-stage liver disease and portal hypertension, the T-cell requirement has been

354

Recent Advances in Liver Surgery

Table 1. Inclusion and exclusion criteria for liver transplantation in different countries Italy39

Spain40

UK41

USA42

No <1 year Some**

Some* No

No after immune-riconstitution

Some* No

CD4+ Count

≥200 ≥100 (DC)

≥100

≥200 ≥100 (PHT)

≥100

HIV-RNA undetectable***

Yes

Yes

Yes

Yes

C Events# • OI • Neoplasms

43

#AIDS defining opportunistic infection (OI) or malignancy; *Spain: TB, PCP or esophageal candidiasis; US: esophageal candidiasis or PCP; **Italy: basal cell carcinoma or in situ carcinoma of the cervix with documented disease-free greater than 5 years; ***If HIV-RNA is detectable, a documented response to previous antiretroviral treatment and being able to achieve viral load (VL) suppression post transplant, is required.

dropped to 100 cells/mL as a result of lower T-cell counts noted in potential liver transplant recipients with splenomegaly and presumed splenic sequestration of T-lymphocytes. A demise in CD4+ T-cell counts associated with rapid decompensation of liver disease has been noted in several co-infected potential liver recipients, which occurs at the same time point at which the Model for End-Stage Liver Disease score escalates to a number required for donor liver allocation. For this reason, the CD4+ T-cell count requirement of 100 cells/mL has been extended to a period of three months prior to the time of the liver transplant in the current multisite National Institutes of Health protocol. Current practice is targeting liver transplantation at patients with: • CD4 counts >100 cells/ml for at least three months • absence of HIV viraemia • absence of AIDS-defining illness after immune reconstitution • therapeutic options available if HIV disease re-activates Differences and similarities among inclusion and exclusion criteria for liver transplantation in different countries are reported in Table 1. As a result of good outcomes of HIV-infected transplant recipients with a history of opportunistic infections who did not experience recurrence of disease, many centers are now including patients with a history of opportunistic infections which were controlled after initiation of HAART therapy. However, opportunistic infections for which there is no reliable therapy remain a contraindication to transplantation in the HIV-infected recipient. Liver allocation is generally based on severity of illness, with the sickest patients receiving priority according to the model for end stage liver disease (MELD) score.44 However, in a study from the University of Pittsburgh,45 the parameters that have proven to be predictive for poor outcome in the MELD system (INR, bilirubin and creatinine) failed to predict the poorer outcome in the subset of HIV-positive patients who succumbed to infection/sepsis. More recently in a study analyzing the results from the entire US cohort enrolled in the multicenter NIH supported trial, a MELD score ≥25 has been found to be an independent risk factor for pretransplantation death in HIV-infected liver transplantation candidates.46 Since it is not clear if MELD score adequately predict overall disease severity and progression to death in HIV-infected liver transplant candidates, this area is under active investigation.

Immunosuppression, HAART and Drug Interactions

The use of immunosuppressive drug therapy in HIV-infected patients has so far not shown major detrimental effects and some drugs in combination with HAART have even demonstrated possible

Liver Transplantation in HIV-Infected Individuals

355

beneficial effects for specific HIV settings.47 Nevertheless, organ transplantation in HIV-infected patients remains a complex intervention and more studies will be required to clarify open questions such as long-term effects of drug interactions between antiretroviral and immunosuppressive drugs. The immunosuppressant medications cyclosporine, tacrolimus and sirolimus interact pharmacokinetically with protease inhibitors due to metabolism by cytochrome p4503A enzymes, the same enzyme complex that is responsible for clearing the calcineurin inhibitors cyclosporine and tacrolimus. In addition, both immunosuppressive and antiretroviral drugs are also substrates and inhibitors of P-glycoprotein, a transporter found on the apical membranes of intestinal epithelial and hepatic cells, whose function is to decrease absorption and increase excretion of its substrates.48 Several case reports have described significant interactions between the agents used in HAART and immunosuppressive drugs (interference with absorption, metabolism, mechanism of action; enhancement of action). Immunosuppressant doses necessary to achieve adequate levels are much lower in patients taking protease inhibitors and often require further reductions over time. On the other hand, efavirenz is a P4503A inducer that might require increased immunosuppressant dosages.49-52

Management of HCV and HBV Recurrence after Transplantation

The ability to control HCV recurrence after liver transplantation has been the major limiting factors in the HCV/HIV infected population. The rapid recurrence of HCV after liver transplantation in the HCV/HIV-coinfected recipient has been seen on several occasions in the early experience and there are significant concerns that the HIV/HCV-coinfected patients are at risk for poorer outcomes than the rest of the HIV-positive recipients.53 For the HCV-positive and HIV-negative transplant recipient, there is nothing in the literature to suggest the rates of HCV clearance are better when the recipients receive preemptive therapy with interferon and ribavirin after transplantation. Furthermore, the complexity of the drug interactions and toxicities which are invariably present in these patients would make preemptive therapy extremely challenging in the early posttransplant period. For all these reasons, the current recommendations for the HIV/ HCV-coinfected recipient are no different from those observed for the HIV-negative negative recipients. HCV treatment should be initiated when there is histologic evidence for progressive or severe recurrence, with an HAI score greater than 8 or fibrosis stage higher than 2. Although dual therapy with interferon and ribavirin has proven more efficacious, caution and dose adjustment of the ribavirin is extremely important in the patients with renal insufficiency. Furthermore adjunctive therapy with growth factors is almost always necessary to correct the drug induced anemia, lymphopenia and thrombocytopenia. The current success of liver transplantation for HBV mediated liver disease is related to significant advances in the ability to control reinfection posttransplant.54-55 Because the HIV/ HBV-coinfected patients are often resistant to lamivudine as a result of the use of this agent in many HAART regimens, there were concerns that the HIV-positive patient with lamivudine resistance would be at an increased risk for recurrent HBV posttransplant. However, in the early experience, recurrent HBV has been controlled with long term management with hepatitis B immune globulin, lamivudine, adefovir and/or tenofovir.56

Worldwide Experience of Liver Transplantation in the HAART Era

The ability to suppress HIV viral replication with HAART therapy was the initial motivation for reconsidering liver transplantation in HIV-infected individuals. The first liver transplant performed in the HAART era in an hemophilia patients co-infected with HCV and HIV has been reported in 1999 by the Pittsburgh group.22 Since then there have been numerous reports of successful liver transplantation in people with HIV during the HAART era.17-29 Unfortunately, many of the published reports include some of the same subjects so it is difficult to determine the total number of recipients and their outcome. In the largest report which pooled data from the University of Pittsburgh, University of Miami, University of California San Francisco, King’s College (London) and the University of Minnesota,

356

Recent Advances in Liver Surgery

survival data was compared to a United Network for Organ Sharing (UNOS) database cohort of matched HIV-negative controls. Cumulative survival at years 1, 2 and 3 (87%, 73% and 73%) was similar to age- and race-matched HIV-negative recipients from the UNOS database (87%, 82% and 78%). However, poorer survival rates within the HIV-positive recipients were associated with HCV infection, intolerance of HIV medication posttransplant and posttransplant CD4 counts less than 200. Although the HCV cohort had significantly poorer survival in the HIV-positive recipients, the difference in survival between HCV monoinfected (UNOS database) versus coinfected recipients did not reach statistical significance at the P_0.05 level.24 In a recently published prospective series of liver and kidney transplant recipients with stable HIV disease,29 11 liver and 18 kidney transplant recipients were followed for a median of 3.4 years. One- and 3-year liver recipients’ and graft’s survival was 91% and 64% and 82% and 64%, respectively. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999-2004 transplants in the US national database. CD4+ T-cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). Two-thirds of hepatitis C virus (HCV)-infected patients, but no patient with hepatitis B virus (HBV) infection, recurred.

Conclusions

With the advent of HAART, HIV infection has changed from a rapidly progressive and fatal disease to a chronic condition and end-stage liver failure is now the most common cause of mortality in HIV-infected patients. Although many questions about HIV and transplantation remain unanswered, the extension of the indications for liver transplantation to HIV-infected individuals is now a reality in many countries, offering new opportunities to patients dying from end-stage liver disease. Reasonable transplant and HIV-related outcomes among liver recipients suggest in fact that transplantation may be an option for selected HIV-infected patients cared for at centers with adequate expertise. The advances in HIV management have made it difficult to continue denying solid organ transplantation to this population based upon futility arguments alone. In view of the complexities and uncertainties inherent in transplantation of HIV-infected individuals, it seems likely that the number of potential recipients may remain small and that such procedures will be limited to selected centres that can develop the required experience and be able to prefer protocols for a full audit and refinement. A multisite NIH-sponsored study, with a targeted enrollment of 125 liver and 150 kidney transplants in HIV+ individuals patients was started in the USA in 2003 and is currently ongoing. The primary aim is to verify if HIV-infected liver and kidney recipients will have survival rates similar to other patient groups without HIV infection that are currently considered acceptable transplant candidates.57 Other studies are ongoing in many European countries with the aim to answer to the multiple unanswered questions in this special patient’s population. Pooling the data from the US and EU cohort will allow further analysis and refinements of the current patient’s selection and management strategies. The exclusion of HIV-infected patients can no longer be justified based on the early results demonstrating the safety and efficacy of transplantation in this group of patients. It is imperative the HIV-positive patients, HIV health care providers and the transplant community are aware that transplant is a viable option for the HIV-infected patient. Unnecessary and unacceptable delays in referral will result in increased rates of morbidity and mortality.58

References

1. Palella FJ Jr, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators. N Engl J Med 1998; 338:853-860. 2. Babiker A, Bhaskaran K, Darbyshire J et al. CASCADE collaboration determinants of survival following HIV-1 seroconversion after the introduction of HAART. Lancet 2003; 362:1267-1274.

Liver Transplantation in HIV-Infected Individuals

357

3. Palella FJ Jr, Baker RK, Moorman AC et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43:27-34. 4. Crum NF, Riffenburgh RH, Wegner S et al. Comparisons of causes of death and mortality rates among HIV-infected persons: analysis of the pre, early and late HAART (highly active antiretroviral therapy) eras. J Acquir Immune Defic Syndr 2006; 41:194-200. 5. Sackoff JE, Hanna DB, Pfeiffer MR et al. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med 2006; 145:397-406. 6. Bica I, McGovern B, Dhar R et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32:492. 7. Weber R, Sabin CA, Friis-Moller N et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006; 166:1632-1641. 8. Imhof A, Ledergerber B, Gunthard HF et al. Risk factors for and outcome of hyperlactatemia in HIV-infected persons: is there a need for routine lactate monitoring? Clin Infect Dis 2005; 41:721-728. 9. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000; 356:1423-1430. 10. Friis-Moller N, Sabin CA, Weber R et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993-2003. 11. Mehta SH, Thomas DL, Torbenson M et al. The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection. Hepatology 2005; 41:123-131. 12. Sulkowski MS, Mehta SH, Torbenson M et al. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS 2005; 19:585-592. 13. Rubin HR, Jenkins RL, Shaw BW et al. The acquired immunodeficiency syndrome and transplantation. Transplantation 1987; 44:1-4 14. Dummer JS, Erb S, Breinig MK et al. Infection with human immunodeficiency virus in the Pittsburgh transplant population. Transplantation 1989; 47:134-140. 15. Tsakis AG, Cooper MH, Dummer JS et al. Transplantation in HIV+ patients Transplantation 1990; 49:354-358. 16. Bouscarat F, Samuel D, Simon F et al. An observational study of 11 French liver transplant recipients infected with human immunodeficinecy virus type 1. Clin Infect Dis 1994; 19:854-859. 17. Roland ME, Stock PG. Solid organ transplantation is a reality for patients with HIV infection. Current HIV/AIDS Reports 2006; 3:132-138. 18. Halpern SD, Asch DA, Shaked A et al. Determinants of transplant surgeons’ willingness to provide organs to patients infected with HBV, HCV or HIV. Am J Transplant 2005; 5:1319-1325. 19. Halpern SD, Ubel PA, Caplan AL. Solid-organ transplantation in HIV-infected patients. N Engl J Med 2002; 347:284-287. 20. Roland ME, Havlir DV. Responding to organ failure in HIV-infected patients. N Engl J Med 2003; 348:2279-2281. 21. Grossi P. Liver transplantation in HIV-positive individuals: a new paradigm. Transplant Proc 2003; 35:1005-1006. 22. Ragni MV, Dodson SF, Hunt SC et al. Liver transplantation in a hemophilia patient with acquired immunodeficiency syndrome. Blood 1999; 93:1113-1114. 23. Neff GW, Bonham A, Tzakis AG et al. Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease. Liver Transpl 2003; 9:239-247. 24. Ragni MV, Belle SH, Im K et al. Survival of human immunodeficiency virus-infected liver transplant recipients. J Infect Dis 2003; 188:1412-1420. 25. Stock PG, Roland ME, Carlson L et al. Kidney and liver transplantation in human immunodeficiency virus-infected patients: A pilot safety and efficacy study. Transplantation 2003; 76:370-375. 26. Roland ME, Stock PG. Liver transplantation in HIV-infected recipients. Semin Liver Dis 2006; 26:273-284. 27. Roland ME, Carlson LL, Frassetto LA et al. Solid organ transplantation: referral. Management and outcome in HIV infected patients. AIDS Reader 2006; 16:664-668. 28. Schreibman I, Gaynor JJ, Jayaweera D et al. Outcomes after orthotopic liver transplantation in 15 HIV-infected patients. Transplantation 2007; 84:697-705. 29. Roland ME, Barin B, Carlson L et al. HIV-infected liver and kidney transplant recipients: 1- and 3 year outcomes. Am J Transplant 2008; 8:355-365. 30. Ockenga J, Tillmann HL, Trautwein C et al. Hepatitis B and C in HIV-infected patients. Prevalence and prognostic value. J Hepatol 1997; 27:18. 31. Staples CT Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta VA (Veterans Affairs Medical Center) Cohort Study (HAVACS): The effect of coinfection on survival. Clin Infect Dis 1999; 29:150.

358

Recent Advances in Liver Surgery

32. Rockstroh JK, Mocroft A, Soriano V et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis 2005; 192:992-1002. 33. Konopnicki D, Mocroft A, de Wit S et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS 2005; 19:593-601. 34. Rosenthal E, Pialoux G, Bernard N et al. Liver-related mortality in human-immunodeficiency-virus -infected patients between 1995 and 2003 in the French GERMIVIC Joint Study Group Network (MORTAVIC 2003 Study). J Viral Hepat 2007; 14:183-188. 35. Puoti M, Bruno R, Soriano V et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS 2004; 18:2285-2293. 36. Jain MK. Drug-induced liver injury associated with HIV medications. Clin Liver Dis 2007; 11:615-639. 37. Rivero A, Mira JA, Pineda JA. Liver toxicity induced by nonnucleoside reverse transcriptase inhibitors. J Antimicrob Chemother 2007; 59:342-346. 38. Mazzaferro V, Regalia E, Doci R et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334:693-699. 39. Protocollo per il trapianto di fegato nei soggetti con infezione da HIV. http://www.ministerosalute. it/imgs/C_17_normativa_426_allegato.pdf 40. Miro JM, Laguno M, Moreno A et al. Management of end stage liver disease (ESLD): what is the current role of orthotopic liver transplantation (OLT)? J Hepatol 2006; 44(Suppl 1):S140-145. 41. O’Grady J, Taylor C, Brook G. Guidelines for liver transplantation in patients with HIV infection (2005). HIV Med 2005; 6 Suppl 2:149-153. 42. Solid organ transplantation in the HIV-infected patient. Am J Transplant 2004; 4(Suppl 10):83-88. 43. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992; 41(RR-17):1-19. 44. http://www.mayoclinic.org/meld/mayomodel6.html 45. Ragni M, Eghtesad B, Schlesinger K et al. Pretransplant survival is shorter in HIV-positive than HIV-negative subjects with end-stage liver disease. Liver Transpl 2005; 11:1425-1430. 46. Subramanian A, Sulkowski M, Barin B et al. Model for end stage liver disease score predicts risk of mortality before liver transplantation in HIV-infected individuals. Program and abstracts of the 15th conference on retroviruses and opportunistic infections;2008; Boston, Massachusetts. Abstract 64. 47. Ciuffreda D, Pantaleo G, Pascual M. Effects of immunosuppressive drugs on HIV infection: implications for solid-organ transplantation. Transpl Int 2007; 20:649-658. 48. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13:129-134. 49. Jain AKB, Venkataramanan R, Shapiro R et al. Interaction between tacrolimus and antiretroviral agents in human immunodeficiency virus positive liver and kidney transplantation patients. Transplantation Proceedings 2002; 34:1540-1541. 50. Tseng A, Nguyen ME, Cardella C et al. Probable interaction between efavirenz and cyclosporine. AIDS 2002; 16:505-506. 51. Izzedine H, Launay-Vacher V, Baumelou A. Antiretroviral and immunosuppressive drug-drug interaction: an update. Kidney International 2004; 66:532-541. 52. Frassetto LA, Browne M, Cheng A et al. Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients. Am J Transplant 2007; 7:2816-2820. 53. de Vera ME, Dvorchik I, Tom K et al. Survival of liver transplant patients coinfected with HIV and HCV is adversely impacted by recurrent hepatitis C. Am J Transplant 2006; 6:2983-2993. 54. Gish RG, McCashland T. Hepatitis B in liver transplant recipients. Liver Transpl 2006; 12:S54-S64. 55. Tan J, Lok AS. Antiviral therapy for pre and postliver transplantation patients with hepatitis B. Liver Transpl 2007; 13:323-326. 56. Terrault NA, Carter JT, Carlson L et al. Outcome of patients with hepatitis B virus and human immunodeficiency virus infections referred for liver transplantation. Liver Transpl 2006; 12:801. 57. www.HIVTransplant.com 58. Stock PG, Roland ME. Evolving clinical strategies for transplantation in the HIV-positive recipient. Transplantation 2007; 84:563-571.

Appendix

Partial Hepatectomy after Liver Transplantation:

Inclusion Criteria, Timing of Surgery and Outcome Franco Filipponi* and Franco Mosca

Abstract Background

P

artial hepatectomy is uncommon after liver transplantation (LT) but can be a graft saving procedure in selected cases. Inclusion criteria, outcome and timing of a single Center series are here presented.

Materials and Methods

From January 1996 to December 2007, 879 LT were performed on 824 recipients at our Center; 14 (1.6%) patients underwent a liver graft resection for ischemic type biliary lesion (ITBL)(n = 6, 42.8%), segmental hepatic artery thrombosis (S-HAT)(n = 3, 21.4%), recurrent hepatocellular carcinoma (HCC)(n = 2, 14.2%), liver metastasis from colic cancer (n = 1, 7.1%); liver abscess (n = 1, 7.1%) and liver trauma (n = 1, 7.1%). Patient were divided in Group 1(n = 3): early resection (within three months from LT, all affected by S-HAT) and Group 2(n = 11):late resection (after three months). Outcome and post operative mortality (within 30 days) were compared in both Groups.

Results

Five left lobectomies, 3 right hepatectomies, 2 extended right hepatectomies, 2 segmentectomies, 1 anterior trisegmentectomy and 1 right lateral sectoriectomy were performed. Perioperative mortality was 66.5% in Group 1(1 myocardial infarction and 1 sepsis) and 18.1% in Group 2 (1 sepsis and 1 case of hepatic failure).

Conclusion

Late resections in stable patients with limited damage of the graft have a good prognosis and even major resections should be considered feasible graft saving procedures. On the contrary, early hepatic resections in S-HAT are associated with a worse outcome and should be referred for retransplantation as first choice option. Sepsis significantly influences the post-surgical course.

Partial Hepatectomy after Liver Transplantation: Inclusion Criteria, Timing of Surgery and Outcome Background

Currently, few reports1,7 advocate hepatic resection as graft saving procedure after complications such as segmental hepatic artery thrombosis (S-HAT) and ischemic type biliary lesions (ITBL): *Corresponding Author: Franco Filipponi—Liver Transplant Unit, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa. Italy. Email: f.fi[email protected]

Recent Advances in Liver Surgery, edited by Renzo Dionigi. ©2009 Landes Bioscience.

360

Recent Advances in Liver Surgery

Dousset and colleagues showed in 1994 that the transplanted liver could be safely resected in patients with localized ischemic type damage.1 Honoré and colleagues reported a series of 4 right hepatic lobectomies performed for biliary strictures and ischemic necrosis, showing good patient survival.3 Here a major single Centre series is reported to assess the indication criteria of hepatic resection after liver transplantation and their outcome, with special emphasis to the timing of partial graft resection.

Materials and Methods

From January 1996 to December 2007, 879 orthotopic liver transplantations were performed in 824 patients. Fourteen patients (1.6%) underwent liver graft resection for: ischemic type biliary lesion (ITBL)(n = 6, 41.6%; min 304 days, max 2710 days after LT), segmental hepatic artery thrombosis (S-HAT)(n = 3, 21.4%; min 5, max 70 days after LT), recurrent hepatocellular carcinoma (HCC)(n = 2, 14.2%; min 575, max 700 days after LT), liver abscess (n = 1, 7.1%; 220 days after LT), liver metastasis (n = 1, 7.1%, 1825 days after LT) and liver trauma (n = 1, 8.3%; 1421 days after LT). Two groups of patients were identified: Group 1 early resections (n = 3) within 3 months from OLT, all affected by S-HAT; Group 2 late resections (n = 11) after 3 months from OLT. At surgery, the portal pedicle was controlled, with no Pringle’s manoeuvre and no mobilization of the remnant liver, avoiding any ischemic injury. A typical resection according to the functional anatomy was performed; moreover the portal pedicle was controlled and divided within the liver parenchyma in order to avoid extensive dissection of the hepatic pedicle which may compromise arterial blood supply to the bile ducts, or cause vascular injuries. The perioperative mortality (within 30 days after surgery) was assessed in both groups.

Results

Five left lobectomies, 3 right hepatectomies, 2 extended right hepatectomies, 2 segmentectomies, 1 anterior trisegmentectomy, and 1 right lateral sectorectomy were performed. Group 1—early resection: 3 patients underwent left lobectomy (segments II, III) for accessory or segmental left HAT (Table 1). Patient #1 died on 6th postoperative day(pod) for acute myocardial infarction with patency of HA and improvement of liver function tests. Patient #2 is alive and well after 87 months from hepatic resection. Patient #3 died on 20th pod due to sepsis and portal vein thrombosis. The perioperative mortality of Group 1 was 66.5%. Group 2—late resection: 3 patients underwent right hepatectomy (segment V, VI, VII, VIII) for ITBL(n = 1), liver abscess (n = 1) and trauma (n = 1); 2 underwent extended right hepatectomy; (segment IV, V, VI, VII, VIII) for ITBL; 2 patients underwent anterior trisegmentectomy (segment IV, V, VI) and segmentectomy (segment IV) for ITBL; left lobectomy (segment II, III) and right lateral sectorectomy (segment VI, VII) were performed in 2 patients with HCC recurrence; one left lobectomy was performed for ITBL, and 1 segmentctomy for a single colon cancer liver metastasis(Table 1). The perioperative mortality was 18.1%, and due to sepsis (n = 1) and hepatic failure (n = 1). Moreover, 2 patients died of recurrent HCC after 18 and 20 months from hepatic resection, 1 patient died 18 months after graft resection of HCV recurrence; 5 patients are alive with well functioning grafts at 63, 64, 75, 92, 30 months after resection; 1 patient is alive with multiple lung and liver colon cancer metastases 27 months after resection.

Conclusions

In conclusion, hepatic graft resection is a feasible graft saving option, however early diagnosis and correct timing are crucial. When associated with hepatic sepsis, re-transplantation seems a preferred option for early cases, whereas late resections have a better prognosis if the procedure is performed before the development of cholestasis and sepsis.

Pt #

Indication

Type of Resection (Segment)

Days from OLT

Outcome

Functioning Graft

1

Accessory left HAT

Left lateral (II, III)

5

Exitus (3 days-IMA)

Yes

2

Accessory left HAT

Left lateral (II, III)

45

Alive (87 months)

Yes

3

Segmental left HAT

Left lateral (II, III)

70

Exitus (20 days-sepsis)

Yes

Late resections (>3 months) 4

Liver abscess

Right (V, VI, VII, VIII)

235

Exitus (18 days-sepsis)

Yes

5

ITBL

Segmentectomy (IV)

304

Alive (64 months)

Yes

6

HCC recurrence

Left (II, III)

575

Exitus (18 months-HCC)

Yes

7

HCC recurrence

Right lateral (VI, VII)

600

Exitus (20 months-HCC)

Yes

8

ITBL

Anterior trisegmentomy (IV, V, VI)

623

Alive (75 months)

Yes

9

ITBL

Right (V, VI, VII, VIII)

683

Exitus (29 months-HCV recurrence)

Yes

10

ITBL

Extended right (IV, V, VI, VII, VIII)

1095

Alive (92 months)

Yes

11

ITBL

Extended right (IV, V, VI, VII, VIII)

1265

Exitus (8 days-hepatic failure)

No

12

Trauma

Right (V, VI, VII, VIII)

1421

Alive (63 month)

Yes

13

Liver metastasis

Segmentectomy (VII)

1825

Alive (27 months)

Yes

14

ITBL

Left (II,III)

2710

Alive (30 months)

Yes

Appendix: Partial Hepatectomy after Liver Transplantation

Table 1. Early (<3 months) and late (>3 months) liver graft resections

361

362

References

Recent Advances in Liver Surgery

1. Dousset B, Filipponi F, Soubrane O et al. Partial hepatic resection for ischemic graft damage after liver transplantation: A graft saving option? Surgery 1994; 115:540-545. 2. Chari RS, Baker ME, Sue SR et al. Regeneration of a transplanted liver after right hepatic lobectomy. Liver Transpl Surg 1996; 2:233-234. 3. Honoré P, Detry O, Hamoir E et al. Right hepatic lobectomy as liver graft-saving procedure. Liver Transpl 2001; 7:269-273. 4. Filipponi F, Vistoli F, Urbani L et al. Extended right hepatectomy as graft saving option in non anastomotic biliary strictures after liver transplantation. Hepatogastroenterology 2002; 49(48):1679-1681. 5. Catalano G, Urbani L, Filipponi F et al. Right hepatectomy for trauma in a liver transplant patient: indication criteria, timing and surgical peculiarities. Transplantation 2004; 77(4):636-637. 6. Catalano G, Urbani L, Biancofiore G et al. Hepatic resection after liver transplantation as a graft saving procedure: indication criteria, timing and outcome. Transplant Proc 2004; 36:545-546. 7. Guckelberger O, Stange B, Glanemann M et al. Hepatic resection in liver transplant recipients: single center experience and review of the literature. Am J of Transplantation 2005; 5:2403-2409.

Index Symbols 3-Dimensional reconstruction 222 7-Ethoxycoumarin O-diethyl (ECOD) 339 7-Ethoxyresorufin-O-de-ethylases (EROD) 339 90-Yttrium 284, 300

A Acute phase response 245, 246, 250, 254 Albumin 37, 41, 44, 47, 49, 50, 52, 53, 55, 57, 107, 115, 167, 250, 252, 253, 333, 335, 338-340, 345, 354 Allogeneic blood transfusion 141, 142, 145, 148, 149 Anatomy 1-7, 12, 15-17, 60, 61, 65, 66, 69, 80, 89, 112, 113, 130, 132, 153, 154, 187-189, 192, 214, 262, 306, 310, 311, 322, 361 Arterio-portal shunt 98, 99 Atrophy 98, 105, 107, 109

B Barcelona clinic liver cancer model (BCLC) 37-40, 42, 44, 49, 50, 54-57 Benign stricture 273 Berengario da Carpi 3, 6 Bile duct 8, 16, 61, 63, 65, 66, 69, 75, 81, 86, 98, 101, 115, 122, 132, 134, 166, 173-176, 178, 187, 190-192, 195-197, 199-201, 203, 204, 206-211, 225-228, 240, 246, 249, 260-263, 265-268, 270, 271, 273, 275-277, 309-311, 320, 325, 326, 328-330, 335, 361 Bile duct injury 115, 240, 260, 261, 263, 268 Bile leak 75, 222, 226, 249, 261-263, 277, 327, 330 Biliary complication 261, 263, 277, 308, 310, 313, 320-322, 325-329, 331 Biliary drainage 60, 134, 166, 173, 176, 187, 189, 192, 193, 196, 199, 212, 246, 247, 249, 261, 266-268, 270, 271, 273, 275-277, 313, 316, 327-329, 331 Biliary fistula 13, 76, 253, 321, 327-329

Biliary stenosis 327 Biliary stent 199, 271 Biliary stricture 132, 260, 270, 271, 273, 278, 310, 320, 321, 323, 327, 361 Bilioplasty 268, 271, 273, 278, 327-329 Biloma 260, 262, 265, 268, 269, 275, 277, 278, 320-322, 328 Bio-artificial liver device 332 Biopsy 116, 126, 129, 132, 133, 189, 275, 284, 308, 312, 314, 323, 324, 336-338 Bisegmentectomy 232 Bland embolization 112-114 Bleeding 1, 6, 13, 14, 16, 68, 69, 71, 76, 80-84, 86-89, 91-93, 113-116, 142, 166, 180, 235, 240, 247, 248, 251, 268, 269, 275, 277, 278, 310, 323, 329, 330 Bleeding control 68, 88 Blood product 141, 146, 147, 149 Blood transfusion 80, 81, 141-149, 247, 251, 254, 310 Breast tumor 72, 145, 215-217, 285

C Cancer 20-27, 35, 36, 44-46, 49-52, 54, 56, 57, 70, 115, 117, 122, 134, 141, 142, 144, 145, 149, 157, 189, 192, 196, 199, 210, 214, 216-219, 222, 233-235, 241-243, 254, 287, 288, 317, 336, 338, 342, 347, 360, 361 Cancer liver Italian program score (CLIP) 52, 55 Caudate lobectomy 146, 169, 192, 196, 200, 204, 206, 207, 209 Central venous pressure 68, 80, 81, 89, 92, 93, 195, 229, 248, 310, 311 Child-Pugh score 46, 49, 50, 53-55 Chinese university prognostic index (CUPI) 37, 38, 40, 45, 49, 50, 53, 55-57 Cholangiocarcinoma 146, 175, 187-189, 212, 246, 247 Cholangiography 173, 176, 187, 189-191, 199, 263, 267, 270, 273, 275, 276, 311, 320-322, 327-330, 331 Chronic liver failure 332, 343

364

Cirrhosis 6, 20-22, 24, 26, 35-40, 42, 49, 50, 52, 56, 80, 99, 107, 116, 117, 122, 126, 133, 137, 145, 161, 214, 222, 245, 246, 249, 271, 300, 332, 334, 344, 346, 353, 354 Co-infection 354 Collagenase 338 Color doppler ultrasonography 130, 133, 134, 275, 312, 320, 321 Colorectal hepatic metastasis 135, 242 Complication of hepatobiliary surgery 260 Complication of interventional radiology 312 Computed tomography 116, 132, 155, 168, 187-189, 235, 238, 239, 263, 284 Computer-assisted resection planning 60 Congestion 61, 63, 66, 80, 81, 83, 84, 86-88, 91, 92, 134, 316 Continuous pringle moneuvre (CPM) 83-85 Contrast-enhanced CT 137, 240, 265, 267, 272, 276, 290, 294 Contrast-enhanced ultrasound 240, 287, 292 Couinaud 16, 17, 60, 64, 98, 132, 196 Crush-clamp technique 69, 75 Cryopreservation 339-341

D Diagnosis 20, 28, 49, 116, 117, 126, 131, 137, 154-156, 166, 173, 175, 183, 187, 210, 219, 222, 241, 254, 260, 261, 263, 268-270, 275, 294, 301, 321, 324, 325, 327, 331, 361 Dipeptidyl peptidase IV-deficient rat 333 Drug eluting bead 112, 117

E ECOG performance status 48 E-flow 134, 136 Embolization 86, 98, 102, 103, 105, 112, 113-115, 122-127, 161, 187, 189, 195, 212, 215, 240, 248, 250, 276, 277, 284, 289, 300, 317, 320, 324, 325, 330 Encapsulation 342, 343, 345 Encephalopathy 41, 44, 113, 114, 116, 245, 249, 253, 342, 344, 345, 354 Endovascular ligature 277

Recent Advances in Liver Surgery

End stage liver disease 36, 42, 354, 355 Epoxide hydrolase activity 339 Experimental liver resection 12-14 Extracellular matrix (ECM) 341, 342

F Finger-fraction technique 69 Foetal hepatocyte 335, 344, 345 Fulminant hepatic failure 344, 354 Future liver remnant (FLR) 65, 98, 99, 101, 102, 105, 122-127

G Galen 1-3, 5 Genetics 20, 28 Glisson 7-9, 65, 69, 71, 229 Glutathione S-transferee 339 Graft rejection 270 Greek anatomist 1 Groupe d´Etude de Traitement du Carcinoma Hepatocellulaire (GRECTH) 49, 50, 57

H HAART 353-357 Harvey 3, 5-8 HBV 21, 22, 27, 353, 354, 356, 357 HCV 21-23, 27, 317, 353-357, 361, 362 Hemihepatectomy 65, 99, 167, 169, 170, 180, 187, 190, 192, 196-202, 205, 206, 210 Hemobilia 105, 175, 262, 273, 275-278 Hemodilution 142, 145-147, 250 Hepatectomy 16, 54, 60, 64, 68, 73-76, 80, 85, 91-93, 98-101, 103, 105, 107-109, 122, 124-126, 130, 141, 142, 145, 146, 148, 154, 161, 166, 167, 173, 189, 194, 202-204, 206, 212, 216-218, 222, 224-226, 229-232, 241, 242, 247, 249, 250, 252-254, 308, 310, 311, 334, 336, 337, 360, 361 Hepatic artery 14, 16, 63, 65, 81, 82, 86, 87, 90, 113, 122-125, 132-135, 167, 177, 178, 180, 196-200, 202, 204, 206-212, 215, 225-227, 240, 263, 276, 277, 284, 290, 309-313, 315, 316, 321-324, 330, 345, 360, 361

365

Index

Hepatic functional reserve 99, 101, 107, 166, 173, 187, 192, 194 Hepatic metastasis 135, 214-219, 222, 234, 242, 293 Hepatico-jejunal anastomosis 328, 330 Hepatic resection 17, 42, 55, 71, 72, 74, 77, 83, 85, 93, 98, 99, 105, 107, 109, 122, 125, 126, 129, 130, 132, 133, 137, 141, 142, 145, 167, 214-219, 221, 222, 231, 232, 236, 241, 242, 245, 260, 262, 312, 343, 360, 361 Hepatic resection for neuroendocrine tumors 215 Hepatic steatosis 354 Hepatic total vascular exclusion (HTVE) 161 Hepatic vein 4, 44, 61, 63-66, 69, 73, 74, 76, 80-83, 86-90, 92, 94, 125, 132, 134, 136, 137, 142, 154, 155, 157, 166-168, 170, 176-180, 182, 183, 185, 197, 199, 202, 203, 206, 208, 210, 211, 224-226, 229-232, 309-313, 322, 325 Hepatic venous thrombus 167, 176 Hepatobiliary resection 166, 173, 187, 189, 194, 210, 212 Hepatocellular carcinoma (HCC) 20-28, 35-42, 44, 49-52, 54-57, 86, 98, 99, 101, 102, 104, 105, 107, 109, 112, 114-117, 122-126, 131-133, 135, 137, 141-146, 148, 149, 155, 158, 160-162, 166, 167, 169, 171, 173, 175-178, 180, 181, 183, 222, 242, 282, 288-295, 299-301, 317, 332, 354, 360-362 Hepatocyte 22, 23, 70, 107, 246, 247, 249, 250, 254, 308, 332-348 Hepatocyte transplantation 332-334, 337, 339, 342-348 Hepatotomy 229 Hilar bile duct cancer 122, 134 Hilar cholangiocarcinoma 187-189, 212, 246, 247 Human immunodeficiency virus (HIV) 141, 333, 353-357 Hyperbilirubinemia 245, 249, 251-254 Hypertrophy 98, 99, 102, 105, 107, 109, 122-124, 126, 127, 161, 187, 194 Hypocholesterolemia 250, 251, 253 Hypophosphatemia 254 Hypoxia 115, 337

I Ileocolic vein 101 Immunosuppression 141, 318, 333, 353-355 Indocyanine green retention rate at 15 minutes (ICGR R15) 55, 101, 107 Infectious complication 141, 147, 148, 194 Inferior vena cava 16, 69, 81, 82, 93, 153, 154, 156-158, 160, 162, 167, 176, 196, 197, 200, 202, 203, 207, 209, 226, 230, 231, 325 Inflow 17, 68, 73, 77, 80-89, 91, 92, 141, 158, 178, 180, 206, 210, 225, 226, 231, 240, 316 In-flow occlusion 77 Intermittent pringle maneuvre (IPM) 84-86 Interventional radiology 260, 261, 278, 312, 320, 321, 325, 331 Intrahepatic anatomy 16, 17, 89 Intrahepatic cholangiocarcinoma 146, 175 Intraoperative autotransfusion 142 Intraoperative isovolemic hemodilution 142, 145 Intraoperative ultrasonography (IOUS) 17, 65, 129-135, 137, 138, 167, 169, 178, 180, 184, 194, 206 Intraoperative ultrasound 74, 310 Ischemia 68, 69, 75, 80, 83, 85, 88, 91, 113, 115, 117, 124, 158, 247, 248, 250, 251, 253, 254, 263, 270, 289, 300, 322, 323, 337, 338 Ischemic type biliary lesion 360, 361

J Japan integrated staging ( JIS) 37-39, 42, 46, 49, 50, 53-57

K Karnofsky index 40, 46, 48, 50, 51, 57 Keen 14, 69 Kupffer cell 135, 246, 247, 249, 254

L Laparoscopic 1, 70, 72, 74, 76, 85, 130, 221-223, 225, 226, 228, 229, 232, 234, 260, 262, 265, 267, 275 Laparoscopic surgery 70, 74, 76, 130, 221 Laparoscopic ultrasonography 222, 223

366

Laser ablation 234, 242 Liver anatomy 12, 17, 60, 61, 65, 66, 130 Liver-based metabolic disorder 332 Liver biopsy 275, 308, 312, 314, 323, 336-338 Liver cancer 20, 23, 24, 26, 27, 35, 44, 46, 49, 50, 52, 54, 56, 57, 338 Liver cirrhosis 20, 24, 26, 35-37, 40, 42, 99, 133, 245, 249, 334, 344 Liver dysfunction 41, 50, 52, 245, 246, 249, 250, 252, 254, 261, 312, 354 Liver failure 36, 60, 80, 85, 98, 107, 112, 115, 117, 125-127, 142, 166, 187, 250, 254, 307, 309, 313, 316, 320, 321, 332, 334, 336, 342-345, 357 Liver insufficiency 249, 251-253 Liver ischemia 91, 248, 250, 251, 253, 254 Liver metastasis 122, 132, 133, 135, 214, 216, 217, 219, 234, 241, 242, 252, 336, 362 Liver regeneration 12, 17, 99, 251, 253, 254, 312, 317 Liver resection 1, 8, 12-14, 17, 52, 60, 61, 64-66, 68, 69, 72-77, 80, 81, 84, 85, 90-93, 98, 109, 122, 124, 125, 141-149, 153, 154, 162, 166, 199, 216-219, 221, 232, 245-254, 306, 310, 314, 338 Liver transection 68, 77, 80, 84, 90-93, 131-134, 137, 167, 178, 184, 195, 201-204 Liver transplantation 1, 20, 36, 50, 52, 85, 93, 98, 132, 252, 260-263, 270, 275, 277, 306, 307, 308-310, 312, 313, 315-317, 320, 321, 331-335, 345, 347, 353-357, 360, 361 Liver volume 37, 60-62, 64, 66, 99, 101, 105, 125-127, 308, 311, 316, 343 Liver wound 8 Liver cancer study group of japan (LCSGJ) 37, 38, 39, 46, 54, 55, 57 Living donors liver transplantation (LDLT) 307, 310, 311, 313, 315-317 Living-related liver transplantation 312 Long-term outcome 98, 254, 338 Loreta 13, 14 Long-term results 99

Recent Advances in Liver Surgery

M Magnetic resonance (MR) 116, 135, 154, 155, 188, 189, 237, 240, 263, 276, 282, 284, 285, 287, 289-293, 295, 299-301, 311, 312, 320-322, 331 Magnetic resonance angiography (MRA) 321, 322 Magnetic resonance cholangiography (MRC) 320-322 Magnetic resonance cholangiopancreatography 188, 189, 263 Major hepatectomy 68, 76, 93, 99, 101, 122, 126, 166, 167, 189, 212, 225, 226, 229, 231, 232 Major hepatic resection 85, 98, 99, 107, 109, 125, 145, 221, 262, 312 Makuuchi 17, 98, 103, 129, 130, 133, 161 Malignancy 13, 20, 22, 25, 60, 61, 80, 83, 113, 122, 141, 142, 153, 161, 210, 214, 221, 222, 232, 268, 271, 282, 284, 286, 287, 293, 300, 333, 335, 336, 355 Matrix 24, 341-343, 345 Melanoma 215-218 Metallic stent 271, 273, 278, 312, 323-326, 328 Microbiology 248 Microwave ablation 234, 241, 242 Minimally invasive procedures 112, 117, 221, 222, 232, 233, 240, 243, 282, 284, 300, 301 Minor 48, 69, 75, 86, 93, 126, 147, 154, 225, 232, 240, 262, 275, 283, 299, 308 Model for end-stage liver disease (MELD) 36, 37, 39, 42, 46, 50, 54, 55, 313, 355 Mortality 14, 17, 36, 39, 42, 50, 60, 68, 75, 80, 85, 88, 107-109, 114, 117, 126, 127, 146, 162, 187, 192, 214-216, 232, 240, 245-247, 250, 254, 260, 261, 263, 277, 278, 306-308, 310, 312, 317, 320, 321-323, 325, 342, 353, 357, 360, 361 MR diffusion 282, 284, 285, 292, 300, 301 MR spectroscopy 282, 284, 285, 287, 293, 300, 301 Multidetector computed tomography (MDCT) 187-189, 192, 197, 315, 320-322

367

Index

N Neuroendocrine tumor 214, 215 Non-heart beating donor (NHBD) 334 Non-invasive technique 249, 261, 320, 322

O Obstructive jaundice 98, 105, 166, 167, 173, 175 Occult sepsis 252, 253, 270 Okuda score 49, 50, 52, 56 Opportunistic infection 353-355, 357 Organ procurement 308, 337 Orthotopic liver transplantation (OLT) 320-323, 325-327, 329-333, 342, 344-348, 353, 354, 361, 362 Outflow 17, 80, 82, 84, 87-89, 91, 160, 226, 229, 231, 310-312

P p53 20-22, 35, 36, 41 PDGF signalling 25 Pediatric liver transplantation 321 Pedicular clamping 80-82, 84, 89-92 Percutaneous approach 101, 234, 267, 268, 320, 321, 325, 328, 329, 331 Percutaneous drainage 247, 249, 269, 277, 278, 328 Percutaneous transhepatic angioplasty (PTA) 323-325, 327 Percutaneous transhepatic biliary drainage (PTBD) 166, 173, 176, 187, 189, 191-194, 199, 212, 266, 327 Percutaneous transhepatic bilioplasty (PTB) 327, 328, 330 Percutaneous transhepatic cholangiography (PTC) 263, 265, 266, 268, 270, 271, 275, 316, 321, 323, 327-330 Percutaneous treatment 38, 52, 235, 260, 262, 269, 271, 277, 299, 320-324, 326-328, 330, 331 Performance status 35, 37, 40-42, 44, 48, 50, 54, 57, 112, 116, 161 Physical status 49, 50, 54, 57 Plasma fibrinogen 254 Plastic biliary endoprosthesis 273

Polytetrafluoroethylene (PTFE) 158, 160, 162 Portal vein 4, 5, 7, 8, 14, 16, 36, 40, 41, 45-47, 49-52, 57, 63-65, 74, 81, 82, 86, 90, 98, 101, 102, 112, 113, 116, 122-127, 132-134, 161, 166-172, 177, 178, 180, 187, 189, 190, 193-197, 199-202, 204-212, 223, 225-228, 240, 248, 250, 277, 289, 300, 310-313, 315, 316, 322, 325, 326, 333, 345, 354, 361 Portal vein embolization (PVE) 86, 98-102, 104-107, 109, 122-127, 161, 187, 189, 194, 195, 202, 207, 212, 248, 250 Portal vein invasion 36, 40, 41, 193, 354 Portal venous flow/pressure 98, 105 Positron emission tomography (PET) 222, 235, 282, 284, 287, 293, 300, 301 Power doppler ultrasonography 130, 299 Predisposition 245, 247, 249, 250 Preoperative autologous blood donation 142, 144, 145, 147 Preoperative work-up 222 Pringle manoeuvre 14, 15, 73, 141 Prognosis 22-24, 35-42, 49, 50, 52, 54-56, 109, 133, 142, 145, 148, 153, 154, 158, 167, 218, 250, 252, 360, 361 Prognostic model 49, 50, 56, 216 Prognostic score 56 Prognostic staging system 49-52, 56, 57 Prognostic variable 35-37, 40, 42, 142 Prophylaxis 222, 232, 248, 277, 353 Protein induced by vitamin K absence or antagonist II (PIVKA-ΙΙ) 54

R Radioembolization 112, 113, 115, 116, 284, 299, 300 Radiofrequency ablation (RFA) 37, 40, 68, 72, 73, 75, 77, 214, 217, 221, 237, 238, 242, 275, 284, 292-296, 299-301 Ras signaling 24, 25 RECIST criteria 283, 291 Reduced-size liver transplantation 307

368

Resection 1, 8, 10, 12-14, 16, 17, 20, 36-39, 41, 42, 52, 54-56, 60-62, 64-66, 68, 69, 71-77, 80, 81, 83-87, 90-94, 98, 99, 105, 107, 109, 112, 114, 116, 122-127, 129, 130, 132, 133, 137, 141-149, 153, 154, 158-162, 166, 167, 170, 172, 173, 175-178, 180, 182, 187, 189, 190, 192, 194, 196, 199, 201, 202, 204-207, 209, 210, 212, 214-219, 221-225, 231, 232, 234, 236, 241-243, 245-254, 260, 262, 284, 306, 310, 312, 314, 337, 338, 343, 347, 360-362 Retinoblastoma protein (Rb) 20, 26 Retransplantation 307, 309, 320, 322, 323, 325, 348, 360 Right hepatectomy 64, 107, 122, 124, 125, 203, 222, 224, 225, 229, 232, 252, 360, 361

S Sarcoma 216, 217 Secondary sclerosing cholangitis 252, 253, 271 Segment 16, 60-62, 81, 82, 86, 98, 99, 102, 104, 105, 107, 125, 126, 154-156, 158, 173, 175, 187, 188, 194, 196, 200, 207, 209, 216, 221, 222, 225-227, 229, 230, 232, 248, 268, 270, 271, 288-294, 299, 300, 307, 309, 310-313, 328-330, 335, 361, 362 Segmentectomy 133, 142, 187, 231, 232, 360-362 Sepsis 240, 245-254, 277, 317, 323, 328, 333, 355, 360-362 Sequential TACE 99, 105-107, 109, 122, 124-127 Small-for-size syndrome 252, 311, 316 Sonazoid 135 SonoVue 135 Splenic artery embolization 317 Split liver 306-310, 315, 317, 321, 332 Split liver transplantation 307, 308, 310 Staging algorithm 35, 41 Staging for hepatocellular carcinoma 35, 49, 51, 56 Staging system 35-42, 44, 49-57 Stapler 68, 73, 74, 76, 77, 202, 206, 210, 223, 226, 229 Stem cell 332, 335, 347

Recent Advances in Liver Surgery

Stricture 132, 172, 188, 202, 260, 261-263, 270, 271, 273, 275, 277, 278, 308, 310, 311, 320-323, 327-330, 361 Subsegmentectomy 133 Surgery 1, 3, 9-17, 28, 42, 50, 52, 54, 60, 62, 64-66, 68-71, 74, 76, 77, 80, 82, 85, 90-93, 101, 125, 129, 130, 132, 135, 137, 141-146, 148, 153, 154, 158, 160-162, 166, 167, 178, 180, 183, 187, 192, 194, 196, 210, 212, 219, 221-223, 232, 234, 241, 243, 247, 254, 260-262, 270, 275, 277, 306, 310, 311, 317, 320, 321, 324, 330, 331, 342, 360, 361 Surgical bile duct injuries (SBDI) 260-262, 278 Surgical complication 312 Surgical technique 15, 82, 89, 98, 130, 141, 145, 146, 158, 166, 167, 177, 183, 187, 189, 212, 214, 260, 273, 277, 306, 307, 309, 313, 317, 320, 321, 326, 331, 337 Survival 20, 27, 35, 36, 38, 40-42, 49-52, 54, 57, 107-109, 112-117, 122, 124-127, 141, 142, 144, 145, 149, 154, 162, 166, 175, 176, 183, 187, 214-219, 232, 234, 241-243, 250, 273, 300, 310, 313, 316, 317, 320, 321, 331, 333-335, 341-343, 345, 353, 354, 357, 361 Synergism 245, 249, 250, 254

T TGFβ pathway 23, 24 Telemonitoring surgery 138 Three-dimensional ultrasonography 17, 129 Thrombectomy 166, 167, 169, 172, 175, 176, 313, 322 Tokyo score 39, 47, 49, 50, 53, 56 Total vascular exclusion 80, 87, 92, 161 Transarterial chemoembolizations (TACE) 36-38, 40, 42, 52, 54, 55, 98-102, 104-109, 112-115, 117, 122-127, 173, 284, 288-294, 300 Transcatheter arterial embolization 277, 284 Transducer 17, 70, 130, 131, 158, 229 Transplantation 1, 20, 36, 39, 50, 52, 85, 93, 98, 112, 116, 130, 132, 252, 260-263, 270, 275, 277, 306-313, 315-318, 320-322, 331-348, 353-357, 360, 361 Trisectionectomy 64, 146, 161, 187, 204-209, 211, 360, 361

369

Index

Tumor 11-13, 17, 20-28, 35-37, 40, 42, 44, 45, 47, 60, 61, 65, 70, 72, 75, 76, 80, 82-84, 86-91, 93, 94, 98-102, 104, 105, 107, 109, 112-117, 122-127, 129-136, 141, 142, 144-146, 148, 153-158, 160, 166-185, 187, 189, 190-192, 194, 199, 202, 204, 214-219, 221-223, 229, 232, 234-243, 282-295, 299-301, 306, 317, 320, 321 Tumor progression 23, 24, 36, 37, 42, 98, 99, 240 Tumor thrombus 101, 124, 132, 155, 157, 166-185 Tumor vascularity 135, 285, 299 Tumour, nodule, metastasis (TNM) 37-39, 42, 44-47, 49, 50, 52-55, 57 Tumour stage 49, 50, 52, 54

U UDP-gluronosyl transferase 339 Ultrasonic 68, 70-77, 81, 91, 102, 129, 130-132, 135, 223, 229, 310 Ultrasonography 17, 51, 65, 129, 131, 134, 155, 156, 167, 172, 184, 189, 191, 194, 206, 312, 315 Ultrasound 70, 74, 105, 129, 130, 132, 157, 158, 222, 223, 237, 238, 240, 263, 284, 292, 296, 310, 320, 321 Ultrasound and color doppler ultrasound (US-CDUS) 320, 321 University of Bologna 13 Urea 338, 341, 347

V Vascular endothelial growth factor (VEGF) 115, 342, 345 Vascular occlusion 1, 14, 16, 68, 72, 74, 81, 82, 85, 87, 91, 93 Vascular risk analysis 61, 64-66 Venousbiliary fistula 260, 262, 273, 277 Veno-venous by pass 311 Vesalius 3-5, 7 Viena survival model for hepatocellular carcinoma (VISUM-HCC) 49, 50, 56, 57 Virtual liver surgery 60

W Waiting period 98, 105, 107 Wedge resection 161, 204 WHO criteria 282 Wisconsin solution 311, 338, 340 Wnt signalling pathway 22, 23

X Xenogenic hepatocyte 335, 336, 347

Z Zambeccari 12

MEDICAL INTELLIGENCE UNIT

The chapters in this book, as well as the chapters of all of the five Intelligence Unit series, are available at our website.

Biotechnology Intelligence Unit Medical Intelligence Unit Molecular Biology Intelligence Unit Neuroscience Intelligence Unit Tissue Engineering Intelligence Unit

DIONIGI

INTELLIGENCE UNITS

MIU

Recent Advances in Liver Surgery