Surgical Management of Hepatobiliary and Pancreatic Disorders, Second Edition (Oncologysurgery)

Second Edition Edited by Graeme J. Poston, Michael D’Angelica, and René Adam About the book Hepato-Pancreato-Biliary (HPB) surgery is now firmly established within the repertoire of modern general surgery. This new edition has been completely rewritten by world-leading surgeons to reflect the considerable advances made in the surgical management of HPB disorders since the highly successful first edition. This new edition includes:

• A comprehensive section on anatomy, imaging, and surgical technique • Over 20 new chapters, including a complete account of pediatric HPB disorders • Almost 300 high-resolution images, many in full color Surgical Management of Hepatobiliary and Pancreatic Disorders, Second Edition, comprehensively covers the full spectrum of common HPB diseases and associated surgical techniques to assist not only the general surgeon in regular practice, but also surgical trainees and those in related specialties of oncology, radiology, gastroenterology, and anesthesia.

About the Editors Graeme j. Poston, MS, FRCS (Eng), FRCS (Ed), is Director of Surgery and Hepatobiliary Surgeon, University Hospital Aintree, Liverpool, UK. He is the President of the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS), PresidentElect of the European Society of Surgical Oncology (ESSO), Past President of the British Association of Surgical Oncology (BASO), and author of numerous publications and national/international guidelines relating to the practice of HPB surgery. Michael D’Angelica, MD, is an Associate Attending at Memorial Sloan-Kettering Cancer Center and an Associate Professor at Cornell University/Weill Medical Center. He is currently the Program Chairman of the American Hepato-Pancreato-Biliary Association and a writing member of the National Comprehensive Cancer Network (NCCN) practice guidelines for hepatobiliary malignancy. René Adam, MD, PHD, is Hepatobiliary Surgeon and Professor of Surgery, Hôpital Paul Brousse, Université Paris-Sud, Villejuif, France.

This book demonstrates the wisdom of the new knowledge and technical skills of these diverse disciplines where cooperative efforts contribute toward the benefit of the patients with HPB disorders. Also Available Hepatocellular Carcinoma: A Practical Approach Edited by Bandar Al Knawy, K. Rajendra Reddy and Luigi Bolondi ISBN: 9780415480802 e-ISBN: 9780203092880

Improved Outcomes in Colon and Rectal Surgery Edited by Charles B. Whitlow, David E. Beck, David A. Margolin, Terry C. Hicks and Alan E. Timmcke ISBN: 9781420071528 e-ISBN: 9781420071535

Textbook of Surgical Oncology Edited by Graeme J. Poston, R. Daniel Beauchamp, and Theo J. M. Rogers ISBN: 9781841845074 e-ISBN: 9780203003220

Surgical Management of Hepatobiliary and Pancreatic Disorders

• An in-depth coverage of benign and malignant disorders of the liver, pancreas, and bile ducts and gallbladder

With a Foreword by Yuji Nimura, MD, President of the Aichi Cancer Center, Japan, and Past President of the IHPBA

Poston • D’Angelica • Adam

Surgical Management of Hepatobiliary and Pancreatic Disorders

Second Edition

Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK 52 Vanderbilt Avenue, New York, NY 10017, USA

www.informahealthcare.com

Surgical Management of

Hepatobiliary and Pancreatic Disorders Second Edition

Edited by

Graeme J. Poston Michael D’Angelica René Adam

Surgical Management of Hepatobiliary and Pancreatic Disorders

Surgical Management of Hepatobiliary and Pancreatic Disorders Second Edition Edited by Graeme J. Poston MS, FRCS (ENG), FRCS (ED) Centre for Digestive Diseases University Hospital Aintree and Department of Surgery The Royal Liverpool University Hospitals Liverpool, UK

Michael D’Angelica MD Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center New York, New York, USA and

René Adam MD, PHD AP-HP Hôpital Paul Brousse Centre Hépato-Biliaire Villejuif, France

First published in 2003 by M. Dunitz Ltd, United Kingdom This edition published in 2010 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK. Simultaneously published in the USA by Informa Healthcare, 52 Vanderbilt Avenue, 7th floor, New York, NY 10017, USA. © 2011 Informa UK Ltd, except as otherwise indicated. No claim to original U.S. Government works. Reprinted material is quoted with permission. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, unless with the prior written permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP, UK, or the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA (http://www.copyright.com/ or telephone 978750-8400). Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. This book contains information from reputable sources and although reasonable efforts have been made to publish accurate information, the publisher makes no warranties (either express or implied) as to the accuracy or fitness for a particular purpose of the information or advice contained herein. The publisher wishes to make it clear that any views or opinions expressed in this book by individual authors or contributors are their personal views and opinions and do not necessarily reflect the views/opinions of the publisher. Any information or guidance contained in this book is intended for use solely by medical professionals strictly as a supplement to the medical professional’s own judgement, knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures, or diagnoses should be independently verified. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as appropriately to advise and treat patients. Save for death or personal injury caused by the publisher’s negligence and to the fullest extent otherwise permitted by law, neither the publisher nor any person engaged or employed by the publisher shall be responsible or liable for any loss, injury or damage caused to any person or property arising in any way from the use of this book. A CIP record for this book is available from the British Library. ISBN-13: 978-1-84184-693-4 Orders may be sent to: Informa Healthcare, Sheepen Place, Colchester, Essex CO3 3LP, UK Telephone: +44 (0)20 7017 5540 Email: [email protected] Website: http://informahealthcarebooks.com/ For corporate sales please contact: [email protected] For foreign rights please contact: [email protected] For reprint permissions please contact: [email protected]

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Contents List of contributors Foreword Preface I

vii x xi

1 17

Margo Shoup and Jason W. Smith

3 Hepatic resection

166

C. Kahlert, R. DeMatteo, and J. Weitz

Robert Jones and Graeme J. Poston

2 Anatomy of the pancreas

154

Kaori Ito

17 Noncolorectal, nonneuroendocrine metastases

ANATOMY/IMAGING/SURGICAL TECHNIQUE 1 Surgical anatomy of the liver and bile ducts

16 Management of neuroendocrine tumor hepatic metastasis

18 Chemotherapy-associated hepatotoxicity

19 Thermal ablation of liver metastases 24

173

Martin Palavecino, Daria Zorzi, and Jean-Nicolas Vauthey

180

Samir Pathak and Graeme J. Poston

Ajay V. Maker and Michael D’Angelica

4 Ultrasound for HPB disorders

36

20 Resection for hepatocellular carcinoma

Duan Li and Lucy Hann

5 Liver surgery in elderly patients

46

Rajesh Satchidanand, Stephen W. Fenwick, and Hassan Z. Malik

53

21 Treatment of laparoscopically discovered gallbladder cancer

Gerardo Sarno and Graeme J. Poston

6 Small solitary hepatic metastases: when and how? David L. Bartlett and Yuman Fong

7 Managing complications of hepatectomy

63 73

Thilo Hackert, Moritz Wente, and Markus W. Büchler

9 Surgical complications of pancreatectomy

81

Steven C. Katz and Murray F. Brennan

10 Laparoscopy in HPB surgery

89

Nicholas O’Rourke and Richard Bryant

11 Cross-sectional imaging for HPB disorders (MRI and CT)

192

197

Jason K. Sicklick, David L. Bartlett, and Yuman Fong

Fenella K. S. Welsh, Timothy G. John, and Myrddin Rees

8 Pancreatic resection

ii. Primary

22 Liver transplantation for HCC: Asian perspectives Shin Hwang, Sung-Gyu Lee, Vanessa de Villa, and Chung Mao Lo

23 Non-surgical treatment of hepatocellular carcinoma

Lawrence H. Schwartz

216

Ghassan K. Abou-Alfa and Karen T. Brown

24 Resection of intrahepatic cholangiocarcinoma

223

Junichi Arita, Norihiro Kokudo, and Masatoshi Makuuchi

25 Transplantation for hilar cholangiocarcinoma 100

208

229

Julie K. Heimbach, Charles B. Rosen, and David M. Nagorney

26 Rare vascular liver tumors

233

Jan P. Lerut, Eliano Bonaccorsi-Riani, Giuseppe Orlando, Vincent Karam, René Adam, and the ELITA-ELTR Registry

II LIVER A. Malignant i. Metastases 12 Liver metastases: detection and imaging

109

Valérie Vilgrain, Ludovic Trinquart, and Bernard Van Beers

13 Surgery for metastatic colorectal cancer

27 Management of recurrent pyogenic cholangitis 118

René Adam and E. Hoti

14 Chemotherapy for metastatic colorectal cancer

135

Gerardo Sarno and Graeme J. Poston

242

W. Y. Lau and C. K. Leow

28 Liver abscess: amebic, pyogenic, and fungal

Derek G. Power and Nancy E. Kemeny

15 Multimodal approaches to the management of colorectal liver metastases

B. Benign

253

Purvi Y. Parikh and Henry A. Pitt

29 Benign solid tumors of the adult liver

261

Mark Duxbury and O. James Garden

148

30 Liver trauma

271

Timothy G. John, Myrddin Rees, and Fenella K. Welsh

v

CONTENTS 31 Portal hypertension

280

Michael D. Johnson and J. Michael Henderson

32 Liver transplantation for acute and chronic liver failure

A. Malignant 288

Vincent Kah Hume Wong and J. Peter A. Lodge

33 Benign cystic disease of the liver

301

Stephen W. Fenwick and Dowmitra Dasgupta

34 Management of hydatid disease of the liver

308

Adriano Tocchi

35 Surgical management of primary sclerosing cholangitis

324

401

Michael G. House and Keith D. Lillemoe

44 Cystic tumors of the pancreas

407

Peter J. Allen and Murray F. Brennan

414

Stephen N. Hochwald and Kevin Conlon

432

B. Benign 329

Hiromichi Ito and William R. Jarnagin

47 Acute pancreatitis

439

C. Ross Carter, A. Peter Wysocki, and Colin J. McKay

333

Yuji Nimura

48 Chronic pancreatitis

451

Jakob R. Izbicki, Oliver Mann, Asad Kutup, and Kai A. Bachmann

343

Nick Stern and Richard Sturgess

49 Pancreatic injury

463

Demetrios Demetriades, Beat Schnüriger, and Galinos Barmparas

B. Benign 39 Choledochal cyst detected in adulthood

43 Palliation of pancreas cancer

Jooyeun Chung, Lisa J. Harris, Hamid Abdollahi, and Charles J. Yeo

A. Malignant

38 Endoscopic management of malignant biliary obstruction

380

André L. Mihaljevic, Jörg Kleeff, and Helmut Friess

46 Rare tumors of the pancreas

III BILE DUCTS AND GALLBLADDER

37 Extrahepatic cholangiocarcinoma

42 Adenocarcinoma of the pancreas

45 Neuroendocrine pancreatic tumors

Jason A. Breaux and Steven A. Ahrendt

36 Management of advanced gallbladder cancer

IV PANCREAS

50 Pancreas transplantation 354

470

Khalid Khawaja

Bilal Al-Sarireh and Hassan Malik

40 Bile duct injuries and benign biliary strictures

360

Steven M. Strasberg

41 Gallstones and common bile duct stones—surgical and non-surgical approaches Matthew P. Dearing and Michael Rhodes

vi

V PEDIATRIC HPB DISORDERS 51 Pediatric HPB disorders

373

478

Maureen McEvoy and Michael P. La Quaglia

Index

489

List of contributors Ghassan K. Abou-Alfa MD Assistant Attending, Memorial Sloan-Kettering Cancer Center, and Assistant Professor, Weill Medical College at Cornell University, New York, New York, USA Hamid Abdollahi MD Senior Resident (General Surgery), Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA René Adam MD, PhD AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm, Unité 785, and Université Paris-Sud, UMR-S 785, Villejuif, France Steven A. Ahrendt MD Associate Professor of Surgery, University of Pittsburgh Medical Center, UPMC Passavant Cancer Center, Pittsburgh, Pennsylvania, USA Peter J. Allen MD Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Bilal Al-Sarireh MBBCh, FRS, PhD Consultant Hepatopancreatobiliary and Laparoscopic Surgeon, Swansea University, and Department of Surgery, Morristown Hospital, Swansea, UK Junichi Arita MD, PhD Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan Kai A. Bachmann Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Galinos Barmparas Division of Trauma and Surgical Critical Care, University of Southern California, Los Angeles, California, USA David L. Bartlett Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, and National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA Eliano Bonaccorsi-Riani Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires St Luc Université catholique de Louvain, Department of Abdominal and Transplantation Surgery, Brussels, Belgium Jason A. Breaux MD Surgical Oncology Fellow, University of Pittsburgh Medical Center, UPMC Cancer Pavilion, Pittsburgh, Pennsylvania, USA Murray F. Brennan Benno C. Schmidt Clinical Chair in Oncology, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Karen T. Brown MD Attending Radiologist, Memorial Sloan-Kettering Cancer Center, and Professor of Clinical Radiology, Weill Medical College at Cornell University, New York, New York, USA

C. Ross Carter West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK Jooyeun Chung MD Department of Surgery, The Methodist Hospital, Houston, Texas, USA Kevin Conlon Professor of Surgery, University of Dublin, Trinity College Dublin, and Professorial Surgical Unit, Education Centre, AMNCH, Dublin, Ireland Michael D’Angelica MD Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center, New York, New York, USA Dowmitra Dasgupta MD, FRCS Consultant Hepato-Pancreatico-Biliary Surgeon, Department of Upper GI Surgery, Castle Hill Hospital, Cottingham, UK Matthew P. Dearing Department of Surgery, Norfolk & Norwich University Hospital, Norwich, UK R. DeMatteo Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Demetrios Demetriades Division of Trauma and Surgical Critical Care, University of Southern California, Los Angeles, California, USA Mark Duxbury Clinical Surgery, University of Edinburgh Royal Infirmary, Edinburgh, UK Stephen W. Fenwick MD, FRCS Consultant Hepatobiliary Surgeon, North Western Hepatobiliary Unit, University Hospital Aintree, Lower Lane, Liverpool, UK Yuman Fong MD Hepatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Helmut Friess Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany O. James Garden Regius Professor of Clinical Surgery, Clinical and Surgical Sciences (Surgery), University of Edinburgh, Royal Infirmary, Edinburgh, UK Thilo Hackert Department of Surgery, University of Heidelberg, Heidelberg, Germany Lisa J. Harris MD Senior Resident (General Surgery), Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA J. Michael Henderson Chief Quality Officer, Cleveland Clinic, Cleveland, Ohio, USA

Richard Bryant MBBS, FRACS Royal Brisbane Hospital, Brisbane, Queensland, Australia

Stephen N. Hochwald MD Chief, Division of Surgical Oncology, University of Florida, Gainesville, Florida, USA

Markus W. Büchler Department of General Surgery, University of Heidelberg, Heidelberg, Germany

Michael G. House MD Assistant Professor, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA

vii

LIST OF CONTRIBUTORS Lucy Hann MD Professor of Radiology, Weill Cornell Medical Center, and Director of Ultrasound Memorial Sloan-Kettering Cancer Center, New York, New York, USA Julie K. Heimbach Mayo Clinic, Rochester, Minnesota, USA Steven N. Hochwald University of Florida Medical School, Box 100286, Gainesville, FL 32610–0286, USA E. Hoti AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France, and Liver Transplant Unit, Saint Vincent’s University Hospital, Dublin, Ireland Shin Hwang Professor, Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea Hiromichi Ito MD Department of Surgery, Michigan State University, Lansing, Michigan, USA Kaori Ito MD Department of Surgery, Michigan State University, Lansing, Michigan, USA Jakob R. Izbicki FACS Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany William R. Jarnagin MD Hepatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Timothy G. John MD, FRCSEd (Gen) Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK Michael D. Johnson MD Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA Robert Jones MB, ChB, MRCS Clinical Fellow, North Western Hepatobiliary Centre, Aintree University Hospital, Liverpool, UK C. Kahlert Department of Surgery, University of Heidelberg, Heidelberg, Germany Vincent Karam Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France Steven C. Katz MD Director of Surgical Immunotherapy, Roger Williams Medical Center, Providence, Rhode Island, USA Khalid Khwaja MD Director of Kidney and Pancreas Transplantation, Senior Staff Surgeon, Lahey Clinic, Burlington, Massachusetts, USA Nancy E. Kemeny MD Memorial Sloan-Kettering Cancer Center, New York, New York, USA Jörg Kleeff Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Norihiro Kokudo MD, PhD Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan Asad Kutup Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

viii

W. Y. Lau Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, SAR C. K. Leow Mount Elizabeth Medical Centre, Singapore, Singapore Keith D. Lillemoe MD Jay L. Grosfeld Professor and Chairman, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA Sung-Gyu Lee Professor, Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea Michael P. La Quaglia MD Department of Surgery, Pediatric Surgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Jan P. Lerut MD, PhD, FACS Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires St Luc Université catholique de Louvain, Department of Abdominal and Transplantation Surgery, Brussels, Belgium Duan Li MD Assistant Attending Radiologist, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Chung Mao Lo Professor, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China J. Peter A. Lodge MD, FRCS Professor and Clinical Director, HPB & Transplant Unit, St. James’ University Hospital, Leeds, UK Ajay V. Maker MD Director of Surgical Oncology, Creticos Cancer Center–Advocate Illinois Masonic Medical Center; Departments of Surgery and Microbiology/Immunology, University of Illinois at Chicago, Chicago, Illinois, USA Masatoshi Makuuchi MD, PhD Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan Hassan Malik MD, FRCS Hepatobiliary Unit, Department of Surgery, University Hospital Aintree, Liverpool, UK Oliver Mann Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Maureen McEvoy MD Department of Surgery, Pediatric Surgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Colin J. McKay West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK André L. Mihaljevic Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany David M. Nagorney Mayo Clinic, Rochester, Minnesota, USA Yuji Nimura MD President, Aichi Cancer Center, Chikusaku, Nagoya, Japan Giuseppe Orlando Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires St Luc Université catholique de Louvain, Department of Abdominal and Transplantation Surgery, Brussels, Belgium

LIST OF CONTRIBUTORS Nicholas O’Rourke MBBS, FRACS Royal Brisbane Hospital, Brisbane, Queensland, Australia Martin Palavecino MD Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Purvi Y. Parikh MD Department of Surgery, Albany Medical College, Albany, New York, USA Samir Pathak MD, ChB, MSC, MRCS Clinical Fellow, North Western Hepatobiliary Centre, Aintree University Hospital, Liverpool, UK Henry A. Pitt MD Indiana University, Indianapolis, Indiana, USA Graeme J. Poston MS, FRCS (Eng), FRCS (Ed) Centre for Digestive Diseases, University Hospital Aintree, and Department of Surgery, The Royal Liverpool University Hospitals, Liverpool, UK Derek G. Power MD Memorial Sloan-Kettering Cancer Center, New York, New York, USA Myrddin Rees MS, FRCS, FRCS (Ed) Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK Michael Rhodes Department of Surgery, Norfolk & Norwich University Hospital, Norwich, UK Charles B. Rosen Mayo Clinic, Rochester, Minnesota, USA

Jason W. Smith MD Chief Resident, Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA Nick Stern Consultant Gastroenterologist, Digestive Diseases Department, University Hospital Aintree, Liverpool, UK Richard Sturgess Consultant Gastroenterologist and Clinical Director, Digestive Diseases Department, University Hospital Aintree, Liverpool, UK Adriano Tocchi Head of 1st Department of Surgery and Chief of the Gastro-intestinal and Hepato-biliary Surgical Service, University of Rome Sapienza Medical School, Rome, Italy Ludovic Trinquart Department of Radiology, Assistance-Publique Hôpitaux de Paris, Hôpital Beaujon, Clichy, France Bernard Van Beers Department of Radiology, Assistance-Publique Hôpitaux de Paris, Hôpital Beaujon, Clichy; Université Paris; and Centre de recherche biomédicale Bichat-Beaujon, Paris, France Jean-Nicolas Vauthey MD Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Valérie Vilgrain Department of Radiology, Assistance-Publique Hôpitaux de Paris, Hôpital Beaujon, Clichy; Université Paris; and Centre de recherche biomédicale Bichat-Beaujon, Paris, France

Gerardo Sarno MD Clinical Fellow, North Western Hepatobiliary Centre, Aintree University Hospital, Liverpool, UK

Vanessa de Villa Assistant Professor, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China

Rajesh Satchidanand MD, FRCS Clinical Fellow, North Western Hepatobiliary Centre, Aintree University Hospital, Liverpool, UK

J. Weitz MD Department of Surgery, University of Heidelberg, Heidelberg, Germany

Beat Schnüriger Division of Trauma and Surgical Critical Care, University of Southern California, Los Angeles, California, USA Lawrence H. Schwartz Department of Radiology, Columbia University College of Physicians and Surgeons, and Radiologist-in-Chief, New York–Presbyterian Hospital/ Columbia University Medical Center, New York, New York, USA Margo Shoup MD, FACS Chief, Division of Surgical Oncology, Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA Jason K. Sicklick Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Steven M. Strasberg MD, FRCS(C), FACS, FRCS (Ed) Pruett Professor of Surgery and Head Hepato-Pancreato-Biliary and Gastrointestinal Surgery, Washington University in Saint Louis and Barnes-Jewish Hospital, Saint Louis, Missouri, USA

Fenella K. S. Welsh MA, MD, FRCS (Gen Surg) Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK Moritz Wente Department of Surgery, University of Heidelberg, Heidelberg, Germany Vincent Kah Hume Wong MBCB, MRCS Research Fellow in Hepatopancreatobiliary & Transplant Surgery, HPB & Transplant Unit, St. James’ University Hospital, Leeds, UK A. Peter Wysocki Department of Surgery, Logan Hospital, Meadowbrook, Queensland, Australia Charles J. Yeo MD The Samuel D. Gross Professor and Chair, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Daria Zorzi MD Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

ix

Foreword As recent progress in hepato-pancreato-biliary (HPB) surgery has been evident since the first edition of this book was published eight years ago, Dr. Graeme Poston, Dr. Mike D’Angelica, and Dr. René Adam, internationally recognized authorities in HPB surgery, have attempted to rewrite the second edition, joined by selected numerous worldwide specialists renowned as expert authors in each field to present a current view of the surgical and non-surgical management of benign and malignant HPB disorders. This book demonstrates the wisdom of the new knowledge and technical skills of these diverse disciplines where cooperative

x

efforts contribute toward the benefit of the patients with HPB disorders. The general surgeon will find this volume to be a useful source of current thoughts on how to manage the diverse HPB diseases. Yuji Nimura MD President, Aichi Cancer Center Professor Emeritus, Nagoya University Graduate School of Medicine Past President, International Hepato-Pancreato-Biliary Association (IHPBA)

Preface Hepato-pancreato-biliary (HPB) surgery is now firmly established within the repertoire of modern general surgery. Indeed, in many major tertiary centers there are now specific teams for both pancreatic and liver surgery. However, in most hospitals outside these major centers the day-to-day management and decision-making for patients with these disorders remains the remit of the general surgeon. Following the launch of the highly successful first edition of this book eight years ago there have been considerable advances in the surgical management of HPB disorders. Many of these relate to related specialties (radiology, oncology, gastroenterology, and anesthesia) and also directly to surgery (liver transplantation, caval bypass and replacement, laparoscopic surgery to name but a few). As such the second edition has been completely rewritten from scratch. As with the first edition, the purpose of this edition is twofold. First, it is intended to cover the spectrum of common

HPB diseases that will confront the general surgeon in his or her regular practice. Second, we hope that this work will be sufficiently comprehensive to cover the broad spectrum of HPB surgery for candidates coming to examinations at the completion of surgical training. We are indebted to the many international contributors for their perseverance and patience over the gestation of this project, which is greatly appreciated. Lastly, we are grateful to our publishers, Informa Healthcare, for their help during the preparation of this project. Graeme J. Poston Michael D’Angelica René Adam September 2010

xi

1

Surgical anatomy of the liver and bile ducts Robert Jones and Graeme J. Poston

The success of any surgical intervention on the liver and bile ducts is totally dependent on a thorough working knowledge of their anatomy. As the number of patients undergoing hepatobiliary surgery is increasing, good understanding of the anatomy of this area is increasingly important for any surgeon with an interest in the gastrointestinal tract. Command of this anatomy is also essential for the successful interpretation of functional imaging of hepatobiliary anatomy. When operating on the liver and biliary tree, the surgeon has to obey three basic tenets. ● ●

●

Remove all pathologically involved tissue. Preserve the maximal amount of functioning nonpathological liver tissue. Perform safe resection, while ensuring adequate blood supply to the remaining hepatic parenchyma.

Historically, the liver was described according to its morphological appearance (1,2). However, these three tenets have altered the approach to surgery, and the liver is now considered from a functional and therefore surgical perspective.

morphological anatomy Historically, when viewed at laparotomy, the liver appears divided into a larger “right” lobe, and a smaller “left” lobe by the umbilical fissure and falciform ligament (Figs. 1.1 and 1.2) (3). Situated on the inferior surface of the right lobe is the transverse hilar fissure, which constitutes the posterior limit of the right lobe. The “quadrate” lobe was defined as the portion of the right lobe lying anterior to this transverse hilar fissure and to the right of the umbilical fissure, its other margin being defined by the gallbladder fossa. The “caudate” lobe, which is anatomically and functionally separate from the rest of the liver, lies posterior to the hilum, between the portal vein and the inferior vena cava (IVC) (4). This historical anatomical approach does not consider the vasculature or biliary drainage of the liver and is of only limited use when planning surgical resection.

early application of the functional anatomy Isolated liver wounds, usually as a result of military action, had been successfully treated since the early seventeenth century (5,7), but the first attempt at resection of a liver tumor was not made until 1886, when the French surgeon Luis excised a solid liver tumor by ligating and cutting through a pedunculated left lobe “adenoma.” Attempts to suture the severed pedicle were unsuccessful, and the stump was returned to the peritoneal cavity. Not surprisingly, the patient succumbed some six hours later (8). In 1888, Rex reported a “new” arrangement of the right and left lobes of the liver and further refined our understanding of

lobar anatomy (2). The first successful elective liver resection was performed two years later by von Langenbuch, who excised a portion of the left lobe of the liver containing an adenoma in 1888 (9). He had to reopen the abdomen several hours after the operation because of reactionary hemorrhage, but was able to ligate the bleeding vessels and return the oversewn liver to the abdomen. Two years later in 1890, the Baltimore surgeon McLane Tiffany reported the successful removal of a benign liver tumor (10), and the following year Lucke described the successful resection of a cancerous growth of the liver (11). Surgery was now becoming a recognized treatment for liver pathology. Advances in surgery closely mirrored increased understanding of the functional anatomy of the liver (12–14). The first attempt to define the functional anatomy of the liver, which could possibly guide current surgical practice, was made by Cantlie in 1898, while working in Hong Kong. He dissected the livers of executed prisoners (15) and making vascular casts, he demonstrated that the main division between the right and left lobe in fact extended from approximately the gallbladder fossa, to the right side of the IVC, posterosuperiorly. Cantlie’s line, therefore, follow a line drawn from the gallbladder fossa, along the middle hepatic vein, to the IVC (Figs. 1.2 and 1.3) (3). In 1911, Wendel reported the first case of right lobectomy for a primary tumor (16), however this procedure did not follow the precise anatomical plane described by Cantlie. In 1939, while working in Paris, the Vietnamese surgeon Ton That Tung described the venous drainage of the liver in relation to the true lobar anatomy (Fig. 1.4) (17). The first anatomically correct description of a left lateral segmentectomy was made by Raven in 1948 while resecting metastatic colon cancer (18). Four years later, Lortat-Jacob and Robert finally described a similar approach to the true right hepatic lobectomy, based on the anatomical principles described by Cantlie (Fig. 1.6) (19). Healey and Schroy were the first to demonstrate in 1953 that the right lobe was further divided into an anterior and a posterior sector (20). They also showed that the left lobe was divided into a medial and lateral sector by the line of the falciform ligament and umbilical vein (Fig. 1.5). Understanding of the functional anatomy of the liver continued to develop, and in 1957, Goldsmith and Woodburne described a number of anatomical planes through the liver parenchyma that followed this functional anatomy. Their paper finally defined true right lobectomy (right hepatectomy), left lobectomy (left hepatectomy), and left lateral segmentectomy (Fig. 1.6) (21).

appreciation of segmental anatomy Probably the most important anatomical contribution to modern liver surgery comes from the work of the late Claude

1

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS IVC

Middle hepatic vein lying among Cantlie's line

IVC

Left lobe Right lobe

IVC

IVC Right free border of lesser omentum

Cantlie's line

Figure 1.1 Morphological anatomy.

Gallbladder

Figure 1.3 Cantlie’s line.

Umbilical fissure

Cantlie's line

Gallbladder

Quadrate lobe

supply (inflow and outflow), and therefore viability, to the remaining hepatic parenchyma. The description of Couinaud is the most complete and exact, and also the most useful for the operating surgeon, and therefore it is this description that will be used throughout this book.

segmental anatomy of the liver Transverse hilar fissure Gastrohepatic omentum

Common bile duct, hepatic artery and portal vein

IVC Caudate lobe

Figure 1.2 Anatomical features.

Couinaud, who in 1957 produced a huge number of vasculobiliary casts of the liver (23,24). Couinaud was able to demonstrate that the liver appeared to consist of eight anatomical segments, each of which could potentially be separately resected without affecting the physiological viability of the other segments. Couinaud redefined the caudate lobe as segment 1 and Goldsmith and Woodburne’s left lobe as segments 2 and 3. The quadrate lobe was termed segment 4, and more recently has been subdivided by further studies of its portal blood supply into 4A (superiorly) and 4B (inferiorly). The right liver consists of segments 5 (anteroinferiorly), 6 (posteroinferiorly), 7 (posterosuperiorly), and 8 (anterosuperiorly) (Fig. 1.7). Couinaud later suggested a further clarification, in which the caudate lobe to the left of the IVC remained segment 1, with that to the right being redefined as segment 9 (25). Resections based on these anatomical segments enable the surgeon to safely operate following the three central tenets described above; remove all pathologically involved tissue, preserve the maximal amount of nonpathological liver tissue, and perform safe resection, while ensuring an adequate blood

2

These anatomical studies of the functional anatomy of the liver allow us to define hepatic segments based upon both the distribution of the portal pedicles and the drainage of the hepatic veins (Fig. 1.5). The three main hepatic veins (right, middle, and left) divide the liver into four sectors, each of which receives a portal pedicle containing branches of the hepatic artery, hepatic duct, and portal vein; thus producing an alternation between hepatic veins and portal pedicles. These four sectors, demarcated by the hepatic veins, are the portal sectors, each sector therefore receiving an independent portal supply. For the same reason, the scissurae containing the hepatic veins are termed the portal scissurae while the scissurae containing portal pedicles are the hepatic scissurae (Fig. 1.5). Thus, the liver is divided by the main portal scissura along the line of the middle hepatic vein into two discrete hemilivers, along the line previously described by Cantlie (15). We therefore refer to these hemilivers as right and left livers, rather than right and left lobes, to avoid confusion with the anatomical lobes, particularly since there is no visible surface marking that permits individualization of the “true” lobes. As described by Cantlie, the main portal scissura runs posteriorly from the middle of the gallbladder fossa to the right side of the IVC (Fig. 1.5). Therefore, the right and left livers, demarcated by the main portal scissura, are independent in terms of their portal and arterial vascularization and their biliary drainage. These right and left livers are both further divided into two by the other two portal scissurae, delineated by the right and left hepatic veins. Goldsmith and Woodburne refer to these further divisions as “segments” (21), but for the rest of this book, we will use the more generally accepted nomenclature of Couinaud, which refers to these divisions as “sectors” (23). The

SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS Right liver

Left liver

IVC

Middle hepatic vein (usually enters left vein before IVC)

Left heptic vein

Right hepatic vein

Caudate hepatic veins (variable)

Right inferior hepatic vein (variable) IVC Gallbladder, note that the middle vein may lie superficially in the gallbladder fossa Figure 1.4 Venous drainage of the liver.

IVC

Middle hepatic vein in main portal scissura following Cantlie's line

7

2

Right hepatic vein in right portal scissura

8

Left hepatic vein in left portal scissura Lateral segment of left lobe

3 1 4

Right posterior sector

Falciform ligament 6

5 Medial segment of left lobe Right anterior sector Right liver

Portal vein Left liver

Figure 1.5 Functional sectoral anatomy and relationship to hepatic scissurae.

right liver is divided by the right portal scissura (right portal vein) into an anteromedial (or anterior) sector containing segments 5 inferiorly and 8 superiorly, and a posterolateral (or posterior) sector containing segments 6 inferiorly and 7 superiorly (Fig. 1.5). When the liver lies in its normal position within the upper abdominal cavity, the right posterolateral sector lies directly behind the right anteromedial sector, and this scissura is therefore almost in the coronal plane. Therefore in the clinical setting (particularly when imaging the liver), it is better to speak of these anterior and posterior sectors (Fig. 1.5). The exact location of the right portal scissura is imprecise, because it has no external landmarks. According to Couinaud (23), it extends from the edge of the liver at the middle point between the back of the liver and the right side of the

gallbladder bed along the right hepatic vein posteriorly to the confluence of the right hepatic vein and the IVC (26–28). The venous drainage of the right liver is variable in that, in addition to the right and middle hepatic veins, there are often a number of smaller hepatic veins draining directly into the IVC from segments 6 and 7. Not infrequently (63–68%) segment 6 drains directly into the IVC through a distinct inferior right hepatic vein, larger than these other venous tributaries to the IVC, which can be a significant bonus in the preservation of residual hepatic function when undertaking extended left hepatectomies (Fig. 1.4) (29,30). The left portal scissura, along the left hepatic vein, divides the left liver into two sectors: an anterior sector containing segments 3 and 4 and a posterior sector containing segment 2

3

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A)

(B)

(C)

(D)

(E) Figure 1.6 Formal hepatectomies: (A) right hepatectomy; (B) left hepatectomy; (C) left lateral segmentectomy; (D) extended left hepatectomy; (E) extended right hepatectomy.

2

8 8

7

7

1

2

3 1 5

4

3

4 5

6 6

(A)

(B)

Figure 1.7 Functional division of the liver and of the liver segments according to Couinaud’s nomenclature (A) as seen in the patient and (B) in the ex vivo position.

4

SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS (Fig. 1.5). It is important to note that the left portal scissura does not follow the umbilical fissure; this portal scissura contains a hepatic vein and the umbilical fissure contains a portal pedicle. Therefore the left portal scissura lies posterior to the ligamentum teres, inside the left lobe of the liver (Fig. 1.5). The middle hepatic vein (defining the main portal scissura) usually enters the left hepatic vein some 1 to 2 cm before the left hepatic vein joins the IVC (Fig. 1.4) (30). Occasionally the middle and left hepatic veins enter the IVC separately, and in 2 out of 34 of Couinaud’s casts, the middle vein and left veins joined at more than 2.5 cm from the IVC (30). Such an anomaly must be detected and excluded during isolated resection of segment 4, since if it is not seen, and the last 2 cm of the left vein is damaged, segments 2 and 3 will be needlessly sacrificed (and in the case of extended right hepatectomy, threaten future remnant liver viability). The caudate lobe (segments 1 and 9) is the dorsal portion of the liver, lying posteriorly and surrounding the retrohepatic IVC. It lies directly between the portal vein (anteriorly) and the IVC (posteriorly). The main bulk of the caudate lobe lies to the left of the IVC, with its left and inferior margins being free in the lesser omental bursa (Fig. 1.2). The gastrohepatic (lesser) omentum separates the caudate from segments 2 and 3 of the left liver. The left portion of the caudate lobe lies inferior to the right between the left portal vein and the IVC, as the caudate process. This process then fuses inferiorly with segment 6 of the right liver. The amount of caudate lobe that lies on the right side is variable, but usually small. The anterior surface of the caudate lobe lies within the hepatic parenchyma against the posterior intrahepatic surface of segment 4, demarcated by an oblique plane slanting from the left portal vein to the left hepatic vein. The caudate lobe must be considered functionally as an isolated autonomous segment, since its vascularization is independent of the portal division and of the three main hepatic veins. It receives a variable arterial and portal blood supply from both the right and left portal structures, although the right caudate lobe consistently receives an arterial supply from the right posterior artery. Biliary drainage is likewise into both the right and left hepatic ducts. However, the left dorsal duct can also join the segment 2 duct. The small hepatic veins of the caudate lobe drain directly into the IVC. This independent functional isolation of the caudate lobe is clinically important in Budd–Chiari syndrome; if all three main hepatic veins are obliterated, the only functioning hepatic venous drainage is through the caudate lobe, which therefore undergoes compensatory hyperplasia.

anatomical classification of hepatectomies Hepatic resections can be classified as “anatomical” and “nonanatomical.” Anatomical hepatectomies (hepatectomies reglees) are defined by resection of a portion of liver parenchyma defined by the functional anatomy. These resections are called left or right hepatectomies, sectorectomies, and segmentectomies. Nonanatomical hepatectomies involve resection of a portion of hepatic parenchyma not limited by anatomical scissurae. Such resections are usually inappropriate,

as they will leave behind devascularized residual liver and will also probably not adequately excise all the pathologically involved parenchyma. The usual anatomical hepatectomies can be considered in two groups: right and left hepatectomies in which the line of transection is the main portal scissura separating the right and left livers along the middle hepatic vein, and right and left hepatectomies in which the line of transection commences in the umbilical fissure. For some time the latter definition, initially proposed by Goldsmith and Woodburne (21), has been the accepted convention. We would encourage the use of the former definition, as segment 4 (quadrate lobe) is anatomically part of the left liver (Fig. 1.9), and this convention was adopted universally at the 2000 Brisbane Congress of the IHPBA (Brisbane Convention), and will be used hereafter in this book. Using this functional approach to liver anatomy, we can define numerous potential liver resections based upon the order (first, second, third) of the hepatic divisions (main portal scissura, anterior and posterior right portal scissurae, left portal scissura) (28). With regard to the first order division, right hepatectomy or hemihepatectomy (removal of the right liver/hemiliver) therefore consists of the resection of segments 5 to 8 (stipulating ± segment 1). Left hepatectomy or hemihepatectomy (removal of the left hemiliver or liver) is the removal of segments 2–4 (stipulating ± segment 1) (Fig. 1.6). In certain pathologies (multiple liver metastases or large tumors transgressing the main portal scissura) hepatectomies can be extended to include adjacent segments and sectors of the other liver. Therefore extended right hepatectomy (right trisegmentectomy or extended right hemihepatectomy) will also include resection of segment 4 (stipulating ±segment 1), taking portal structures to the right of the falciform ligament (Fig. 1.6). Similarly, extended left hepatectomy (left trisegmentectomy or extended left hemihepatectomy) would include resection of segments 5 and 8 en bloc with segments 2 to 4 (stipulating ± segment 1) (Fig. 1.6). When discussing second order divisions, individual sectors can be resected in isolation or in adjacent pairs depending upon the distribution of pathology. Therefore right anterior sectionectomy refers to the en bloc resection of segments 5 and 8 (between the main portal scissura (middle hepatic vein) and right portal scissura (right portal vein) on their pedicle of the anterior division of the right portal vein). Right posterior sectionectomy (previously referred to as right posterior or lateral sectorectomy) is the contiguous resection of segments 6 and 7, posterior to the right portal scissura (on the pedicle of the posterior division of the right portal vein) (Fig. 1.8). On the left side, isolated excision of segment 4 can be described as left median sectionectomy, although it is also legitimate to refer to it as resection segment 4 or segmentectomy 4. One area of confusion in these definitions of hepatectomies comes in the simultaneous resection of segments 2 and 3 (Fig. 1.10). Goldsmith and Woodburne originally described this procedure as a left hepatic lobectomy (21). Describing this as left lateral segmentectomy is technically wrong since the true left lateral segment (and sector) comprises no more than segment 2 (excision of which in isolation can therefore be

5

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS described as left lateral or posterior sectorectomy). It is now accepted convention that resection of segments 2 and 3 is regarded as a left lateral sectionectomy (but can also legitimately be referred to as bisegmentectomy 2–3). With regard to the third order divisions, resection is now at the level of the individual hepatic segment(s). Therefore these resections are referred to as segmentectomy (classified according to the segment being removed: 1–9). Similarly, segments 5 and 6 can be resected en bloc (and this used to be described as a right inferior hepatectomy) and this should now be described as bisegmentectomy 5–6. If there is a significant right inferior hepatic vein draining segments 5 and 6, then segments 7 and 8 can be resected with the right hepatic vein (bisegmentectomy 7–8) (Fig. 1.8).

surgical approach to the caudate lobe This resection (segmentectomy 1 or 9, or 1 and 9 en bloc) is initially achieved by dissection of the coronary ligament up to the right of the IVC, being careful to avoid the right hepatic vein. The falciform ligament is then dissected to the IVC, the

lesser omentum being incised close to the liver. Opening the left coronary ligament allows ligation of the inferior phrenic vein. The caudate veins running directly to the IVC are now exposed and can be divided between ligatures as they run up the back of the caudate lobe. After the hilar plate is lowered to expose the right and left portal pedicles, the portal inflow to both the right and left caudate segments can be identified, ligated, and divided. The caudate lobe is now isolated and the main portal fissure is divided to separate segments 4, 7, and 8. Note that the caudate segment 1s not defined macroscopically from segment 6.

the biliary tract Accurate biliary exposure and precise dissection are the two most important steps in any biliary operative procedure and are both totally dependent on a thorough anatomical understanding of these structures. Several authors have described the anatomy of the biliary tract (17,22,23), but unfortunately the surgical implications have been incompletely described and continue to be misunderstood by many surgeons.

(A)

(B)

(C)

(D)

(E) Figure 1.8 Other hepatic sectorectomies: (A) right posterior sectorectomy; (B) right anterior sectorectomy; (C) left medial sectorectomy (segments 4A and 4B); (D) right inferior hepatectomy; (E) right superior hepatectomy.

6

SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS

intrahepatic biliary anatomy The right liver and left liver are respectively drained by the right and the left hepatic ducts. The caudate lobe (segments 1 and 9) is drained by several ducts joining both the right and left hepatic ducts (20). The intrahepatic ducts are tributaries of the corresponding hepatic ducts, which form part of the major portal tracts invaginating Glisson’s capsule at the hilus and penetrating the liver parenchyma (Fig. 1.11). There is variation in the anatomy of all three components of the portal triad structures (hepatic ducts, hepatic arteries, and portal vein), but it is the portal vein that shows the least anatomical variability. In particular, the left portal vein tends to be consistent in location (23). Bile ducts are usually located above the portal vein whereas the corresponding artery will lie below. Each branch of the intrahepatic portal vein corresponds to one or two intrahepatic bile ducts, which converge outside the liver to form the right and left hepatic ducts, in turn joining to form the common hepatic duct. The left hepatic duct drains segments 2, 3, and 4, which constitute the left liver. The duct draining segment 3 is found a little behind the left horn of the umbilical recess, from where it passes directly posteriorly to join the segment 2 duct to the left

of the main portal branch to segment 2. At this point, the left branch of the portal vein turns forward and caudally in the recessus of Rex (23) (Figs. 1.12 and 1.13). As the duct draining segment 3 begins its posterior course it lies superficially in the umbilical fissure, often immediately under Glisson’s capsule. As such it is usually easily accessible at surgery to allow a biliary– enteric (segment 3 hepaticojejunostomy) anastomosis for biliary drainage if such access is not possible at the porta hepatis. The left hepatic duct then passes beneath the left liver at the posterior base of segment 4, lying just above and behind the left branch of the portal vein. After the left duct crosses the anterior edge of that vein it joins the right hepatic duct to form the common duct at the hepatic ductal confluence. In this transverse portion, where it lies below the liver parenchyma, it receives one to three small branches from segment 4 (23). The right hepatic duct (Fig. 1.14) drains segments 5 to 8 and arises from the convergence of the two main sectoral (anterior 5 and 8, and posterior 6 and 7) tributaries. The right posterior sectoral duct runs almost horizontally (26) and comprises the confluence of the ducts from segments 6 and 7 (Fig. 1.15). The right posterior duct joins the right anterior sectoral duct (formed by the confluence of the ducts from segments 5 and 8)

Figure 1.9 Completion of segment 4 resection with portal bifurcation lying inferiorly in front of the inferior vena cava.

Figure 1.11 Exposing the hilar plate by raising the inferior surface of segment 4B, thus demonstrating the condensation of Glisson’s capsule, which will cover the extra hepatic confluence of the right and left hepatic ducts.

Figure 1.10 Left lateral segmentectomy immediately prior to division of the portal structure lying inferiorly and the left hepatic vein lying superiorly.

Figure 1.12 Exposing the recessus of Rex by distraction of the falciform ligament to demonstrate the bifurcation of segment 3 and segment 4 bile ducts.

7

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 4 RPV

2

RHD RHA

4 (ant.) 3

CHD

PV

HA

Recessus of Rex

Figure 1.13 Biliary and vascular anatomy of the left liver. Note the position of segment 3 duct above the corresponding vein and its relationship to the recessus of Rex.

as it descends vertically (26). This right anterior sectoral duct lies to the left of the right anterior sectoral branch of the intrahepatic portal vein as it ascends within the parenchyma (Fig. 1.15). The junction of the two main right biliary ducts usually occurs immediately above the right branch of the portal vein (23). The right hepatic duct is considerably shorter than its counterpart on the left, which it joins to form the common hepatic duct in front of the right portal vein (Fig. 1.15). The caudate lobe (segments 1 and 9) has its own separate biliary drainage. This segment comprises two anatomically and functionally distinct portions, a caudate lobe proper (which consists of a right and left part) located at the posterior aspect of the liver, and a caudate process passing behind the portal structures to fuse with segment 6 of the right liver. In nearly half of individuals, three separate bile ducts drain these distinct parts, while in a quarter of individuals, there is a common biliary duct between the right portion of the caudate lobe proper and the caudate process, while the left part of the caudate lobe is drained by an independent duct. However, the site of drainage of these ducts is variable. Most authors advocate en bloc resection of the caudate lobe during resection of hilar cholangiocarcinoma (31), since the tumor usually infiltrates these ducts draining the caudate lobe. Certainly these authors have demonstrated that in 88% of cases of hilar cholangiocarcinoma coming to resection there is histological evidence of tumor infiltration of the caudate lobe along these ducts.

extrahepatic biliary anatomy

Figure 1.14 Demonstration of the right hepatic duct lying within the gallbladder fossa.

The detail of this section will be confined to the upper part of the extrahepatic biliary tree, above the common bile duct, since the common bile duct is also covered in chapter 2. The right and left hepatic ducts converge at the right of the hilum of the liver, anterior to the portal venous bifurcation and overlying the origin of the right portal vein. The biliary confluence

Anterior sectoral duct

8

5 7 Posterior sectoral duct

LHD LPV 6 LHA CHD

HA PV

Figure 1.15 Biliary and vascular anatomy of the right liver. Note the horizontal course of the posterior sectoral duct and the vertical course of the anterior sectoral duct.

8

SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS is separated from the posterior aspect of the base of segment 4 by a fusion of connective tissue investing from Glisson’s capsule to form the fibrous hilar plate. This hilar plate has no vascular interposition and, when opened behind the posterior aspect of the base of segment 4, will display the extrahepatic confluence of the right and left hepatic ducts (Fig. 1.16). The main bile duct is divided into its upper part, the common hepatic duct, and lower part, the common bile duct, by the entry of the cystic duct from the gallbladder. This point of confluence of hepatic and cystic ducts to form the common bile duct is widely variable, and any surgeon performing the operation of cholecystectomy has a duty of care to their patient to be fully aware of this anatomic variability (lest they mistake the common bile duct, or less frequently the common or right hepatic ducts for the cystic duct, resulting in catastrophic consequences for the patient). The main bile duct normally has a diameter of up to 6 mm and passes downward anterior to the portal vein in the right free border of the lesser omentum. The bile duct is closely related to the hepatic artery as it runs upwards on its left side before dividing into its left and right branches, the right hepatic artery usually passing posteriorly to the bile duct. The cystic artery, which usually arises from the right hepatic artery, crosses the common hepatic duct as frequently anteriorly as it does posteriorly (Figs. 1.17 and 1.18). Calot’s triangle was originally defined by the common hepatic duct lying medially, inferiorly by the cystic duct and superiorly by the cystic artery (32). However, the usually accepted surgical definition of this triangle has been modified to that of the “cholecystectomy” triangle, which defines the

upper border as the inferior surface of the liver (and therefore contains the cystic artery) (33). The junction of the cystic duct and common hepatic duct varies widely and may even occur behind the pancreas. The retropancreatic portion of the bile duct approaches the duodenum obliquely, accompanied by the terminal part of the duct of Wirsung (see chap. 2). These two ducts join to enter the duodenum through the sphincter of Oddi at the papilla of Vater (34,35).

gallbladder and cystic duct The gallbladder lies within the cystic fossa on the underside of the liver in the main liver scissura, thereby defining the junction between the right and left hemilivers. It is separated from the hepatic parenchyma by the cystic plate, which is an extension of connective tissue from the hilar plate (described previously). The anatomical relationship of the gallbladder to the liver ranges from hanging by a loose peritoneal reflection to being deeply embedded within the liver parenchyma. The gallbladder varies in size and consists of a neck, body, and fundus, which usually reaches the free edge of the liver, still closely applied to the cystic plate. Large gallstones impacting within the neck of the gallbladder may create a Hartmann’s pouch (33), and inflammation secondary to this can obscure the anatomical plane between the gallbladder and the common hepatic duct (thus obliterating the cholecystectomy triangle). This degree of inflammation can make dissection during cholecystectomy difficult, increasing the risk of damage to the common hepatic duct (36). Other structures similarly threatened during this dissection as part of cholecystectomy for

Segment 4 Glisson's capsule Lig.teres

RHD RHA

LPV LHD LHA

RPV Cystic artery Cystic duct Gallbladder CHD

Umbilical fissure

HA

Line of incision of hilar plate to expose left hepatic duct CBD

Retroduodenal artery Gastroduodenal artery Splenic vein

Cystic plate

Hilar plate

Figure 1.16 Demonstration of the relationship between the posterior aspect of the base of segment 4 and the biliary confluence. Note the extension of Glisson’s capsule to invest the portal structures at the hilum (hilar plate) and extending over the hepatic surface of the gallbladder (cystic plate). Exposure of the extrahepatic left hepatic duct is achieved by incising the hilar plate at the base of segment 4 medially as far as the umbilical fissure.

Superior mesenteric artery and vein Figure 1.17 Anterior aspect of biliary anatomy. Note the hepatic duct confluence anterior to the right hepatic artery and origin of the right portal vein. Note also the course of the cystic artery, arising from the right hepatic artery and passing posteriorly to the common hepatic duct.

9

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS chronic cholecystitis include the right hepatic artery (in up to 50% of cholecystectomy bile duct injuries, so rendering the upper bile duct ischemic with ramifications for the timing of bile duct repair), the right hepatic duct, and in exceptional circumstances, a low-lying middle hepatic vein lying superficially just below the gallbladder fossa.

(A)

(B)

(D)

(E)

(G)

biliary anomalies

(C)

(F)

(H)

Figure 1.18 The eight most common variations in the anatomy of the arterial supply (cystic artery) to the gallbladder.

(A)

The cystic duct arises from the neck of the gallbladder and in 80% of people descends to join the common hepatic duct in its supraduodenal course. Its length varies widely but its luminal diameter is usually between 1 and 3 mm. The mucosa of the cystic duct is arranged in spiral folds (valves of Heister) (33). In a small number of cases, the cystic duct joins the right hepatic duct or occasionally a right hepatic sectoral duct. The gallbladder receives its blood supply by the cystic artery, the anatomy of which varies widely (Fig. 1.18). The most common variant arises directly from the right hepatic artery, then dividing into an anterior and posterior branch. The venous drainage of the gallbladder is directly through the gallbladder fossa to the portal vein in segment 5 (Fig. 1.19).

The biliary anatomy described above, comprising a right and left hepatic duct joining to form a common hepatic duct occurs in between 57% (23) and 72% (8) of cases. This variance may be explained by Couinaud’s (23) description of a triple confluence of right posterior sectoral duct, right anterior sectoral duct, and left hepatic duct in 12% of cases, which Healey and Schroy do not describe. There are many other abnormalities in biliary anatomy. Couinaud described a right sectoral duct joining the main bile duct in 20% of individuals (right anterior sectoral in 16%, right posterior sectoral in 4%). In addition, a right sectoral duct (posterior in 5%, anterior in 1%) may join the left hepatic duct in 6% of cases. In 3% of cases, there is an absence of a defined hepatic duct confluence with all the sectoral ducts joining separately and in 2% the right posterior sectoral duct may join the neck of the gallbladder or be entered by the cystic duct (23) (Fig. 1.20). Similarly, there are common variations of the intrahepatic biliary anatomy. Healey and Schroy (20) describe the classical intrahepatic biliary arrangement outlined above in 67% of

(B) Figure 1.19 (A) Venous drainage of the gallbladder. (B) The lymphatic drainage of the gallbladder towards the coeliac axis.

10

SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS cases, with ectopic drainage of segment 5 in 9%, segment 6 in 14%, and segment 8 in 20% of the cases. In addition, they describe a subvesical duct in 20% to 50% of the cases (8,37). This subvesical duct may lie deeply embedded in the cystic plate and can join either the common or right hepatic ducts. This duct does not drain any specific area of the liver and never communicates with the gallbladder, but may be damaged during cholecystectomy and therefore contribute to postoperative biliary leak. On the left side, the commonest anomaly is a common union of ducts of segments 3 and 4 (25% of cases), and in only 2% does the segment 4 duct independently join the common hepatic duct (Fig. 1.21). Gross described a number of anomalies of the accessory biliary apparatus in 1936 (38). These include bilobed and

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(E)

ra rp Ih

2% (F) Figure 1.20 Main variations of the hepatic duct confluence.

duplicated gallbladder (39,40), septum and diverticulum of the gallbladder, and variations in cystic duct anatomy including a double cystic duct (41). More rare is agenesis of the gallbladder (42,43) (Fig. 1.22). Furthermore, the gallbladder may be abnormally positioned, either lying deep within the liver parenchyma or lying under the left liver (44). The union of the cystic duct with the common hepatic duct may be angular, parallel, or spiral. The most frequent union is angular (75%) (45), while the cystic duct may run parallel with the hepatic duct in 20%, both encased in connective tissue. In 5% of cases, the cystic duct may approach the hepatic duct in a spiral fashion, usually passing posteriorly to the common hepatic duct before entering on its left side (Fig. 1.23).

the arterial blood supply of the bile ducts The hepatic artery usually arises as one of the three named branches of the coeliac trunk, along with the left gastric and splenic arteries (Fig. 1.24). The first named branch of the hepatic artery is the gastroduodenal artery and either of these arteries may then give rise to the right gastric and retroduodenal arteries (Fig. 1.24). The hepatic artery then divides into right (giving rise to the cystic artery) and left hepatic arteries. This arrangement holds true for 50% of cases. In nearly 25% of cases, the right hepatic artery arises separately from the superior mesenteric artery, indicative of the joint fore- and mid-gut origin of the liver (Fig. 1.25). In the remaining 25% of cases, the left hepatic artery arises from the left gastric artery. Occasionally, other variations will occur. These variations will be readily apparent to an experienced surgeon at operation. The authors do not advocate preoperative angiography to delineate these anomalies prior to routine hepatectomy. The extrahepatic biliary system receives a rich arterial blood supply (46), which is divided into three sections. The hilar section receives arterioles directly from their related hepatic arteries and these form a rich plexus with arterioles from the supraduodenal section. The blood supply of the supraduodenal section is predominantly axial. Most vessels to this section arise from the retroduodenal, right hepatic, cystic, gastroduodenal, and retroportal artery. Usually, eight small arteries, each 0.3 mm in diameter, supply the supraduodenal section. The most important of these vessels run along the lateral borders of the duct and are referred to as the 3 o’clock and 9 o’clock arteries. Of the arteries supplying the supraduodenal section, 60% run upward from the major inferior vessels while 38% run downward from the right hepatic artery. Only 2% are nonaxial, arising directly from the main trunk of the hepatic artery as it runs parallel to the bile duct. The retropancreatic section of the bile duct receives its blood supply from the retroduodenal artery. The veins draining the bile duct mirror the arteries and also drain the gallbladder. This venous drainage does not enter the portal vein directly but seems to have its own portal venous pathway to the liver parenchyma (47). It has been proposed that arterial damage during cholecystectomy may result in ischemia leading to postoperative stricture of the bile duct (47), although it seems unlikely that ischemia is the major mechanism in the causation of bile duct stricture after cholecystectomy.

11

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 7

8

7

6 91% 7

8 7

8

7

8

86%

5

7

7 8

6 5%

8

8

6

4%

5

(A) seg V

5

5 10%

2%

2%

(B) seg VI

7 6

80%

3

3

6 5

2

2

7

5

20%

a 67%

b 1%

2

(C) seg VIII 3 c 1% 2

2 3

3

d 25%

e 1% 2

3 f 1% 2

3 g 4% (D) seg IV Figure 1.21 Variations of the intrahepatic biliary anatomy.

the anatomy of biliary exposure Although intraoperative ultrasound has made easier the location of dilated intrahepatic biliary radicals, surgical exposure of the extrahepatic biliary confluence and the segment 3 duct demands knowledge of precise anatomical landmarks. Biliary– enteric anastomosis necessitates precise bile duct exposure to facilitate the construction of a mucosa to mucosa apposition (36,48–50). To expose the extrahepatic biliary confluence, the base of the quadrate lobe (segment 4) is lifted upward and Glisson’s capsule is incised at its base (see Fig. 1.16) (51). This technique is also sometimes referred to as “lowering the hilar plate.” In only 1% of cases is this made difficult by any vascular imposition between the hilar plate and the inferior aspect of the liver. This maneuver will expose considerably more of the left hepatic duct than the right, which runs a shorter extrahepatic course.

12

Contraindications to this approach include patients with a very deep hilum, which is displaced upward and rotated laterally (36), and those patients who have undergone removal or atrophy of either the right or left livers resulting in hilar rotation. In this situation, the bile duct may come to lie behind the portal vein. When approaching the segment 3 duct (segment 3 hepaticojejunostomy), follow the round ligament (in which runs the remnant of the obliterated umbilical veins) through the umbilical fissure to the point where it connects with the left branch of the portal vein within the recessus of Rex. This junction may sometimes be deeply embedded within the parenchyma of the fissure. The bile ducts of the left liver are located above the left branch of the portal vein, whereas the corresponding arteries lie below the portal vein. Dissection of the round ligament on its left side allows exposure of either

SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS

(A)

(B)

1

2

1

(D)

2

1

liver split to the left of the umbilical fissure in order to widen the fissure to achieve adequate access to the biliary system. Access to the right liver system is less readily achieved than to the left as the anatomy is more imprecise. However, intraoperative ultrasonography greatly enhances the ability of the surgeon to locat e these ducts at surgery. The ideal approach on the right side is to the segment 5 duct (52), which runs on the left side of its corresponding portal vein (23). The duct is exposed by splitting the liver over a short distance to the right of the gallbladder fossa, commencing at the right side of the porta hepatis. The segment 5 duct should lie relatively superficially on the left aspect of the portal vein to that segment.

3

1

(C)

2

Figure 1.22 Main variations in gallbladder and cystic duct anatomy: (A) bilobed gallbladder; (B) septum of gallbladder; (C) diverticulum of gallbladder; (D) variations in cystic duct anatomy.

(A) 75%

(B) 20%

(C) 5%

Figure 1.23 Different types of union of the cystic duct and common hepatic duct: (A) angular (75%); (B) parallel (20%); (C) spiral (5%).

the pedicle or anterior branch of the duct from segment 3. This dissection is achieved by mobilizing the round ligament and pulling it downwards, thereby freeing it from the depths of the umbilical fissure. This procedure usually requires the preliminary division of the bridge of liver tissue that runs between the inferior parts of segments 3 and 4. The umbilical fissure is then opened and with downward traction of the ligamentum teres an anterior branch of the segment 3 duct is exposed on its left side. Sometimes it may be necessary to perform a superficial liver split to gain access to this duct. In the usual situation of chronic biliary obstruction with dilatation of the intrahepatic bile ducts, the segment 3 duct is generally easily located above the left branch of the portal vein. However, in the situation of left liver hypertrophy, it may be necessary to perform a more extensive

radiological anatomy of the liver Accurate preoperative localization of liver pathology using radiological techniques is of increasing importance, as any potential resection depends largely on the segmental localization. Imaging is generally performed using ultrasound, computed tomography (CT), and magnetic resonance (MR). Ultrasound is excellent for imaging bile ducts, cysts, abscesses, and tumors. Hepatic circulation can also be accurately assessed using a Doppler technique. Ultrasound is also the imaging modality of choice for the biliary tree. However, the accuracy of ultrasound imaging is very operator dependent, and fine detail can be limited. Examination is limited by body habitus, and can be restricted by overlying bowel gas. CT scanning is an excellent method of assessing the liver parenchyma. It is able to identify a variety of different pathologies, and CT with IV contrast is the most commonly used method of imaging liver metastases. MR is excellent for the imaging and characterizing primary liver tumors, and is useful for the identification of hemangiomas, which can resemble metastases on CT scanning. Methods for defining segmental anatomy on ultrasound, CT, and MR images follow the anatomical landmarks previously described (53). These methods generally involve using three vertical planes along the lines of the main hepatic veins to divide the liver into its four sectors, with a transverse scissura along the portal vein further subdividing these four sectors to give the eight Couinaud segments. These anatomical landmarks are generally easily identifiable on standard imaging. The middle hepatic vein, left hepatic vein, and ligamentum teres provide good landmarks for dividing the left liver into its four segments. The right hepatic vein can usually be clearly seen dividing the right liver into its two sectors.

hepatic veins In an oblique ultrasonic view, the three hepatic veins join the IVC to form a characteristic W, with its base on the IVC. A similar view can be seen on CT scan. These veins are usually easily seen: the left hepatic vein separating segment 2 from segments 3 and 4, the middle hepatic vein separating segment 4 from 5 and 8, and the right hepatic vein separating 5 and 8 from 6 and 7.

portal system The portal supply to the left lobe, when viewed obliquely, can be seen as a side-on “H,” with the left portal vein giving its

13

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Left branch of the hepatic artery Right branch of the hepatic artery Hepatic artery

3 o'clock artery 9 o'clock artery Common hepatic artery Retroduodenal artery

Gastroduodenal artery

(A)

M.H. artery L.H. artery R.H. artery

Left gastric

Cystic

Aorta

Proper hepatic

Celiac trunk

Right gastric Splenic

Supraduodenal

Common hepatic

Gastroduodenal (B)

Figure 1.24 (A) The biliary duct blood supply; (B) conventional arterial anatomy of the liver (50%).

branch to segment 2, before dividing into the terminal branches to 3 and 4. The portal supply to the right lobe also demonstrates a sideon “H” in the oblique view. The right branch of the portal vein forms the cross bar of the H, with the branches to segment 5 to 8 forming the arms.

gallbladder, ligamentum venosum, and falciform ligament Radiological landmarks of these structures are fallible (Figs. 1.26–1.28). Significant variations in intrahepatic vascular anatomy may result in incorrect identification of lesion location. A study by Rieker et al. looked at CT scans of patients who underwent liver resection. The location of the lesion was

14

identified using the landmarks outlined above. The scans were then reviewed, with the lesion being attributed to the nearest portal branch. Sixteen percent of lesions had a different segmental location if the portal branch was used instead of the conventional technique (Fig. 1.29) (54).

key points ●

●

A full understanding of the lobar, sectoral, and segmental anatomy of the liver and biliary system is an essential prerequisite for successful liver surgery. The surgeon must appreciate the wide variation in extrahepatic biliary anatomy.

SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS

2

4a

8 (A)

IVC

(B)

7

(C)

(D)

(E)

(F)

Figure 1.27 CT scan of upper liver in venous phase showing the left, middle and right hepatic veins draining into the inferior vena cava (IVC).

Figure 1.25 Variations in anatomy of hepatic arterial supply.

Figure 1.28 CT scan of the liver in portal phase showing the left portal vein passing anteriorly between segments 3 and 4 within the recessus of Rex.

RAPV LPV

RPPV

Figure 1.26 Portal phase CT scan through porta hepatis showing the left portal vein (L) lying centrally and the anterior (RA) and posterior (RP) divisions of the right portal vein (R).

MPV

Figure 1.29 Percutaneous direct portogram showing the relationships of the anterior (RAPV) and posterior (RPPV) to the main (MPV) and left (LPV) portal veins.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

references 1. Glisson F. Anatomia Hepatis. London: Typ. Du-Gardianis, 1654. 2. Rex 1888. Cited in Hobsley M. The anatomical basis of partial hepatectomy. Proc R Soc Med Engl 1964; 57: 550–4. 3. Schwartz SI. Historical Background. In: McDermott WV Jr, ed. Surgery of the liver. Boston, MA: Blackwell Scientific, 1989: 3–12. 4. McIndoe AH, Counsellor VX. A report on the bilaterality of the liver. Arch Surg 1927; 15: 589. 5. Lau WY. The history of liver surgery. J R Coll Surg Edin 1997; 42: 303–9. 6. Mikesky WE, Howard JM, DeBakey ME. Injuries of the liver in three hundred consecutive cases. Int Abstr Surg 1956; 103: 323–4. 7. Dalton HC. Gunshot wound of the stomach and liver treated by laparotomy and suture of the visceral wounds. Ann Surg 1888; 8: 81–100. 8. Luis A. Di un adenoma del fegato. Centralblatt fur chirg 1887; 5: 99. Abstract from Ganzy, delle cliniche 1886, 23, No 15. 9. Langenbuch C. Ein Fall von Resektion eines linksseitigen Schnurlappens der Leber. Berl Klin Wosch 1888; 25: 37–8. 10. Tiffany L. The removal of a solid tumor from the liver by laparotomy. Maryland Med J 1890; 23: 531. 11. Lucke F. Entfernung der linken Krebsiten Leber Lappens. Cantrallbl Chir 1891: 6: 115. 12. Cattell RB. Successful removal of liver metastasis from carcinoma of the rectum. Lehey Clin Bull 1940; 2: 7–11. 13. Wangensteen OH. The surgical resection of gastric cancer with special reference to: (1) the closed method of gastric resection; (2) coincidental hepatic resection; and (3) preoperative and postoperative management. Arch Surg 1943; 46: 879–906. 14. 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. Ann Surg 1899; 30: 267–83. 15. Cantlie J. On a new arrangement of the right and left lobes of the liver. J Anat Physiol (Lond) 1898; 32:4–9. 16. Wendel W. Beitrage zur Chirurgie der Leber. Arch Klin Chir Berlin 1911; 95: 887–94. 17. Ton That Tung. La vascularisation veineuse du foie et ses applications aux resections hepatiques. These, Hanoi, 1939. 18. Raven RW. Partial hepatectomy. Br J Surg 1948; 36: 397–401. 19. Lortat-Jacob JL, Robert HG. Hepatectomie droite regle. Presse Med 1952; 60: 549–50. 20. Healey JE Jr, Schroy PC. Anatomy of the biliary ducts within the human liver. Arch Surg 1953; 66: 599–616. 21. Goldsmith NA, Woodburne RT. Surgical anatomy pertaining to liver resection. Surg Gynaecol Obstet 1957; 195: 310–18. 22. Hjortsjo CH. The topography of the intrahepatic duct systems. Acta Anat 1951; 11: 599–615. 23. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Paris: Masson, 1957. 24. Couinaud C. Lobes et segments hepatiques. Note sur l’architecture anatomiques et chirurgicales du foie. Presse Med 1952; 62: 709–12. 25. Couinaud C. Anatomy of the dorsal sector of the liver. In: Couinaud C, ed. New Considerations on Liver Anatomy. Paris: Couinaud, 1998: 39–61. 26. Ton That Tung. Les Resections Majeures et Mineures Du Foie. Paris: Masson, 1979. 27. Caprio G. Un caso de extirpacion die lobulo izquierdo die hegado. Bull Soc Cir Urag Montevideo 1931; 2: 159. 28. Bismuth H, Houssin D, Castaing D. Major and minor segmentectomies “reglees” in liver surgery. World J Surg 1982; 6: 10–24. 29. Mancuso M, Nataline E, Del Grande G. Contributo alla conoscenza della struttura segmentaria del fegato in rapportto al problema della resezione epatica. Policlinico, Sez Chir 1955; 62: 259–93.

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30. Couinaud C. Surgical anatomy of the liver revisited. C Couinaud, 15 rue Spontini, Paris, 1989. 31. Mizumoto R, Kawarada Y, Suzuki H. Surgical treatment of hilar carcinoma of the bile duct. Surg Gynecol Obstet 1986; 162: 153–8. 32. Rocko JM, Swan KG, Di Gioia JM. Calot’s triangle revisited. Surg Gynecol Obstet 1981; 153: 410–14. 33. Wood D. Eponyms in biliary tract surgery. Am J Surg 1979; 138: 746–54. 34. Byden EA. The anatomy of the choledochaoduodenal junction in man. Surg Gynecol Obstet 1957; 104: 641–52. 35. Delmont J. Le sphincter d’Oddi: anatomie traditionelle et fonctionelle. Gastroenterol Clin Biol 1979; 3: 157–65. 36. Bismuth H, Lazorthes F. Les Traumatismes Operatoires de la Voie Biliaire Principale. Paris: Masson, Vol 1, 1981. 37. Champetier J, Davin JL, Yver R, Vigneau B, Letoublon C. Aberrant biliary ducts (vasa aberrantia): surgical implications. Anat Clin 1982; 4: 137–45. 38. Gross RE. Congenital anomalies of the gallbladder. A review of a hundred and forty-eight cases with report of a double gallbladder. Arch Surg 1936; 32: 131–62. 39. Hobby JAE. Bilobed gallbladder. Br J Surg 1979; 57: 870–2. 40. Rachad-Mohassel MA, Baghieri F, Maghsoudi H, Nik Akhtar B. Duplication de la vesicule biliaire. Arch Francais des Maladies de l’Appareil Digestif 1973; 62: 679–83. 41. Perelman H. Cystic duct duplication. J Am Med Assoc 1961; 175: 710–11. 42. Boyden EA. The accessory gallbladder. An embryological and comparative study of aberrant biliary vesicles occurring in man and the domestic mammals. Am J Anat 1926; 38: 177–231. 43. Rogers HI, Crews RD, Kalser MH. Congenital absence of the gallbladder with choledocholithiasis. Literature review and discussion of mechanisms. Gastroenterology 1975; 48: 524–9. 44. Newcombe JF, Henley FA. Left sided gallbladder. A review of the literature and a report of a case associated with hepatic duct carcinoma. Arch Surg 1964; 88: 494–7. 45. Kune GA. The influence of structure and function in the surgery of the biliary tract. Ann R Coll Surg Engl 1970; 47: 78–91. 46. Northover JMA, Terblanche J. A new look at the arterial blood supply of the bile duct in man and its surgical implications. Br J Surg 1979; 66: 379–84. 47. Northover JMA, Terblanche J. Applied surgical anatomy of the biliary tree. In: Blumgart LH, ed. Biliary Tract, Vol 5. Edinburgh: Churchill Livingstone, 1982. 48. Bismuth H, Franco D, Corlette NB, Hepp J. Long term results of Roux-enY hepaticojejunostomy. Surg Gynecol Obstet 1978; 146: 161–7. 49. Voyles CR, Blumgart LH. A technique for construction of high biliary enteric anastomoses. Surg Gynecol Obstet 1982; 154: 885–7. 50. Blumgart LH, Kelley CJ. Hepaticojejunostomy in benign and malignant bile duct stricture: approaches to the left hepatic ducts. Br J Surg 1984; 71: 257–61. 51. Hepp J, Couinaud C, L’abord et L’utilisation du canal hepatique gauche dans le reparations de la voie biliaire principale. Presse Med 1956; 64: 947–8. 52. Smadja C, Blumgart LH. The biliary tract and the anatomy of biliary exposure. In: Blumgart LH, ed. Surgery of the Liver and Biliary Tract, 2nd edn. Edinburgh: Churchill Livingstone, 1994: 11–24. 53. Strunck H, Stuckmann G, Textor J et al. Limitations and pitfalls of Couinauds segmentation of the liver in transaxial imaging. Eur Radiol 2003; 13: 2472–82. 54. Rieker O, Mildenberger P, Hintze C et al. Segmentanatomie der Leber in der Computertomographie: Lokalisieren wir die Lasionen richtig. Rofo 2000; 171: 147–52.

2

Anatomy of the pancreas Margo Shoup and Jason W. Smith

topography of the pancreas The shape and size of the pancreas are highly variable but in general it has a roughly trapezoidal shape and lies in the retroperitoneum of the upper abdomen (1). It is a finely lobular structure with a tan to dull yellow color that reaches from the medial concavity of the duodenum up and to the left terminating at the hilum of the spleen. The volume of the pancreas increases rapidly during childhood, plateaus from 20 to 60 years, and then steadily decreases; however, the percentage of parenchyma versus fat in the pancreas continues to increase during life slowly replacing functional tissue (2) (Fig. 2.1). The pancreas is divided into three major regions, the head and uncinate, the neck, and the body and tail (3). The head is the most medial portion of the gland. It is the widest and thickest part, having the most globular ultrastructure and is cradled in the concavity of the duodenum lying just to the right of the second lumbar vertebra (1). There is an inferior projection to the head of the pancreas that lies posterior to the superior mesenteric vessels, which makes up the uncinate process. The head and uncinate are intimately associated with the duodenum, sharing an abundant network of anastomosing vessels. The posterior surface of the head of the pancreas is in apposition to the inferior vena cava, aorta, right spermatic and ovarian vessels, and right renal vessels and separated from them by the avascular fusion fascia of Treitz (4). The anterior surface is covered by the transverse colon and its mesentery (5,6). The neck of the pancreas is 2 to 3 cm in length and overlies the confluence of the superior mesenteric vein (SMV) and splenic vein by which it is grooved. It is related superiorly to the pylorus and first portion of the duodenum (3,4). The body of the pancreas extends from body of the second lumbar vertebra over the left kidney and begins to taper into the tail as it reaches the hilum of the spleen. The prismatic shape of the pancreas flattens in the tail. The splenic vein runs the length of the pancreas on the posterior surface, while the artery courses along the superior edge of the body. The body of the pancreas lies over the aorta and the left renal pedicle and kidney and is separated from these structures by the fusion fascia of Toldt (4). Inferiorly, it abuts the mesentery of the transverse mesocolon, while superiorly and anteriorly it abuts the stomach but is separated from it by the posterior parietal peritoneum (7).

ductal anatomy of the pancreas There are numerous configurations of the ducts of the pancreas and their relationships to each other, the duodenum and the common bile duct. The significance of the pancreas became understood only after the discovery of the main pancreatic duct by Wirsung in 1643. He noted that there was a duct that traversed the length of the organ with numerous

tributary ducts coming off at near right angles and that this duct opened into the duodenum, and he saw that there were occasionally two ducts in the gland (1). It was Santorini who finally concluded that, in the normal condition, there existed two ducts with the smaller of the two emptying into the duodenum by way of a small papilla approximately 2 cm nearer to the stomach than the major duct and this smaller duct bears his name (5). The smaller duct is patent all the way to the duodenum in only 60% of specimens and the duct of Wirsung represents the larger of the two; however, in about 10% of specimens, the duct of Santorini is the main drainage for the pancreas. Also in about 10% of cases, the two ducts are not in communication with each other (1) (Fig. 2.2). The parenchyma of the pancreas consists of small lobules divided by connective tissue. These lobules are centered around the main tributary ducts that run to the main pancreatic duct. Smaller branches off of these tributaries define further septated regions within the lobules of pancreatic tissue. The main branches of the pancreatic duct tend to meet the main duct on its superior and inferior aspect. The diameter of the main pancreatic duct is reported to be between 2.6 and 4.8 mm in the head, 2.0 and 4.0 mm in the body, and 0.9 and 2.4 mm in the tail (3). The duct runs in a relatively superficial position in the tail and after traversing the neck of the pancreas it dives deep into the parenchyma as it crosses the head and is near the dorsal surface of the pancreas as it nears the confluence with the common bile duct (CBD) and the duodenum (1). The lower portion of the CBD lies in contact with the head of the pancreas for between 2 and 7 cm and 40% of the time it lies in a groove between the surface of the pancreas and the duodenum. In the remainder of cases, it lies within the parenchyma of the pancreas (7). During embryological development, the lower duct of Wirsung arises in the ventral pancreatic bud adjacent to the early hepatic duct. Therefore, the association of the duct of Wirsung with the CBD is a consistent feature of the ductal anatomy of the pancreas (1). The duct of Wirsung and the CBD unite 6 to 8 mm within the papilla and form a common channel, which is slightly dilated and referred to as the ampulla of Vater. In just over 10% of cases, the two ducts do not form a short common channel and instead enter the duodenum independently on the papilla (5).

arterial anatomy of the pancreas The pancreas enjoys an abundant arterial blood supply that draws from both the celiac axis and the superior mesenteric artery (SMA). The pancreas is supplied from the celiac axis by the superior pancreaticoduodenal artery from the gastroduodenal artery (GDA), and the dorsal pancreatic and pancreatica magna arteries from the splenic artery (Fig. 2.3). The distal and inferior borders of the pancreas are supplied by the caudal and inferior pancreatic arteries, which are formed by

17

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Figure 2.1 Overview of the relationship of the pancreas to other important structures in the upper abdomen. Plate 1098, From Anatomy of the Human Body, Henry Gray 1918.

(A)

(B)

(C)

Figure 2.2 (A) Duct of Santorini is patent all the way to the duodenum. (B) Duct of Santorini is the main drainage. (C) The two ducts are not in communication with each other.

ramifications with the dorsal pancreatic, pancreatica magna, and splenic arteries. The SMA gives rise to the more variable inferior pancreaticoduodenal (IPD) artery, which divides into branches to form both an anterior and posterior anastomotic arcade with branches from the superior pancreaticoduodenal artery (8). Superior Pancreaticoduodenal Artery The superior pancreaticoduodenal is a short branch of the GDA that arises after the takeoff of the right gastroepiploic artery (Fig. 2.4). It is angiographically identifiable in about 10% of specimens and is generally about 8 mm in length (9). Although rare, it is reported to occasionally arise from the left hepatic artery. When present, the superior pancreaticoduodenal artery divides into anterior and posterior branches, which anastomose with the inferior branches from the SMA. In the remaining cases, the posterior superior pancreaticoduodenal

18

(PSPD) artery is seen arising from the GDA prior to the right gastroepiploic takeoff. The anterior superior pancreaticoduodenal (ASPD) artery has a caliber between 1 and 3 mm and is considered the most important blood supply to the head of the pancreas. In the majority of cases, it is a terminal branch of the GDA after it has given off the PSPD and the right gastroepiploic arteries. The ASPD can be duplicated in up to 7% of cases and rarely is absent. Case reports of extremely rare anomalies exist, reporting the origin of this artery from almost all of the major branches of the celiac and SMAs (9). Posterior Superior Pancreaticoduodenal Artery This artery forms the superior portion of the posterior arcade that forms anastomoses with the posterior branch of the IPD artery. The PSPD artery is most commonly found as a branch of the GDA 1 to 2 cm after the takeoff of the hepatic artery (10). Up to 10% of cases may see the PSPD arise from the superior

ANATOMY OF THE PANCREAS

Cystic artery

Probe passed through epiploie foramen

a S

C r e a t o r

t

o

c

h

m

O x e n t e

Figure 2.3 Arterial anatomy of the pancreas, the celiac axis and its major branches. Plate 532, From Anatomy of the Human Body, Henry Gray 1918.

pancreaticoduodenal and in rare instances may arise from any of the hepatic arteries. The most common course of the PSPD after it leaves the GDA posteriorly is it runs over the portal vein (PV) and the anterior edge of the top of the pancreas where it enters the gland and finds the common bile duct and makes a right-handed spiral around the duct passing posterior to it just above the ampulla. It then runs deep in the parenchyma of the pancreas to find its connection with the posterior inferior artery. The PSPD gives off collateral branches to form the blood supply to the intrapancreatic portion of the common bile duct, it generally gives off the supraduodenal artery and occasionally the retroduodenal artery, rarely it may give a branch to the gallbladder or an accessory right hepatic artery (10). Inferior Pancreaticoduodenal Artery The IPD artery is present in about 70% of cases and is the common trunk that gives rise to the anterior and posterior inferior pancreaticoduodenal (AIPD and PIPD) arteries that form the anastomotic arcades supplying the head of the pancreas (11). In the remaining 30% of cases, the AIPD and PIPD arise directly from the SMA. The IPD may arise directly from the SMA as the first collateral branch from 2 to 5 cm distal to the origin and take a short course from its posterior takeoff into the inferior edge of the pancreatic parenchyma, or alternatively, it may arise as a common trunk with the first jejunal

branch, the pancreaticoduodenaljejunal (PDJ) trunk in which case it takes a longer course to the pancreas. The IPD crosses posterior to the SMV and the posterior surface of the pancreas and does not give off any branches prior to dividing into its anterior and posterior termini (11). Anterior and Posterior Inferior Pancreaticoduodenal Arteries These arteries supply the inferior part of the anastomotic arches that supply the head of the pancreas. They arise most often from a common IPD artery. They may also originate directly from the SMA or less commonly directly from the first jejunal artery or from a replaced hepatic artery. The main course of the AIPD is to follow the inferior curve of the pancreas and find its partner the ASPD (12). It may give off a branch to the duodenal–jejunal flexure or to form a transverse pancreatic artery. The PIPD runs more posterior and cephalad than the AIPD and ultimately finds the PSPD or alternatively terminates as small end arteries. It may supply a collateral branch to the transverse pancreatic artery when present (12). Dorsal Pancreatic Artery The main blood supply to the neck and body of the pancreas is the dorsal pancreatic (DP) artery. It most commonly arises from the splenic artery near its origin at the celiac axis (13). It may also take its origin from the celiac trunk itself, the

19

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

S t o m a c h

Figure 2.4 Arterial anatomy of the pancreas, demonstrating the gastroduodenal and its branches of the anterior and posterior pancreaticoduodenal arteries forming the anastomotic arcades with the branches from the superior mesenteric artery. Plate 533, From Anatomy of the Human Body, Henry Gray 1918.

common hepatic or the GDA. Alternatively, the DP may arise from the SMA. The course of the DP artery is usually in the form of an inverted “T” with a right and left branch that form after a short 1 to 3 cm course. When the artery arises from the splenic artery, it tends to angle back to the right, if it takes off from the celiac, hepatic, or GDA, then it transverses the neck in a leftward direction. When coming from the SMA it comes up from the bottom of the pancreas. The right branch of the DP forms an anastomosis with left anastomotic pancreatic artery from the ASPD. The left branch becomes the transverse pancreatic artery (13). Caudal and Great Pancreatic Arteries The great pancreatic artery is often present and is given off from the splenic artery at the junction of the body and tail. It collateralizes with the transverse pancreatic artery. The caudal pancreatic artery takes its origin from the left gastroepiploic, the distal splenic artery or a branch from the splenic hilum and forms anastomotic connections with the great pancreatic and transverse pancreatic arteries (3). The arterial blood supply to the pancreas is rich and complex. Most of the primary arterial conduits form some

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anastomotic connection and this shared blood supply is one of the challenges of pancreatic surgery. When operating in the deepest recesses of the abdomen, having an intimate knowledge of the standard arterial anatomy as well as the most common alternatives will allow the pancreatic surgeon to maximize patient safety. That same surgeon must keep in mind that the arterial anatomy in this area is subject to wide variation and that one must always be prepared to address the aberrant anatomy. To that end, having good preoperative imaging to establish before the operation what the arterial anatomy is can be a valuable aid whether by angiography or by computed tomography (CT) angiography. Venous Drainage of the Pancreas The veins of the pancreas follow the course of the corresponding arteries in most cases. They are generally more superficially located than the arteries and depending on the location in the pancreas drain into the PV, SMV, the inferior mesenteric vein, or the splenic vein. In the head of the pancreas, there is a venous arcade that mirrors the arterial anastomoses and of the four main veins all, but the PSPD vein, which empties directly into the PV, find their way to the SMV. In addition, there are

ANATOMY OF THE PANCREAS

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12p1

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Figure 2.5 Lymphatic drainage of the pancreas.

numerous small bridging veins between the head of the pancreas and the SMV and PV as they course behind the pancreas, which must be carefully ligated during a resection. The fact that there are rarely venous branches that enter the SMV or PV on their anterior surfaces makes the dissection along the plane anterior to these vessels possible during pancreaticduodenectomy. Two large veins drain the body and tail of the pancreas, the splenic vein, which courses along the superior edge of the pancreas and the transverse pancreatic vein along the inferior margin. The portal vein is formed on the posterior surface of the neck of the pancreas by the confluence of the splenic vein and the SMV. The inferior mesenteric vein may join at this point as well, but more commonly joins the splenic vein or SMV proximal to the confluence (Fig. 2.4).

lympatic drainage of the pancreas The lymphatic drainage of the pancreas is rich and drains each lobular division with frequent anastomotic connections and the ultrastructure is similar to that in other solid organs of the abdomen(14) (Fig. 2.5). These lobular lymphatics coalesce to form several trunks that empty into the primary lymph node basins for the pancreas before quickly reaching the thoracic duct (15). The drainage of the pancreas can be roughly divided into right and left side based on the ventral and dorsal anlage of the primordial pancreas. The left side of the system drains the upper portion of the head, the neck, and body and tail,

while the right side drains the lower portion of the head, which developed from the ventral bud and constitutes the retroportal lymphatics (15,16). The superior pancreatic nodes drain the upper half of the neck, body and tail of the pancreas, and a portion of the head. They primarily lie along the superior border of the gland or in the gastropancreatic fold and gastrohepatic ligament (17). The inferior pancreatic nodes similarly drain the inferior half of the gland and lie along the inferior border as well as draining into the superior mesenteric nodes or the periaortic nodes. The anterior nodes are located along the surface of the pancreas that lies adjacent to the duodenum and are called the infrapyloric lymph nodes and the pancreaticoduodenal nodes. These anterior nodes may also drain into nodes along the root of the transverse colonic mesentery that is adjacent to the head of the pancreas. The posterior nodes run along the posterior pancreaticoduodenal border and include the nodes along the lower portion of the common bile duct, portal vein and nodes at the origin of the SMA. The tail of the pancreas forms several lymphatic trunks that reach out into the hilum of the spleen and form the superior and inferior lymph nodes (3,16). This simplified lymphatic mapping system is that adapted by the International Union against Cancer (UICC). A more comprehensive and clinically useful system was developed by the Japanese Research System, which divides lymph node stations into 18 different designations and rates them according to the likelihood of metastatic spread. Nodal stations 13 and 17 are the most likely to harbor disease with

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Right gastroepiploic vein Splenic vein

Portal vein

PSPD-V Gastrocolic trunk

Superior mesenteric vein AIPD-V PIPD-V

First jejunal tributary

ASPD-V Figure 2.6 Major venous drainage for the pancreas.

47% and 29%, respectively (18,19) (Fig. 2.6). Classification of lymphatic involvement will become increasingly important as increasing numbers of targeted therapies become available in pancreatic cancer.

innervation of the pancreas The pancreas receives fibers from both the sympathetic and parasympathetic nervous systems. The sympathetic innervation is via the splanchnic nerves, which carry both afferent fibers and efferent fibers, while the parasympathetic innervation is via the vagus nerve, which also has afferent and efferent supply to the pancreas. Parasympathetic innervation provides stimulatory signals to the islet cells to increase insulin secretion in response to food intake, while increased sympathetic tone suppresses insulin secretion and stimulates the secretion of glucagon (20,21). Efferent pain fibers are found in both the splanchnic and vagal nerves and localization of these fibers has been a difficult clinical problem in the management of pain in both inflammatory and malignant diseases of the pancreas. The right, and more prominently the left, celiac ganglion provide the majority of the direct innervation to the posterior head, body, and tail of the pancreas via fibers that course along the splenic artery (16). Neural ganglia around the common hepatic artery also provide fibers that course along the GDA to the head and uncinate process of the pancreas (22). Recently, it has been shown that the celiac ganglion bearing the splanchnic efferent fibers can be identified by endoscopic ultrasound and precise localization of neurolytic therapies can be applied to improve the success of these approaches (23,24). Enteropancreatic nervous connections have also been demonstrated from both the stomach and proximal duodenum to the pancreas (24–26). These connections suggest that there is crosstalk directly from the gastrointestinal tract to the pancreas coordinating exocrine and/or endocrine secretions with gut function.

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The pancreas lies in the recesses of the upper abdomen and remains one of the most challenging organs to manage from a clinical or operative standpoint. Its rich blood supply, close associations with major vascular structures, intimate relation to the common bile duct, and the attachments to the duodenum and spleen all contribute to the complexity of surgical intervention in both malignant and benign disease (7). A thorough understanding of the three dimensional relationship of the arterial blood supply and major veins in proximity to the pancreas make approaching pancreatic resection possible. As we move into an era of minimally invasive surgery, being able to recognize the anatomy and its variations with minimal cues from adjacent structures will become increasingly important and continued study of these complex relationships allows the mind to know, so that the eye may see.

references 1. Opie EL. Anatomy of the Pancreas and its Variations. Disease of the Pancreas: Its Cause and Nature, 1st edn. Philadelphia, PA: J.B. Lippincott Company, 1903: 359. 2. Saisho Y, Butler AE, Meier JJ, et al. Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes. Clin Anat 2007; 20: 933–42. 3. Skandalakis LJ, Colborn GL, Skandalakis JE. Surgical anatomy of the pancreas. In: Baker RJ, Fischer JE, eds. Mastery of Surgery, Vol. 2, 4th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2001: 2448. 4. Kuroda A, Nagai H. Surgical anatomy of the pancreas. In: Howard J, Idezuki Y, Ihse I, Prinz R, eds. Surgical Diseases of the Pancreas, 3rd edn. Baltimore, MD: Lippincott Williams & Wilkins, 1998: 869. 5. Cattell RB, Warren KW. The anatomy and physiology of the pancreas. In: Cattell RB, Warren KW, eds. Surgery of the Pancreas. Philadelphia, PA: Saunders, 1953. 6. Hollinshead WH. The thorax, abdomen and pelvis. In: Hollinshead WH, ed. Anatomy for Surgeons. Vol. 2. New York: Medical Department, Harper and Row Publishers, 1971: 430. 7. Anson BJ, McVay CB, Callander CL. The Abdomen. Surgical Anatomy. Philadelphia, PA: Saunders, 1971. 8. Woodburne RT, Olsen LL. The arteries of the pancreas. Anat Rec 1951; 111: 255–70. 9. Bertelli E, Di Gregorio F, Bertelli L, Mosca S. The arterial blood supply of the pancreas: A review. I. The superior pancreaticoduodenal and the anterior superior pancreaticoduodenal arteries. An anatomical and radiological study. Surg Radiol Anat 1995; 17: 97–106, 101–3. 10. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood supply of the pancreas: A review. II. The posterior superior pancreaticoduodenal artery. An anatomical and radiological study. Surg Radiol Anat 1996; 18: 1–9. 11. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood supply of the pancreas: A review. III. The inferior pancreaticoduodenal artery. An anatomical review and a radiological study. Surg Radiol Anat 1996; 18: 67–74. 12. Bertelli E, Di Gregorio F, Bertelli L, Orazioli D, Bastianini A. The arterial blood supply of the pancreas: A review. IV. The anterior inferior and posterior pancreaticoduodenal aa., and minor sources of blood supply for the head of the pancreas. An anatomical review and radiologic study. Surg Radiol Anat 1997; 19: 203–12. 13. Bertelli E, Di Gregorio F, Mosca S, Bastianini A. The arterial blood supply of the pancreas: A review. V. The dorsal pancreatic artery. An anatomic review and a radiologic study. Surg Radiol Anat 1998; 20: 445–52. 14. Navas V, O’Morchoe PJ, O’Morchoe CC. Lymphatic system of the rat pancreas. Lymphology 1995; 28: 4–20. 15. Pissas A. Anatomoclinical and anatomosurgical essay on the lymphatic circulation of the pancreas. Anat Clin 1984; 6: 255–80. 16. Donatini B, Hidden G. Routes of lymphatic drainage from the pancreas: A suggested segmentation. Surg Radiol Anat. 1992; 14: 35–42.

ANATOMY OF THE PANCREAS 17. Hartley M, Finch-Jones M. Anatomy of the pancreas. In: Poston G, Blumgart L, eds. Surgical Management of Hepatobiliary and Pancreatic Disorders, 1st edn. London: Martin Dunitz, 2002: 19–28. 18. Bogoevski D, Yekebas EF, Schurr P, et al. Mode of spread in the early phase of lymphatic metastasis in pancreatic ductal adenocarcinoma: Prognostic significance of nodal microinvolvement. Ann Surg 2004; 240: 993–1000, discussion 1000–1. 19. Sakai M, Nakao A, Kaneko T, et al. Para-aortic lymph node metastasis in carcinoma of the head of the pancreas. Surgery 2005; 137: 606–11. 20. Benthem L, Mundinger TO, Taborsky GJ, Jr. Parasympathetic inhibition of sympathetic neural activity to the pancreas. Am J Physiol Endocrinol Metab 2001; 280: E378–81. 21. Jarhult J, Falck B, Ingemansson S, Nobin A. The functional importance of sympathetic nerves to the liver and endocrine pancreas. Ann Surg 1979; 189: 96–100.

22. Yoshioka H, Wakabayashi T. Therapeutic neurotomy on head of pancreas for relief of pain due to chronic pancreatitis; a new technical procedure and its results. AMA Arch Surg 1958; 76: 546–54. 23. Levy MJ, Topazian MD, Wiersema MJ, et al. Initial evaluation of the efficacy and safety of endoscopic ultrasound-guided direct Ganglia neurolysis and block. Am J Gastroenterol 2008; 103: 98–103. 24. Kirchgessner AL, Liu MT, Gershon MD. In situ identification and visualization of neurons that mediate enteric and enteropancreatic reflexes. J Comp Neurol 1996; 371: 270–86. 25. Holst JJ, Schwartz TW, Knuhtsen S, Jensen SL, Nielsen OV. Autonomic nervous control of the endocrine secretion from the isolated, perfused pig pancreas. J Auton Nerv Syst 1986; 17: 71–84. 26. Kirchgessner AL, Gershon MD. Innervation and regulation of the pancreas by neurons in the gut. Z Gastroenterol Verh 1991; 26: 230–33.

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3

Hepatic resection Ajay V. Maker and Michael D’Angelica

introduction Though liver anatomy and physiology have been studied for centuries, liver surgery still is a relatively young field. Just 30 years ago, the mortality of major hepatic resection neared 25%. This high mortality limited its utility and deterred patients and referring physicians from considering surgery. The current generation of hepatobiliary surgeons has an increased understanding of the segmental anatomy of the organ and has seen a dramatic decrease in the mortality of liver surgery to nearly 1% largely due to a dramatic decrease in blood loss (1). This chapter will address the basic principles and techniques to safely approach liver resection.

basic principles Surgical Indications: Benign vs. Malignant Disease Though this chapter focuses on the technical aspects of hepatic resection, an understanding of when liver resection is indicated is of paramount importance. Due to advances in modern imaging techniques and an increased knowledge of the natural history of liver lesions, tumors that may have been resected in the past for diagnostic uncertainty are now often observed. Similarly, malignant lesions that were not resected in the past but referred for nonsurgical therapy are now being treated with resection. Indications for specific benign and malignant processes are outlined in other chapters; however, the general principles are mentioned here. Benign Disease Partial hepatectomy for benign conditions should be parenchymal preserving and reserved for lesions that are symptomatic, have premalignant potential, or carry an unclear diagnosis. Wide margins are not necessary, therefore in some cases, for example, focal nodular hyperplasia (FNH) or hemangiomas, enucleation may be safely performed, although in some instances an anatomic segmental resection may be the safest approach (2–4). This is addressed at the end of the chapter and detailed in other chapters. Malignant Disease Partial hepatectomy for malignant conditions must obtain a clear surgical margin, and is suitable for well-selected patients with both primary and metastatic cancer. We have found increased patient survival with margins of at least 1 cm in patients undergoing resection for metastatic colorectal cancer (5–13), though other series suggest that a negative margin, regardless of the distance, is sufficient (14,15). The exception may be in slow-growing tumors with multiple liver metastases, such as neuroendocrine tumors, where tumor debulking may be of value. As long as the functional remnant liver is adequate, usually about 25% liver volume in otherwise

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healthy individuals, excision of tumor can prolong life and in some cases provide long-term disease-free survival. Patient Selection Proper patient selection is critical to both the safety and efficacy of hepatic resection. One should evaluate the patient’s general state of health, the condition of the liver, and the volume of the future liver remnant to properly assess the risk of general anesthesia, major abdominal surgery, and liver resection. Subcostal and upper abdominal incisions are painful and may result in respiratory splinting and increased pulmonary complications compared to other incisions (16). For this reason, assessment of the patient’s ability to mobilize early and ambulate postoperatively must not be underestimated. Though there are many algorithms to evaluate liver function in patients with chronic liver disease, the Child-Pugh classification is a useful preoperative indicator, and patients with a Pugh score of B or C should generally not undergo liver resection. Hepatic resection in cirrhotic patients is particularly difficult with operative mortality increasing with advanced Child classification. Hepatic resection in the setting of portal hypertension is generally not recommended (17), as this condition predisposes the liver to higher portal pressures and diminished ability to increase portal flow to the liver remnant postoperatively, thereby inhibiting normal liver regeneration and increasing the risk of life-threatening bleeding. The cirrhotic liver has decreased regenerative capacity and impairment in liver function is greater, lasts longer, and can result in permanent liver failure. A low platelet count, splenomegaly, ascites, or evidence of varices on preoperative radiography may be the only findings to alert the surgeon to hepatic dysfunction. Many noncirrhotic patients that present for hepatic resection have abnormal liver function due to chemotherapy, diabetes, or obesity. These diseased livers carry an increased risk of functional impairment with large resections and may also have impaired function despite retained volume (18,19). In these livers, careful preoperative planning must be done to achieve a parenchymal sparing resection. Biopsy, if performed, can give clues to the fat content of the liver, as can preoperative imaging (20). Early data suggest that MRI spectroscopy can also accurately quantify hepatic fat content, and this may prove to be a useful tool in preoperative liver assessment and operative planning (20,21). In cases where liver function may be impaired, or where extended resection is necessary to gain tumor-free margins, portal vein embolization is being employed to induce hypertrophy of the proposed liver remnant (22,23). No absolute guidelines for embolization can be made; however, preoperatively induced liver hypertrophy is a valuable tool in planning and executing major liver resections (24). Furthermore, chronic biliary obstruction inhibits liver function and, thus patients with

HEPATIC RESECTION hilar cholangiocarcinomas are also at increased risk of liver failure postoperatively. The functional residual liver volume should be calculated to insure adequate liver function postresection. A healthy, noncirrhotic individual requires a functional hepatic reserve of at least 20% of the original nontumoral liver volume. The regenerative capacity of the liver should enable full functional compensation within weeks of resection; once greater than 70% of liver volume is resected, however, there is a risk of clinically significant liver insufficiency. This risk is minimal if specimen volume has been replaced with tumor, in which case compensatory hypertrophy will have already occurred. Preoperative Imaging (See Also Chapters 3, 4, and 11) Fine-cut triphasic helical computed tomography (CT) with CT angiogram is the single most useful study in preoperative evaluation of liver tumors. When the study includes the chest, abdomen, and pelvis, preoperative staging is reliable and can identify areas outside of the liver that may need further evaluation or confirm nonoperative candidates. CT can define the vascular anatomy, identify anatomical variants, determine resectability, estimate the functional liver residual volume, and identify preoperative biliary drainage strategies, thereby obviating the need for further radiographic studies. CT angiography in particular has almost prevented the need for traditional angiography. 3-D reconstruction of the vasculature is particularly helpful in identifying vascular anomalies quickly and temporally. Furthermore, 3-D reconstruction of the vascular anatomy may lead to more accurate visualization of tumor– vessel relationships and may be a more accurate study to predetermine the operative line of transection (25). Magnetic resonance imaging can also provide high-quality vascular and volumetric assessments of the liver but its principal role is in characterizing liver tumors of unclear etiology. In experienced hands, ultrasound is a fast, inexpensive, and noninvasive modality that can quickly obtain information regarding tumor size and the amount of liver involvement, particularly in gallbladder and biliary tumors. It is especially helpful in distinguishing cysts from solid tumors and should be used in addition to CT to evaluate cysts for the presence of septations or mural thickening, which would suggest cystadenoma or a cystadenocarcinoma. Duplex ultrasound is also particularly helpful as a dynamic study to identify vasculature in relation to tumor masses. Anesthetic Techniques Operative and perioperative morbidity and mortality have been decreased in part due to changes in anesthetic practices over the evolution of hepatic resection. A focus on maintaining low central venous pressure (CVP) can greatly reduce blood loss and keep the operative field clean for proper visualization of the biliary and vascular anatomy during parenchymal transaction. This is accomplished by positioning the patient in mild Trendelenberg and minimizing intravenous fluid to maintain systolic blood pressures above 90 mmHg and urine output to about 25 mL/h. If the IVC is still distended after mobilization of the liver, parenchymal transection can wait until central venous pressure is decreased through use of

narcotics, vasodilatory inhalation agents, or direct vasodilators. A central venous pressure of less than 5 mmHg can be maintained during the periods of liver mobilization and parenchymal transection. Though a cental venous catheter is a useful tool to follow the CVP, the surgeon can also look for a nondistended IVC and for blood coursing through flat intrahepatic veins. If transection is performed under Pringle control, bleeding is generally from hepatic veins, therefore, with a low hepatic venous pressure, even large tears in hepatic veins can be visualized to allow ligation or repair without massive hemorrhage. By Poiseuille’s law, blood flow is exponentially proportional to the radius of the vessel; therefore, even minor decreases in venous distention can decrease blood loss exponentially. With these techniques, the risk of postoperative renal failure has not been shown to be significant, nor has the risk of air embolism, which can be minimized, regardless, by keeping the patient in about 15° of Trendelenberg (26,27). Normal resuscitation is performed after the resection is completed and hemostasis has been achieved.

basic techniques Positioning, Skin Incision, and Exposure The patient should be positioned supine with the arms extended at right angles to the body. Any self-retaining retractor can be utilized, however, we prefer the Goligher retractor to elevate the costal margin, and this crossbar can be fitted to the table to form a 45° angle from top of the crossbar to the xyphoid. The patient should be prepped from the mid-chest to below the umbilicus, and draped to expose the right chest in the event a right thoracotomy is necessary to gain additional exposure. Though some groups routinely make a J-shaped thoracoabdominal incision, in our experience a thoracoabdominal incision was rarely necessary in over 1800 cases (2). We employ selective use of diagnostic laparoscopy based on the risk of unresectable disease (28), and conform the type of incision to the expected resection. For access to both lobes of the liver, a bilateral subcostal incision can be used with or without vertical midline extension. For the great majority of liver resections, we employ a “hockey stick” incision, which includes a right subcostal incision with vertical midline extension to the xyphoid. These incisions, when combined with the Goligher retractor, provide good exposure of the suprahepatic IVC, even with large right-sided tumors. We have found a higher rate of incisional hernia with a “Mercedes” incision compared to a “hockey stick” incision (29). For left-sided resections, a midline incision may suffice. Occasionally, when there is severe right-sided hepatic atrophy or exposure to the suprahepatic IVC is necessary for safety, extension into the right chest can be helpful (Fig. 3.1). Mobilization The ligamentum teres is divided between clamps and ligated, leaving a long secure ligature that is used as a handle to further expose the porta hepatis. The thin veil of the falciform ligament is incised along its length to free it from the anterior abdominal wall and expose the ligamentum teres. In obese individuals, the area where the falciform is fused to the anterior abdominal wall may be invested within a large fat pad. This fat pad can be removed with diathermy from beneath

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS both sides of the exposed fascia, improving exposure and aiding with fascial reapproximation at the end of the case. The falciform ligament is divided up to the suprahepatic IVC (Fig. 3.2). Bimanual palpation of the liver should be performed to assess the extent of hepatic disease. Segment 4 should be carefully retracted cephalad to expose the clear veil of lesser omentum anterior to the caudate lobe and attaching to the ligamentum venosum. This is incised, allowing palpation of

A

F

D

C

B

E

Figure 3.1 Incisions for liver resection. B-D, initial upper midline exploration. A-B-C, ideal for exposure of the whole liver (hockey stick). C-D-E, the classic chevron incision with A-D (Mercedes) extension. C-D, right subcostal incision. F, thoracoabdominal extension. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.

the caudate and celiac axis, and providing access through the foramen of Winslow to the porta hepatis. Intraoperative ultrasound is used at this point to define the extent of disease, vascular relationships, and to confirm resectability. To mobilize the right liver, the leaf of the right coronary ligament is dissected from the falciform ligament and carefully incised over the IVC and territory of the right hepatic vein. This should be done sharply with downward traction on the liver and superior traction on the diaphragm. Once the right hepatic vein is identified, the right coronary ligament is taken close to the liver surface to its furthest extent laterally and the right triangular ligament is divided. To complete the mobilization, the right liver must be freed inferiorly. Omental and peritoneal attachments to the liver and gallbladder are divided to expose the inferior extent of the right triangular ligament. The retroperitoneal attachments are incised off the right adrenal gland and the liver can then be rotated medially to expose the retrohepatic IVC. If the right liver is to be resected or control of the right hepatic vein is needed, the multiple small venous branches from the IVC to the posterior liver must be individually dissected, controlled, and divided. Large accessory inferior right hepatic veins are common and may require division with a vascular stapler or control with vascular clamps and ligatures. It is critical for the surgeon on the left side of the table to retract the right liver medially to expose these branches and prevent injury to the cava. When all of these branches are ligated and divided, all that is left to expose the right hepatic vein will be a fibrous band of tissue that runs lateral to the vein, encircles the IVC, and courses posteriorly to the left and posterior border of the caudate, known as the caval ligament (Fig. 3.3). A tunnel can be safely created medial to this ligament and lateral to the right hepatic vein with a Kelly clamp or renal pedicle clamp in order to allow either a ligature or a

Figure 3.2 Mobilization of the liver begins with downward traction on the liver and division of the falciform ligament to the inferior vena cava. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.

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HEPATIC RESECTION vascular load endo-GIA staple fire. Once this is divided, the right liver is mobile and the lateral aspect of the right hepatic vein is exposed. The left liver is mobilized similarly, however since it does not lie on the vena cava, an extensive caval dissection is not necessary. Sharp and blunt dissection over the suprahepatic IVC will expose the groove between the right vein and the common trunk of the middle and left and middle hepatic veins. Downward traction on the liver and cephalad traction on the diaphragm help expose the left coronary ligament. The groove between the left and middle hepatic veins can be exposed with sharp dissection if there is no long intrahepatic common channel (Fig. 3.4). Care must be taken here to identify the phrenic vein as it courses on the underside of the diaphragm to enter the IVC, as it can be inadvertently injured if the triangular ligament is not properly exposed or not divided close to the liver surface (Fig. 3.5). As the left lateral segment is released

from its peritoneal attachments, it is also useful to place a hand or laparotomy pad under the left lateral segment and anterior to the caudate to provide traction and to protect the stomach, bowel, and spleen from diathermic injury. Further mobilization of the left liver can be accomplished by dividing the lesser omentum as well as the ligamentum venosum either at the left portal vein or left hepatic vein insertions to expose these vessels and the underlying caudate lobe.

vascular isolation Once the liver is mobilized, there are essentially three steps to safely perform a hepatectomy. These involve vascular inflow control, vascular outflow control, and parenchymal transection. Inflow Control All major hepatic resections require control of the vascular inflow to be accomplished safely. Furthermore, adequate

Figure 3.3 Multiple small venous branches from the IVC to the posterior liver must be individually dissected and divided. When all of these branches are controlled, all that is left to expose the right hepatic vein will be a fibrous band of tissue, the caval ligament. A tunnel can be safely created behind this ligament and above the right hepatic vein with a Kelly clamp. Once this is divided, the entire right liver is mobile and the venous outflow can be encircled and controlled. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS hepatic arterial and portal venous inflow must be maintained to the remnant liver. Selective inflow control may be achieved extrahepatically (30), intrahepatically during parenchymal transection (1,31), or by intrahepatic pedicle control via hepatotomies (32,33). In the extrahepatic approach, the hepatic artery and portal vein branches are dissected at the porta hepatis and controlled outside of the liver. In this approach, the individual artery and portal vein have to be separately identified and ligated since they have not yet entered the liver as a portal pedicle. The advantages of this approach are early vascular control prior to transection and demarcation of the liver on its surface. The disadvantages are a somewhat tedious dissection and the potential for injury to contralateral structures. The presence of tumor abutting the hilum may mandate extrahepatic inflow control. The right hepatic artery usually courses posterior to the common hepatic bile duct and can be dissected from the right side of the porta hepatis and controlled. Once divided, the proximal artery stump can be retracted anteriorly exposing the underlying portal vein. All branches must be carefully dissected and identified prior to division to insure that there is no compromise of flow to the future liver remnant, a potentially fatal complication. There is typically a small branch to the caudate process coming off the right portal vein proximally that may have to be controlled. As opposed to the short extrahepatic course from the hilum to the right liver, the vascular inflow to the left liver can be controlled in the umbilical fissure (34). The left portal vein and duct are mobilized by lowering the hilar plate. Here the left hepatic artery is typically found running cephalad along the left side of the porta hepatis anteriorly. It is prudent to insure that one has not inadvertently ligated the artery proximal to the right hepatic artery takeoff by confirming a pulse to the right liver. Once the left hepatic artery is divided, the underlying left portal vein can be dissected behind it. A branch to caudate lobe is very constant and should be preserved if the caudate is not going to be resected. Proximal dissection and identification of the right portal vein from the left side is worthwhile to confirm anatomy. Unless mandated by tumor proximity, we prefer to transect the bile duct (left or right) intrahepatically during parenchymal transection to absolutely avoid contralateral injury. This is especially important on the left side where there is often variant drainage of the major right sectoral ducts to the left hepatic duct. An alternative to extrahepatic inflow control at the hilum is intrahepatic control using a pedicle ligation technique. This technique is most appropriate for right-sided tumors not encroaching on the hilus. The portal triads carry Glisson’s capsule with them into the liver substance forming a sturdy pedicular sheath that can be dissected and clamped. Exposure of the pedicles can be accomplished by parenchymal transection down to the sheaths or by hepatotomies in the liver substance above the pedicle. For exposure of the right-sided inflow pedicle(s), hepatotomies are typically made along the inferior part of the gallbladder fossa and the caudate process and a large clamp is used to encircle the inflow structures. The whole right pedicle can be controlled this way or the right anterior and posterior sectoral pedicles can be encircled separately. The approach is rapid and avoids dissection of the contralateral

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structures in the hilum, but risks injury to the pedicle before encircling the triad, or hemorrhage from coursing veins, which commonly run close to the pedicles. Though total vascular isolation has been employed by some groups (35–38), we have found that total vascular isolation techniques were not necessary in more than 1800 consecutive liver resections (2). Outflow Control Though there are multiple small veins that drain the right lobe and segment I directly into the retrohepatic vena cava, the majority of hepatic blood flow drains into the inferior vena cava (IVC) via the left, middle, and right hepatic veins. In

Figure 3.4 Sharp and blunt dissection over the suprahepatic IVC exposes the right, middle and left hepatic veins. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.

Left phrenic vein

Diaphragm

Left triangular ligament

Diathermy

Figure 3.5 Downward traction on the liver and cephalad traction on the diaphragm help expose the left coronary ligament. Care must be taken here to identify the phrenic vein as it courses on the underside of the diaphragm to enter the IVC, as it can be inadvertently injured if the triangular ligament is not properly exposed or not divided close to the liver surface. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.

HEPATIC RESECTION major hepatectomy, extrahepatic control of these vessels is preferred. Standard anatomy consists of a single right hepatic vein entering the vena cava, and a left and middle hepatic vein that is joined and entering the cava as a single trunk. Autopsy studies of the left and middle hepatic venous trunk have elucidated at least five types of hepatic vein trunk variants (39). The right hepatic vein is typically encircled after the dissection of the vena cava and caval ligament has been carried out as described earlier. The base of the right hepatic vein should be dissected sharply and once exposed, a clamp can be passed between the right and middle hepatic veins. Exposure of the left and middle hepatic vein extraheaptically can be challenging. The groove between the right and middle hepatic veins is initially developed from above the liver. The left liver is mobilized and the ligamentum venosum is divided just before its insertion into the left hepatic vein. Here a tunnel is carefully developed underneath the middle and left hepatic vein and they are encircled (Fig. 3.6). It is often difficult to individually encircle the left or middle hepatic vein extrahepatically but this depends on the anatomy of the common trunk. It is important to identify the hepatic venous anatomy on preoperative imaging and recognize variations in the branching patterns, since bleeding in this area can be difficult to control. Ligation of the hepatic venous outflow of the liver can also be accomplished during parenchymal transection with careful exposure of the cava and the origin of these veins once the liver has been transected to expose them. The exposures for specific resections are discussed later in the chapter. Parenchymal Transection Once vascular inflow and outflow to the lobe or segment has been controlled, all that remains is division of the liver parenchyma. There are many techniques to accomplish this. The instruments used are left to the surgeon’s preference, but it is imperative that the vessels and ducts divided be identified and dissected before division. Transection of the liver should be a deliberate dissection of intrahepatic structures rather than simply coagulation of liver tissue. In addition to the ability to confidently ligate each branch on the transection

(A)

line, it allows one to identify the venous drainage and pedicle inflow to the remnant liver. Moreover, in cases where the tumor margin is adjacent to major hepatic veins and portal pedicles, it allows precise extirpation of the tumor. For these reasons, we prefer a simple crushing technique. Glisson’s capsule is scored with diathermy along the transection line and a Kelly clamp is used to crush the liver tissue and expose the vessels and ducts for clipping, ligation, or bipolar energy sealing. Larger pedicles are suture ligated or stapled (40). The operative surgeon crushes the tissue in small linear planes, the assistant clips or seals the vessels, and the surgeon divides the structures. In this fashion, the transection line is quickly and efficiently completed. Though not always necessary, inflow occlusion with a Pringle maneuver may be used to decrease blood loss, and an entire lobe can often be transected with three to four sessions of 10–15 minutes on Pringle with 5 minutes off. After removal of the specimen, the raw surface is carefully inspected for bile leaks, which are suture ligated or clipped. Some groups advocate injection of dye or intralipid via the cystic duct to identify open biliary tributaries for ligation. Since drainage is associated with prolonged hospital stay, increased infection, and no change in a need for interventional radiology directed drainage, we do not routinely place drains after hepatic resection in the absence of biliary reconstruction (41).

major hepatic resection: definitions and specific considerations Multiple descriptions of liver anatomy and resections by anatomists and surgeons have resulted in terminologies that can be confusing and imprecise. A recent consensus conference in Brisbane, Australia, with the American Hepato-PancreatoBiliary Association has published new guidelines to clarify this nomenclature. When unclear, or if there is confusion about the description of a resection, one should revert to naming the numerical segments involved. The right liver is comprised of segments V–VIII and the left liver is comprised of segments II–IV. Appropriate terms for resection of the right or left liver would be “hepatectomy” or “hemi-hepatectomy.”

(B)

Figure 3.6 (A) Medial retraction of the left lateral segment exposes the ligamentum venosum. (B) The ligamentum venosum is divided sharply where it is tethered to the left hepatic vein, releasing the vein and enabling a tunnel to be dissected under the middle and left hepatic veins and anterior to the IVC. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.

29

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Extending a right hepatectomy to include segment IV or a left hepatectomy to include segments V and VIII would be described as a “right/left trisectionectomy” or “trisegmentectomy.” Resection of segments II and III is often referred to as a “left lateral segmentectomy” or “sectionectomy.” There are essentially five types of major resection. The nomenclature of these resections is based on the anatomical classification (Table 3.1) (Fig. 3.7) (42–45). Right Hemihepatectomy (Right Hepatectomy, Right Hepatic Lobectomy) A right hemihepatectomy involves excision of segments V–VIII. The right lobe is completely mobilized and the right hepatic vein is isolated. The peritoneum overlying the common bile duct and extending into Calot’s triangle is incised to expose the cystic artery and duct. These are ligated and divided. A long tie is left on the proximal cystic stump and used as a retractor to help expose the common bile duct and dissect the vasculature. The hilar plate is lowered to protect the left hepatic duct. We typically do not dissect the right hepatic duct extrahepatically, but address it during parenchymal transection to absolutely avoid any potential for injury to the left hepatic duct. The right hepatic artery usually passes posterior to the common bile duct (Fig. 3.8) and is sharply dissected, ligated, and divided to the right of the common duct. Superior traction on the right hepatic artery stump will help expose the portal vein. The portal bifurcation is approached laterally and posteriorly. When dissecting the right portal vein, care should be taken to identify the first posterior branch to the right side of the caudate. Circumferential control of the right portal vein should not be attempted until this branch is identified and dissected as bleeding from this vein can be troublesome. Once a few centimeters of right portal vein are fully exposed and the left portal vein has been visualized, it is encircled and divided. Clamping of the right portal vein at this point should confirm demarcation of the right liver. Occasionally, the right anterior and posterior sectoral portal vein branches arise independently from the portal vein. In this instance, they must be individually dissected and ligated after confirming flow to the left liver. The right hepatic vein is isolated and divided as described previously. It is important that all the retrohepatic veins are first controlled and divided, that the dissection extends to the

left of the IVC, and that the right hepatic vein is skeletonized completely right at the liver surface. It is especially important to gain extrahepatic control of the vein with large tumors near the hepatic venous confluence or in the posterior sector near the vena cava, where it can be difficult to obtain tumor clearance without excessive traction on the vein. Alternatively, the right hepatic vein can also be controlled from within the liver during parenchymal transection, however, this usually forces the hepatic transection to the right of the true principal midliver plane. After inflow ligation, a line of demarcation becomes evident. Figure-of-eight stay sutures are placed to either side of this line and parenchymal transection can begin safely. The surgeon’s left hand lifts the left lobe from above the IVC carefully as the transection plane is deepened. This will expose the middle hepatic vein, and division of the specimen can proceed to the right or left of the vein depending on tumor clearance. As the dissection proceeds superiorly, the segment V and then VIII hepatic veins are divided along the middle hepatic vein. The main right portal pedicle is exposed and divided with the endo-GIA stapler. This will control the right hepatic duct if it was not controlled extrahepatically. Alternatively, an anterior approach can be used to resect the right lobe of the liver. This approach is advantageous when the right lobe cannot be mobilized due to a large right-sided tumor, or there is a large mass adherent to the diaphragm or IVC (46). In this approach, after extrahepatic inflow division, the liver is transected without mobilization. It is then freed from its venous and ligamentous attachments to the IVC and peritoneum. The parenchyma is transected from the anterior liver surface to the IVC along the line of demarcation, and venous tributaries are controlled from the front, including the right hepatic vein (47,48). To help control bleeding in the deeper parenchymal plane, the “hanging maneuver” may be employed (49). In this maneuver, the anterior plane of the IVC is dissected from the liver undersurface. The most inferior veins draining the caudate are ligated and divided, and a tunnel is carefully created anterior to the IVC to the space between the right and middle hepatic veins with a Kelly clamp. This is a blind tunnel of 4 to 6 cm. A tape is passed that can then be used to elevate the liver away from the anterior surface of the IVC, helping to define the plane of transection and facilitating exposure of the deeper tissues. In this technique, the right portal pedicle

Table 3.1 Anatomy and Classification of Major Hepatic Resections Anatomic Classification Couinaud

Goldsmith and Woodburne

Brisbane

Segments resected

Right hepatectomy Right lobectomya Left hepatectomy Extended left hepatectomya Left lobectomy

Right hepatic lobectomy Extended right hepatic lobectomy Left hepatic lobectomy Extended left lobectomy Left lateral segmentectomy

Right hemihepatectomy Right trisectionectomy Left hemihepatectomy Left trisectionectomy Left lateral sectionectomy

V, VI, VII, VIII IV,V,VI, VII, VIIIb II, III, IV II, III, IV, V, VIIIb II, III

a

Often referred to as trisegmentectomy. May also include segment I.

b

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HEPATIC RESECTION is divided, parenchymal transection is completed to the IVC, the lateral venous attachments to the IVC are ligated and divided, the right hepatic vein is stapled, the coronary and triangular ligaments are divided, and the specimen is removed. Right Trisectionectomy (Right Lobectomy, Extended Right Lobectomy, Right Trisegmentectomy) A right trisectionectomy is a right hemihepatectomy extended to include segment IV. The liver is mobilized as described for a right hepatectomy. To approach the inflow and outflow of segment IV, the ligamentum teres is elevated to expose the umbilical fissure. If a bridge of tissue between segments III and IV is present concealing the fissure, this should be divided with diathermy. Here, the ligamentum teres can be traced to its embryologic origin at the left portal vein. Incising the fibrous tissue that tethers the left main pedicle to the base of the umbilical fissure releases the left-sided structures from the

undersurface of segment IV, and it opens up the fissure. To safely perform a right trisectionectomy, the left hepatic duct should be freed clear of the proposed plane of transection. This is accomplished by lowering the hilar plate as previously described. The inflow and outflow to the right liver are controlled and divided as previously described. Once the right hepatic vein has been divided, the middle vein can usually be encircled. The liver tissue is divided to the right of the falciform ligament and the pedicles feeding segments IVa and IVb are ligated and divided as they come off the main left pedicle (Fig. 3.9). Unless tumor mandates, a deliberate dissection within the umbilical fissure is usually not necessary. As the plane of transection is deepened toward the IVC superiorly, the middle hepatic vein is encountered, dissected, and divided with a stapler. It is absolutely critical to protect the left hepatic vein as narrowing or transection of this vein will likely result in liver failure or massive hemorrhage secondary to a lack of other venous return from the liver.

(A)

(B)

(C)

(D)

(E) Figure 3.7 The anatomy and classification of major hepatic resections. (A) right hepatectomy, (B) left hepatectomy, (C) left lobectomy, (D) extended left hepatectomy, (E) right lobectomy.

31

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Figure 3.9 To expose and control the portal pedicles to segment IV, the liver tissue is divided to the right of the falciform ligament and the pedicles feeding segments IVA and IVB are ligated and divided as they come off the main left pedicle. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.

Figure 3.8 During right hepatectomy, the right hepatic artery usually passes posterior to the common bile duct and is sharply dissected, ligated, and divided to the right of the duct. After cholecystectomy, retraction of the cystic duct will expose the underlying artery. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.

Left Hemihepatectomy (Left Hepatectomy, Left Hepatic Lobectomy) A left hemihepatectomy involves excision of segments II– IV. The left lobe of the liver is mobilized, the umbilical fissure is exposed, and the hilar plate is lowered as previously described. The gastrohepatic ligament is entirely divided, with care taken to identify any accessory or replaced left hepatic arteries not identified on preoperative imaging. The left hepatic artery is dissected at the base of the umbilical fissure and divided. The caudate branch of the portal vein is identified before the left main portal vein enters the umbilical fissure. If the caudate lobe is to be spared, the portal vein is ligated and divided distal to this vein. A line of demarcation marking the right-sided border of segment IV corresponds with a plane that usually extends from the IVC to the base of the gallbladder fossa (“Cantlie’s line”). This “principle plane” is the same as that seen in a right hemihepatectomy. Segments II and III are reflected medially and the middle and left hepatic veins are identified, encircled and divided extrahepatically as described earlier. The left hepatic vein is often not amenable to circumferential extrahepatic exposure initially but can be exposed after splitting the liver back to its origin. Parenchymal transection completes the excision. Left Trisectionectomy (Extended Left Hepatectomy, Extended Left Lobectomy, Left Trisegmentectomy) A left trisectionectomy involves removal of segments II, III, IV, V, and VIII. The entire liver is mobilized. The inflow and outflow to the left lobe are controlled as previously

32

described for a left hemihepatectomy. The inflow to segments V and VII can be addressed in a few ways. The anterior sectoral pedicle can be encircled intrahepatically either through hepatotomies or after transection in the right scissura to the left of the right hepatic vein. The pedicle can be encircled and clamped confirming flow the posterior sector. Alternatively, an extensive hilar dissection can be carried out to identify and divide the arterial and portal branches to the right anterior sector. It is critical that preoperative imaging is reviewed for anatomic variations in the inflow and outflow to the right liver. Once the anterior sectoral inflow is divided, a near horizontal line of demarcation becomes evident anterior to the right hepatic vein and dividing the right anterior and posterior sectors. Parenchymal transection continues anterior to the right hepatic vein and the specimen is removed. The middle hepatic vein is necessarily taken as part of this resection and is addressed as described earlier. A left trisectionectomy is a challenging operation that requires significant experience with major hepatic resections. Left Lateral Sectionectomy (Left Lobectomy, Left Lateral Segmentectomy) A left lateral sectionectomy involves removal of segments II and III. The left lobe of the liver is mobilized and the hilar plate is lowered as previously described. Just to the left of the umbilical fissure, the portal pedicles to segments II and III are identified and divided. These can be identified and controlled through multiple hepatotomies or during parenchymal transaction in a plane just to the left of the falciform ligament. A deliberate dissection in the umbilical fissure is usually not necessary. The left hepatic vein is usually divided after parenchymal resection back to its origin but can also be controlled extrahepatically as described in the “outflow control” section of the chapter.

HEPATIC RESECTION

wedge vs. segmental resection The segmental anatomy of the liver, as defined by Couinaud, divides the liver into eight independent segments, each with its own inflow and biliary drainage (see chapter 1) (42,50). As a result, each segment can be individually resected without affecting the inflow or outflow to the rest of the liver. Segment-oriented hepatectomy spares normal parenchyma and is particularly useful when bilateral noncontiguous segments are involved or in patients with chronic liver disease. Nonanatomic wedge resections can be useful for small peripheral tumors that are not close to major inflow pedicles or venous branches for which adequate tumor margins can be obtained. Though some groups have shown that anatomical resection is not superior to wedge resection for tumor clearance, pattern of recurrence, or survival (51), in our experience anatomic segmental resection resulted in improved tumor clearance and patient survival compared to wedge resection (52). Wedge excision may risk fracturing the plane between the tumor and normal liver, margin positivity, and intraoperative hemorrhage (12,53). Anatomic resection may provide better visibility, decrease the risk of major hemorrhage, and in many cases provide a wider margin of resection. Segmentectomy I (Caudate Resection) The caudate lobe is often resected with a right or left hemihepatectomy, however, isolated caudate resection may be performed for solitary tumors in segment I. The anatomy of the caudate lobe between the IVC, portal triad, and hepatic veins can make resection tedious and challenging. The caudate lobe straddles both hepatic lobes and therefore receives vascular inflow from both the right and left portal pedicles (54). Venous drainage is directly into the IVC via one to nine short hepatic veins (55). The left edge of the caudate fuses with the IVC via a fibrous band of tissue that encircles the IVC and attaches to segment VII. In many patients, this caval ligament may be composed of liver parenchyma. Dissection at the base of the umbilical fissure exposes the caudate branches of the left portal vein and hepatic artery for ligation and division. Segments II and III of the liver are mobilized and reflected to the right, exposing the caudate where it lies on the IVC. The left lateral attachments of the caudate to the IVC are divided (56). Exposure and division of the left caval ligament can be challenging and care should be taken to avoid injury to the cava inferiomedially and the base of the left and middle hepatic veins superiorly. With anterior traction on the caudate, the short hepatic veins draining into the IVC on the posterior aspect of the caudate can be visualized and controlled. If there is a bulky tumor in the caudate or anterior traction of the lobe is difficult, the retrohepatic veins can be approached from the right side, by mobilizing the right lobe and turning it to the left, then dissecting and dividing all the veins starting below the caudate and continuing onto the anterior surface of the IVC (57). The caudate branch from the right portal vein should also be identified and ligated. To complete the resection, the tissue joining the caudate to segment VII must be transected. Anteriorly and superiorly,

care must be taken to avoid injury to the middle and left hepatic veins. Segments II or III The approach to excising either segment II or III is the same as that for a left lateral segmentectomy, except the plane between the segments needs to be defined. This plane is identified by the course of the left hepatic vein, segment 3 being anterior and segment 2 being posterior. Inflow control to either segment is achieved in the umbilical fissure. Ligation of the portal pedicle will guide resection along the plane of demarcation. Care must be taken to divide the branches of the left hepatic vein draining the excised segment, but to leave the main left hepatic vein intact to drain the remnant liver. Segment IV As described in a right trisectionectomy, the inflow to segment IV is found to the right of the umbilical fissure. The hilar plate is lowered to protect the left bile duct and to provide access to the multiple pedicles to segment IV. Ligation of these pedicles will provide a line of demarcation along Cantlie’s line. During parenchymal transection, the venous drainage of segments IVa and IVb are divided sequentially to the left of the middle vein on the lateral border of the segment, and along the umbilical fissure on the medial border of the segment, where the umbilical vein often courses. The middle hepatic vein can be sacrificed in this operation if necessary with adequate drainage of the right liver and segments 2 and 3. Segments V and VIII (Anterior Sector) The inflow to segments V and VIII are from the right anterior sectoral pedicle. This can be approached and controlled extrahepatically or intrahepatically as described for a left trisectionectomy. If the anterior and posterior sectoral pedicles branch within the liver parenchyma, a hepatotomy over the anterior pedicle is necessary. Alternatively, the liver can be transected in the principal plane down to the base of the anterior sector where its origin can be controlled, typically posterior to terminal middle hepatic vein branches. The anterior sector lies between the right and middle hepatic veins, i.e., between Cantlie’s line and a transverse plane anterior to segments VI and VII. This horizontal plane of transection can be better defined by clamping the anterior pedicle to demarcate the right, left, and posterior borders. The transection line between V and VIII is demarcated and defined intrahepatically when control of the isolated segmental inflow is obtained. The middle hepatic vein can usually be safely divided in this operation if necessary, but in the absence of a large accessory right hepatic vein, the right hepatic vein must be preserved for adequate drainage of the posterior sector. Segments VI and VII (Posterior Sector) The inflow to segments VI and VII are from the posterior sectoral pedicle. This can often be approached and controlled in the fissure of Ganz, though the anatomy of anterior and posterior pedicles can be highly variable. If the anterior and posterior sectoral pedicles branch within the liver parenchyma,

33

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS the portal pedicles must be approached during parenchymal transection. The medial plane of transection can be better defined by clamping the posterior pedicle to demarcate the border. The classic description of a single pedicle from the posterior sectoral pedicle feeding either segment VI or VII is the exception rather than the rule (58), therefore, careful parenchymal dissection, preoperative study of the CT, and intraoperative ultrasound are critical to these resections. If a posterior sectorectomy is to be performed, the right hepatic vein can be sacrificed since the anterior sector drains into the middle hepatic vein. Central Hepatectomy (Segments IV, V, and VIII) A central hepatectomy with various amount of extension into any of the three segments can be performed combining the techniques described above. Typically this requires dividing the middle hepatic vein intrahepatically near its origin. The techniques of a segment IV resection and anterior sectorectomy are essentially combined. This is a challenging operation that requires a substantial surface of liver to be transected but can be very useful to spare parenchyma while removing centrally placed tumors.

enucleation of benign tumors ₍see chapters 28, 32, and 33₎ When indicated, hepatectomy for benign conditions should be parenchymal preserving. Though anatomic resection along segmental planes is sometimes necessary, some benign tumors may be enucleated, for example, adenomas, fibronodular hyperplasia, metastatic neuroendocrine tumors, and hemangiomas (2,4). Hemangiomas in particular push liver tissue away as they grow, and create a fibrolamellar plane of tissue that defines the border between cavernous tissue and normal liver parenchyma (2). The arterial supply to the hemangioma can be determined from preoperative imaging and is clamped, allowing the tumor to decompress via the venous outflow. The hepatic tissue over the mass is then incised to enter an avascular plane surrounding the tumor. Small vessels that traverse this plane are ligated and divided. The majority of the dissection can be done with the surgeon’s finger, and the mass is shelled out. This approach preserves normal parenchyma, eliminates the need for hepatic venous outflow control, limits blood loss, and has fewer complications than lobectomy (3,4). Management of benign lesions is covered in further detail in other chapters.

conclusion Major hepatic resections for benign and malignant tumors can be accomplished safely and efficaciously. Proper patient selection, precise preoperative imaging, specific anesthetic techniques, and knowledge of the principal complications are essential. Study of each patient’s segmental anatomy will allow inflow and outflow control and the ability to tailor the resection needed for each individual.

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42. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Le Foie: Etudes Anatomiques et Chirurgicales. 1957. 43. Goldsmith NA, Woodburne RT. The surgical anatomy pertaining to liver resection. Surg Gynecol Obstet 1957;105:310–8. 44. Starzl TE, Iwatsuki S, Shaw BW, Jr, et al. Left hepatic trisegmentectomy. Surg Gynecol Obstet 1982;155(1):21–7. 45. Starzl TE, Koep LJ, Weil R, 3rd, et al. Right trisegmentectomy for hepatic neoplasms. Surg Gynecol Obstet 1980;150(2):208–14. 46. Chik BH, Liu CL, Fan ST, et al. Tumor size and operative risks of extended right-sided hepatic resection for hepatocellular carcinoma: implication for preoperative portal vein embolization. Arch Surg 2007;142(1):63–9; discussion 9. 47. Lai EC, Fan ST, Lo CM, Chu KM, Liu CL. Anterior approach for difficult major right hepatectomy. World J Surg 1996;20(3):314–7; discussion 8. 48. Lai ECS, Fan ST, Lo CM, et al. Hepatic resection for hepatocellular carcinoma: An audit of 343 patients. Ann Surg 1995;221(3):291–8. 49. Belghiti J, Guevara OA, Noun R, Saldinger PF, Kianmanesh R. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 2001;193(1):109–11. 50. Couinaud C. Bases anatomiques des hepatectomies gauche et droite reglees. J Chir 1954;70:933–66. 51. Zorzi D, Mullen JT, Abdalla EK, et al. Comparison between hepatic wedge resection and anatomic resection for colorectal liver metastases. J Gastrointest Surg 2006;10(1):86–94. 52. DeMatteo RP, Palese C, Jarnagin WR, et al. Anatomic segmental hepatic resection is superior to wedge resection as an oncologic operation for colorectal liver metastases. J Gastrointest Surg 2000;4(2):178–84. 53. Polk W, Fong Y, Karpeh M, Blumgart LH. A technique for the use of cryosurgery to assist hepatic resection. J Am Coll Surg 1995;180(2):171–6. 54. Mizumoto R, Suzuki H. Surgical anatomy of the hepatic hilum with special reference to the caudate lobe. World J Surg 1988;12(1):2–10. 55. Heloury Y, Leborgne J, Rogez JM, et al. The caudate lobe of the liver. Surg Radiol Anat 1988;10(1):83–91. 56. Takayama T, Makuuchi M. Intraoperative ultrasonography and other techniques for segmental resections. Surg Oncol Clin N Am 1996;5(2):261–9. 57. Lerut J, Gruwez JA, Blumgart LH. Resection of the caudate lobe of the liver. Surgery Gynecol Obstetrics 1990;171(2):160–2. 58. Hata F, Hirata K, Murakami G, Mukaiya M. Identification of segments VI and VII of the liver based on the ramification patterns of the intrahepatic portal and hepatic veins. Clin Anat 1999;12(4):229–44.

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4

Ultrasound for HPB disorders Duan Li and Lucy Hann

introduction Ultrasound is the initial study of choice in most clinical situations due to the lack of ionizing radiation, relatively low cost, and accessibility in varied settings such as at the bedside or in the operating suite. Ultrasound differs from other crosssectional imaging techniques in that it uses sound propagation and reflection from interfaces within tissue for imaging. Images are generated by piezoelectric material within the transducer that transmits and receives the sound signal. Higher frequency transducers provide the best resolution, but high frequencies are attenuated more rapidly in tissue. For that reason, transducer frequency is selected for the application. Superficial structures are evaluated at frequencies in the range of 6 to 18 MHz and transabdominal ultrasound, which requires better penetration, typically uses frequencies ranging from 3 to 6 MHz. Doppler is a unique feature of ultrasound for imaging vessels and blood flow. When moving blood is insonated, the frequency of the returning signal is proportional to blood velocity. A cursor is placed over a specific blood vessel and images are obtained in both gray scale and Doppler (termed “Duplex scanning”). The Doppler information can then be displayed in three different formats: (1) spectral Doppler, (2) color Doppler, and (3) power Doppler. Spectral Doppler shows a waveform with velocity changes and flow direction over time. Color Doppler displays mean velocities and direction of flow within vessels. The color codes assigned for velocities are usually displayed in the upper left aspect of the image. Power Doppler gives the amplitude of the Doppler signal without direction or frequency information; since it is not angledependent, it is very useful for imaging low flow and tortuous vessels. Ultrasound contrast agents further improve applications for vascular imaging. Current contrast agents use microbubbles encapsulated within thin lipid spheres. After intravenous injection, the microbubbles remain intravascular and do not diffuse into the interstitium as do MRI and CT contrast agents. After a low-power ultrasound signal is applied, the microbubbles oscillate (expand and contract) at harmonic frequencies that are detected by the transducer (1,2). With these ultrasound contrast agents, it is now possible to image tumor vasculature in exquisite detail (3–7) (Fig. 4.1). Despite the versatility of ultrasound, there are limitations. Sound is reflected at bone and air interfaces so scans are obtained from different positions to avoid intestinal air or rib artifact. This lack of standardized perspective compared to axial imaging format of CT and MRI may present difficulty for referring clinicians who are unfamiliar with the technique. To lessen bowel gas interference, 6-hour fast is recommended to improve visualization of the pancreas and liver and to provide sufficient gallbladder distension. Another significant limitation

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is that ultrasound is operator-dependent; skilled technologists and radiologists are essential since diagnosis is made at image acquisition. For best results, the surgeon should communicate to the radiologist the specific clinical questions so that appropriate targeted images can be obtained at the time of the examination. This chapter will discuss ultrasound applications for diagnosis of hepatic, gallbladder, biliary, and pancreatic abnormalities. The role of specialized ultrasound techniques such as endoscopic ultrasound and intraoperative ultrasound will also be addressed.

liver Anatomically the liver is divided into sectors that are defined by the scissurae that contain the hepatic veins; these sectors are then subdivided into individual hepatic segments that each contain intact portal and arterial inflow and hepatic venous outflow and draining bile ducts (8,9). Ultrasound hepatic anatomy is shown in Fig. 4.2. Diffuse Liver Disease Diffuse liver abnormalities include fatty infiltration, hepatitis, and cirrhosis. Hepatic steatosis is present in 17% to 33% of the general population and in 70% of overweight individuals (10). On ultrasound, the liver has diffusely increased echogenicity and in advanced cases significant sound beam attenuation obscures the deep liver. Areas of focal sparring may be seen anterior to the portal confluence and adjacent to the gallbladder. Hepatic steatosis impacts perioperative outcome and accurate preoperative diagnosis would be useful (11). Fatty infiltration increases liver stiffness, which can be measured by tissue displacement in response to the transmitted ultrasound wave. These elastography techniques hold promise for diagnosis of diffuse infiltrative liver diseases such as hepatic steatosis and early-stage hepatic fibrosis (12–14). Focal Hepatic Lesions Cystic lesions Ultrasound is the best modality to differentiate cystic from solid liver masses and to determine the internal architecture of cystic lesions. Simple cysts, found in 2% to 3% of patients (15), have thin wall, no internal echoes, and bright posterior enhancement. Even if the cyst is lobulated or has thin septation, benign diagnosis can be made (16). Symptomatic large simple cysts may be treated with ultrasound-guided aspiration and sclerosis (15,17), but it is extremely important to assess the cyst wall. Mural nodularity, thick tumor rim, and internal vascularity may indicate neoplasm such as biliary cystadenoma and these lesions should not be unroofed or aspirated since complete surgical resection is required. Cystic liver metastases present as complex cysts often with solid or

ULTRASOUND FOR HPB DISORDERS

(A)

(B)

Figure 4.1 Microbubble contrast enhanced ultrasound image of a hypervascular liver mass. (A) Contrast enhanced image shows the intense hypervascularity of this liver lesion (arrow) that proved to be focal nodular hyperplasia. (B) The lesion (arrows) is subtle on the corresponding grayscale image. (Complements of Siemens Medical Solutions, Ultrasound Division. Malvern, PA.)

irregular rim. These are typically from sarcoma, cystadenocarcinomas of the ovary and pancreas, and mucinous colon carcinoma primaries (16,18). Ovarian metastases are characteristically peripheral implants. Squamous cell tumors with necrosis appear as cystic masses and other metastases may cavitate in response to chemotherapy. The appearance of cyst contents on ultrasound can be used for differential diagnosis. Pyogenic abscess initially may be echogenic and later liquified with debris, fluid-fluid levels, and irregular wall (Fig. 4.3). Echogenic reflections with reverberations, seen in 20% to 30% of cases, suggest air within the abscess (18). The classic echinococcal cyst is a complex cyst with well-defined wall, containing double echogenic lines. Multiple, internal echogenic foci, “snowstorm signs” settle in the dependent portions of the cyst. Localized splits in the cyst wall, with floating, undulating membranes, are also characteristic and the cyst wall may calcify (19,20). Hematomas in the acute stage may be echogenic and then they have layering lowlevel echoes from blood, and later become honeycombed with septation. When a preexisting cyst becomes hemorrhagic, internal septation may be thick and irregular, but they float freely in real-time and are not rigid. Solid Liver Lesions Solid liver lesions are further characterized by lesion echogenicity, vascularity, and peripheral halo. Definitive diagnosis of benignity can be made for hemangiomas, focal fatty infiltration, and focal fatty sparing because of their classic ultrasound features. Benign focal nodular hyperplasia can also be identified when the characteristic “spokewheel” vascular pattern, tortuous feeding artery, and marked hypervascularity are seen on contrast-enhanced ultrasound or Doppler images (Fig. 4.1). Hypoechoic liver masses and lesions with a peripheral halo are suspicious for malignancy. Although CT and MRI are used for tumor staging, there can be added benefit from ultrasound to

(1) assess lesions that are “too small to characterize” by CT, (2) define the relationship of tumor to bile ducts, and (3) evaluate vascular encasement and tumor margin (Fig. 4.4). Typical hemangioma, seen in 70% to 80% of cases, is a uniformly echogenic mass with sharp margin (21) (Fig. 4.5A). The multiple vascular interfaces within the hemangioma cause the increased echogenicity and margin is well-demarcated since histopathologically hemangiomas lack a capsule. Hemangiomas have absent or minimal flow on Doppler imaging; they are never hypervascular. Another common appearance of hemangioma is a mass with thin peripheral echogenic rim with mixed central echogenicity (Fig. 4.5B). Giant hemangiomas > 5 cm often lack these characteristic ultrasound features because of central fibrosis, necrosis, and myxomatous degeneration. A study of 213 patients with typical hemangioma appearance and without risk for hepatic malignancy found only one patient with malignancy on long term follow-up and concluded that typical hemangiomas in low-risk patients do not require follow-up (22). This rule does not apply to patients with cirrhosis, hepatitis, or chronic liver disease that places them at increased risk for hepatocellular carcinoma, nor does it apply to patients who already have malignancies, and particularly not to those with primary tumors that exhibit echogenic metastases. Caturelli et al. (23) studied 2,000 patients with cirrhosis. Of these, 44 had hemangioma-like lesions. On follow-up, half proved to be hepatocellular carcinomas and half hemangiomas. Thus, in patients at risk for hepatocellular carcinoma, any echogenic lesion merits further evaluation or follow-up. Other benign conditions such as focal fatty infiltration and focal sparing are diagnosed by geographic margins and typical location in segment 4 anterior to the portal vein bifurcation or less commonly, adjacent to the gallbladder. Focal fat appears echogenic relative to normal liver and areas of focal sparing are less echogenic than fatty infiltrated liver. A useful finding on Doppler evaluation is that vessels cross undisturbed

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS without displacement through areas of focal fat or focal sparring (24,25). A hypoechoic halo around a liver lesion indicates a clinically significant mass, suspicious for malignancy, including hepatocellular carcinoma and hepatic adenoma and metastases from colorectal, gastrointestinal, neuroendocrine, renal cell, choriocarcinoma, and vascular primaries such as Kaposi sarcoma (Fig. 4.4). Pathologically, the halo is caused by proliferating malignant cells, compression of the liver parenchyma, and dilated sinusoids. The hypoechoic halo sign has a 95% positive predictive value and an 87% negative value for differentiating

metastases from hemangioma (26,27). A hypoechoic halo may be seen even in small lesions <1.5 cm. The halo is detected when the tumor is hyperechoic relative to the surrounding liver. In hypoechoic tumors, the lesion and the halo have the similar echogenicity and therefore the halo sign is not evident. Hepatocellular carcinoma (HCC) has a variable sonographic appearance ranging from hypoechoic to echogenic, but a hyperechoic lesion with hypoechoic halo is the common presentation. Small satellite tumors are typically hypoechoic. Doppler evaluation is the key in diagnosing HCC since the tumor is hypervascular and invasion of the portal or hepatic

(A)

(B)

(C)

(D)

(E) Figure 4.2 Normal liver anatomy. (A) Transverse view of the right lobe. The middle hepatic vein separates the right from left hepatic lobes. The right hepatic vein divides the right anterior sector (segments 8 and 5) and the right posterior sector (segments 7 and 6). R = right hepatic vein, M = middle hepatic vein, IVC = inferior vena cava. (B) Longitudinal view of the right lobe reveals the right hepatic vein RHV and the hepatic segments. RK = right kidney. (C) Transverse view of the portal vein bifurcation. Segments are numbered. R = right portal vein, L = left portal vein, RK = right kidney, IVC = inferior vena cava, A = aorta. (D) Longitudinal view of the left lobe. The left hepatic vein separates the posterior left sector segment 2 from the anterior sector (segments 3 and 4). The caudate, segment 1, is demarcated anteriorly by the fissure for the ligamentum venosum (arrowhead) and the inferior vena cava posteriorly. IVC = inferior vena cava. RPV = right portal vein. (E) Color Doppler sagittal image of the portal vein reveals hepatopetal flow.

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ULTRASOUND FOR HPB DISORDERS veins is very common; about 40% of patients have portal venous involvement and 25% show hepatic venous involvement (28). Flow within the tumor is usually of high velocity and low resistance due to arterial-venous shunting within the tumor. Tumor thrombus from HCC can be distinguished from bland thrombus when arterial flow is detected within the

thrombus (29). With ultrasound contrast agents, the hypervascularity and dysmorphic vessels in HCC are more apparent and there is washout in the portal venous phase. Hypoechoic liver masses are suspicious for malignancy. Liver metastases that are hypoechoic are most commonly from breast, lung, esophagus, stomach, pancreas, and non-Hodgkin lymphoma.

gallbladder and bile ducts

Figure 4.3 A 50-year-old woman several years postpancreaticoduodenectomy for duodenal carcinoid developed fever after hepatic artery embolization for control of hepatic metastases. Right hepatic liquified abscess (asterisk) with posterior acoustic enhancement (arrowhead). Small posterior solid metastases (small arrows) are also seen.

(A)

Ultrasound is the procedure of choice for evaluation of the gallbladder and bile ducts. Gallstones are mobile, echogenic, and have posterior acoustic shadows (Fig. 4.5). The shadowing is present with or without gallstone calcification; it is due to the acoustic mismatch between stone and surrounding bile. Stones <3 mm may not generate a shadow because of small size. Gallstones move quickly with positional variation in contrast to sludge, which moves slowly and lacks an acoustic shadow. Gallbladder polyps do not shadow and they are fixed in position. Management of gallbladder polyps depends on size and sonographic appearance. Cholesterol polyps, usually <5 mm and multiple, do not progress as shown in long-term studies, but larger polyps 1 cm or greater or those with irregular margins are at risk for malignancy (30,31).

(B)

Figure 4.4 Colorectal metastasis to left hepatic lobe was evident on ultrasound but not by CT done the same day. (A) The lateral left lobe was considered negative on CT. (B) Longitudinal ultrasound revealed a segment II metastases with peripheral halo (calipers) consistent with malignant lesion.

(A)

(B)

Figure 4.5 Hemangioma. (A) Typical hemangioma (arrow) is uniformly echogenic with no surrounding halo. (B) An atypical hemangioma with a thin bright rim (arrow) is shown in this longitudinal view of the right hepatic lobe. Another hemangioma (arrowhead) is noted peripherally.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Normal gallbladder wall thickness is <3 mm. Mural thickening may occur with adenomyomatosis, inflammation, or neoplasm. Adenomyomatosis may be focal mass (adenomyoma) or diffuse thickening and gallbladder deformity with hourglass configuration. Ring down artifact from cholesterol crystals in Aschoff–Rokitansky sinuses is a diagnostic ultrasound feature of adenomyomatosis. Acute cholecystitis causes diffuse or focal gallbladder wall thickening with a layered appearance and in severe cases, the sloughed mucosa may be seen (Fig. 4.6). Marked edema in the pericholecystic space may mimic acute cholecystitis in patients with pancreatitis or hepatic inflammation.

(A)

It is essential to carefully evaluate the gallbladder wall to exclude gallbladder carcinoma that may coexist with stones (Fig. 4.7). This is particularly important in patients being considered for laparoscopic cholecystectomy since surgical management of gallbladder carcinoma usually requires hepatic resection and recurrences in laparoscopic port sites are frequent (32). Gallbladder carcinoma may cause focal thickening or may obliterate the gallbladder lumen. Associated tumor extension into hepatic segments 4 and 5 and biliary obstruction at the hilus are common. Ultrasound is sensitive for detection of biliary dilation and to determine level of obstruction. Dilated intrahepatic bile

(B)

(C) Figure 4.6 Acute cholecystitis in a 56-year-old woman with abdominal pain. (A) Longitudinal view reveals a laminated appearance to the anterior gallbladder wall (arrowheads) and gallstone (arrow) with posterior acoustic shadow. (B) Transverse view shows thickened wall at 6 mm (calipers). (C) Longitudinal color Doppler image reveals vascular flow within the gallbladder wall.

(A)

(B)

Figure 4.7 Gallbladder carcinoma. (A) Longitudinal and (B) transverse sonogram of the gallbladder reveals a stone (arrowhead) with acoustic shadowing. The anterior fundus is narrowed and surrounded by hypoechoic soft tissue that infiltrates the adjacent liver (arrows).

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ULTRASOUND FOR HPB DISORDERS ducts produce the double duct sign and dilation of the common bile duct >6 mm is considered abnormal. There has been controversy regarding the size of the common bile duct with increasing age and postcholecystectomy, but recent studies have shown that even in the elderly, 98% of ducts are <6 mm and there is no compensatory dilation of the common duct after cholecystectomy (33–36). Cholangiocarcinomas cause biliary obstruction in characteristic patterns. Intrahepatic cholangiocarcinoma arises from the peripheral bile ducts and bile duct obstruction peripheral to the tumor is seen in almost one third of the cases. These tumors are also typically hypovascular, in contrast to HCC. Hilar cholangiocarcinoma are typically smaller since their critical location produces early jaundice. Associated vascular encasement is evident in nearly 50% of the cases (37). Ultrasound is useful for tumor staging that is determined by location of tumor along the ducts and the extent of vascular involvement (38).

pancreas The echotexture of the normal pancreas is uniform and slightly higher echogenicity than liver. With aging and obesity, fatty infiltration of the pancreas may further increase echogenicity. The pancreatic duct is best seen transversely and is normally less than 2 mm in the body and 3 mm in the head (39). Diffuse Pancreatic Diseases In acute pancreatitis, the pancreas may become enlarged and hypoechoic with indistinct margins from edema. The edema may involve the entire gland or only a portion, usually the head. Peripancreatic fluid is a useful diagnostic feature; fluid and vascular mural thickening may also be observed (40) (Fig. 4.8). Pancreatic duct may be dilated. In the most acute stage, ileus limits ultrasound visualization and CT is more useful, but ultrasound has a role to exclude biliary calculi as an etiology for the pancreatitis (41–44). Severe inflammation progresses to inflammatory pancreatic mass or phlegmon with fluid collection, hemorrhage, and necrosis. Fluid is commonly seen within the lesser sac, anterior pararenal spaces, transverse mesocolon, small bowel mesentery, and parapancreatic spaces (45). Pseudocysts may persist for a minimum of 4 weeks after

Figure 4.8 Acute pancreatitis in a patient with AIDS. Transverse sonogram of the pancreas reveals heterogeneous pancreatic parenchyma and edema of the splenic vein (arrow). The vein has a layered appearance with a ring of hypoechoic fluid within the wall of the vessel. Fluid also is seen in the peripancreatic space (arrowheads).

the onset of pancreatitis (46). Identification of infected pseudocyst is limited, but the presence of echogenic foci corresponding to gas bubbles is suggestive of infection. If there is clinical suspicion, ultrasound can provide image guidance for fluid aspiration or drainage. Venous thrombosis and pseudoaneurysms that occur secondary to pancreatitis can also be evaluated sonographically. Ultrasound findings in chronic pancreatitis include alteration of texture, calcification, pancreatic duct, and/or bile duct dilation, and chronic pseudocyst. The gland is usually atrophic and heterogeneous. Calcification, either focal or diffuse, and pancreatic duct dilation are the most classic sonographic features (47). When findings of chronic pancreatitis mimic neoplasm with ductal dilation, CT or MRI is needed to make the distinction. Pancreatic Neoplasms Characterization of pancreatic masses, aspiration and biopsy are increasingly being done with endoscopic ultrasound (EUS). Miniature ultrasound transducers mounted on endoscopes display radial or linear images of the pancreas. EUS is more sensitive for detection of small masses and biopsy can be performed through the posterior gastric wall (48). Adenocarcinoma appears on ultrasound as a focal mass with atrophy and pancreatic duct dilation distal to the mass. Vascular invasion is frequent and bile ducts are dilated commonly for masses in the pancreatic head. Ultrasound is considered reliable for diagnosis of nonresectable tumors and in such cases further imaging is not required; evaluation can proceed directly to biopsy for tissue diagnosis (40,49) (Fig. 4.9). Staging of pancreatic adenocarcinoma by EUS and CT were compared in a prospective study by DeWitt (50). EUS had higher sensitivity than CT for tumor detection (98% vs. 86%), better staging accuracy (67% vs. 41%), and both techniques were equivalent for nodal status. EUS is also useful for biopsy especially when CT-guided biopsy is negative. In a prospective study of patients with negative CT-guided biopsy of pancreatic masses, EUS biopsy had 95% sensitivity and 100% specificity for diagnosis (51). Neuroendocrine tumors such as insulinomas and gastrinomas usually have classical symptoms. When tumors are small, abdominal ultrasound is limited, but laparoscopic ultrasound and intraoperative ultrasound are extremely useful for tumor detection (52,53). Approximately one-third of endocrine tumors are nonfunctioning and these tumors are more likely malignant. Cystic pancreatic neoplasms (serous microcystic adenomas, mucinous adenomas, and solid and cystic pseudopapillary tumors) are best evaluated with EUS. Serous microcystic adenomas are benign tumors with multiple cysts ranging in size from 1 mm to 2 cm. These tumors may appear solid on ultrasound because of numerous interfaces produced by the microscopic cyst walls (54–57). Macrocystic mucinous tumors of the pancreas are malignant or potentially malignant and have cysts >2 cm. The cysts may have thick septation, mural nodules, and calcification may be present (47,56). It is not possible to distinguish between benign and malignant mucinous tumors, but in general, larger cysts and cystic masses with

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A)

(B)

(C) Figure 4.9 Unresectable pancreatic adenocarcinoma. (A) Longitudinal ultrasound image of the pancreas shows an enlarged pancreatic head (m) and dilated common bile duct (arrow), PV = portal vein, IVC = inferior vena cava. (B) Transverse sonogram reveals the pancreatic head mass (m) and dilated pancreatic duct (arrows) anterior to the splenic vein (SV). IVC = inferior vena cava, a = aorta. (C) Transverse sonogram reveals a left hepatic metastasis (arrows). R = right hepatic vein, M = middle hepatic vein, IVC = inferior vena cava.

significant solid component are more likely to be malignant (47,55,58). Aspirates of cystic lesions are relatively acellular but fluid analysis for tumor markers is useful. Brugge et al. (59) reported that elevated cyst fluid CEA level had 79% accuracy for diagnosis of mucinous tumors.

intraoperative ultrasound Intraoperative ultrasound (IOUS) is an important tool for (1) assessment of tumors at the time of resection, (2) vascular mapping during hepatic resection or live split liver donor transplantation, and (3) guidance during intraoperative tumor ablation or biopsy (60–64) (Fig. 4.10). During hepatic resection, IOUS is used to characterize liver lesions that are indeterminate or occult on preoperative imaging. IOUS can accurately assess tumor extent relative to vascular structures and bile ducts (65–68); this is important since approximately 1 to 2 cm margin should be available between the tumor and vessels for optimal surgical outcome and vessel encasement or thrombosis may alter surgical approach (69–72). A prospective study by Cerwenka et al. (73) evaluated the role of IOUS in patients who had partial hepatectomy after standardized hepatic protocol preoperative MRI. Small additional lesions with mean size of 1.5 cm were found by IOUS in 7% of patients and in 5% of patients IOUS findings altered surgical strategy (73,74). IOUS altered management in 20% of patients who had resection for primary or secondary hepatic malignancies. Even with recent improvements in crosssectional imaging, there was no significant difference in resection

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rate (72%), detection of unrecognized additional tumors (20% vs. 14% p=0.70), or detection of vascular involvement when groups in the years1999 to 2003 and 2003 to 2005 were compared (68,74–76). Special dedicated high-frequency (5–10 MHz) transducers are required for IOUS; these transducers can be applied directly on the area of interest to improve resolution compared to transabdominal ultrasound, which is limited by distance and abdominal wall artifact. Typically IOUS probes are small T-shaped linear and hockey-stick-shaped probes, which are easy to manipulate within restricted operative fields. Transducer specifications should include good near field resolution and Doppler capabilities. It is preferable to have the scanner connected to the hospital network to provide (1) access for consultation at remote sites during real-time scanning and (2) permanent image archiving in the electronic record. Review of preoperative imaging is essential before IOUS since preoperative planning increases the efficiency of the procedure. While performing IOUS, the surgeon should avoid applying excessive pressure. If vessels become compressed, it is difficult to assess patency or encasement. Light touch with the transducer can be used as a palpation method to differentiate between soft benign lesions such as hemangiomas, focal fat, and fat sparing versus malignant lesions, which are usually firm (77,78). IOUS may be limited for lesions in the high right lobe or in the posterior subdiaphragmatic location where access is

ULTRASOUND FOR HPB DISORDERS

(A)

(B)

(C) Figure 4.10 Intraoperative ultrasound reveals additional hepatic lesions. (A) A 2 cm segment 7 liver lesion (arrows) with peripheral halo and (B) an 8 mm segment 6 lesion (arrow) were seen on preoperative imaging. (C) A nonpalpable 6 mm lesion (arrow) in segment 4A was not evident on preoperative imaging. Lesions were resected with diagnosis of metastatic neuroendocrine carcinoma; primary site later identified in the pancreas. (Complements of Robert A. Kane, M.D., Professor of Radiology, Harvard Medical School, Chief, Body and Abdominal Ultrasound Imaging, Beth Israel Deaconess Medical Center, Boston, MA.)

difficult. In that situation, scanning from the opposite surface of the liver may improve visualization. Artifacts in the near field of the image may also obscure lesions near the hepatic surface. If this occurs, the surgeon can immerse the liver in a sterile saline bath, thereby changing the focus zone to better visualize the superficial anatomy. Another difficulty may be encountered when attempting to visualize lesions near a surgical margin. Echogenic foci from air bubbles in the parenchyma after cauterization or radiofrequency ablation may mimic echogenic mucin-containing colorectal metastases. This pitfall can be mitigated by imaging before intervention to accurately determine number, size, and location of lesions (79–81). New advances in intraoperative and interventional ultrasound techniques now allow fusion of ultrasound, CT, and MRI images and electromagnetic tracking to more precisely localize lesions for biopsy and thermal ablation procedures. For example, after initial CT data is entered, information from electromagnetic sensors is applied onto the needle device and the patient can guide the needle track in real time even when the needle is out of the ultrasound imaging plane. This process brings two data sets into spatial alignment. Such techniques have shown improved needle tracking for

interventional procedures and better three-dimensional visualization of tumor and treatment zone during radiofrequency ablation (63,82–84).

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ULTRASOUND FOR HPB DISORDERS 59. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004; 126(5): 1330–6. 60. Torzilli G, Makuuchi M. Intraoperative ultrasonography in liver cancer. Surg Oncol Clin N Am 2003; 12(1): 91–103. 61. Torzilli G, Montorsi M, Donadon M, et al. “Radical but conservative” is the main goal for ultrasonography-guided liver resection: prospective validation of this approach. J Am Coll Surg 2005; 201(4): 517–28. 62. Berber E, Garland AM, Engle KL, et al. Laparoscopic ultrasonography and biopsy of hepatic tumors in 310 patients. Am J Surg 2004; 187(2): 213–8. 63. Kleemann M, Hildebrand P, Birth M, et al. Laparoscopic ultrasound navigation in liver surgery: technical aspects and accuracy. Surg Endosc 2006; 20(5): 726–9. 64. Zacherl J, Scheuba C, Imhof M, et al. Current value of intraoperative sonography during surgery for hepatic neoplasms. World J Surg 2002; 26(5): 550–4. 65. Jakimowicz JJ. Intraoperative ultrasonography in open and laparoscopic abdominal surgery: an overview. Surg Endosc 2006; 20 Suppl 2: S425–35. 66. Kane RA. Intraoperative ultrasonography: history, current state of the art, and future directions. J Ultrasound Med 2004; 23(11): 1407–20. 67. Minagawa M, Makuuchi M, Kubota K, et al. Intraoperative three-dimensional visualization of liver vasculature by ultrasonography. Hepatogastroenterology 2004; 51(59): 1448–50. 68. Sahani DV, Kalva SP, Tanabe KK, et al. Intraoperative US in patients undergoing surgery for liver neoplasms: comparison with MR imaging. Radiology 2004; 232(3): 810–4. 69. Santambrogio R, Opocher E, Ceretti AP, et al. Impact of intraoperative ultrasonography in laparoscopic liver surgery. Surg Endosc 2007; 21(2): 181–8. 70. Shukla PJ, Pandey D, Rao PP, et al. Impact of intra-operative ultrasonography in liver surgery. Indian J Gastroenterol 2005; 24(2): 62–5. 71. Silberhumer GR, Steininger R, Laengle F, et al. Intraoperative ultrasonography in patients who undergo liver resection or transplantation for hepatocellular carcinoma. Surg Technol Int 2004; 12: 145–51.

72. Thaler K, Kanneganti S, Khajanchee Y, et al. The evolving role of staging laparoscopy in the treatment of colorectal hepatic metastasis. Arch Surg 2005; 140(8): 727–34. 73. Cerwenka H. Intraoperative ultrasonography during planned liver resections remains an important surgical tool. Surg Endosc 2008; 22(4): 1137–8. 74. Ellsmere J, Kane R, Grinbaum R, et al.. Intraoperative ultrasonography during planned liver resections: why are we still performing it? Surg Endosc 2007; 21(8): 1280–3. 75. Long EE, Van Dam J, Weinstein S, et al. Computed tomography, endoscopic, laparoscopic, and intra-operative sonography for assessing resectability of pancreatic cancer. Surg Oncol 2005; 14(2): 105–13. 76. Ravi K, Britton BJ. Surgical approach to insulinomas: are pre-operative localization tests necessary? Ann R Coll Surg Engl 2007; 89(3): 212–7. 77. Kruskal JB, Kane RA. Intraoperative US of the liver: techniques and clinical applications. Radiographics 2006; 26(4): 1067–84. 78. Machi J, Oishi AJ, Furumoto NL, et al.. Intraoperative ultrasound. Surg Clin North Am 2004; 84(4): 1085–111. 79. Solbiati L, Ierace T, Tonolini M, et al. Guidance and monitoring of radiofrequency liver tumor ablation with contrast-enhanced ultrasound. Eur J Radiol 2004; 51 Suppl: S19–23. 80. Guimaraes CM, Correia MM, Baldisserotto M, et al. Intraoperative ultrasonography of the liver in patients with abdominal tumors: a new approach. J Ultrasound Med 2004; 23(12): 1549–55. 81. Fan RF, Chai FL, He GX, et al. Laparoscopic radiofrequency ablation of hepatic cavernous hemangioma. A preliminary experience with 27 patients. Surg Endosc 2006; 20(2): 281–5. 82. Wood BJ, Zhang H, Durrani A, et al. Navigation with electromagnetic tracking for interventional radiology procedures: a feasibility study. J Vasc Interv Radiol 2005; 16(4): 493–505. 83. Wood BJ, Locklin JK, Viswanathan A, et al. Technologies for guidance of radiofrequency ablation in the multimodality interventional suite of the future. J Vasc Interv Radiol 2007; 18(1 Pt 1): 9–24. 84. Krucker J, Xu S, Glossop N, et al. Electromagnetic tracking for thermal ablation and biopsy guidance: clinical evaluation of spatial accuracy. J Vasc Interv Radiol 2007; 18(9): 1141–50.

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5

Liver surgery in elderly patients Gerardo Sarno and Graeme J. Poston

introduction The recent increase in the geriatric population in society and increased life span have raised the expectation from surgeons to expand their operative indications to include geriatric patients. In liver surgery, the indications for hepatectomy have been expanded to include patients aged 70 and older, and several studies have demonstrated acceptable long-term survival of elderly patients after such surgery (1,2). In 1937, Brooks reported the results of surgery for 287 patients aged 70 and older. The operative mortality rate was high (19%), and onethird of patients who had abdominal operations died in hospital. Nevertheless, the author emphasized that with the rapid growth of the elderly population, and prolonged life expectancy, surgeons will increasingly be confronted with surgical problems among the elderly and must therefore strive to improve their results by studying physiologic processes in the aged (2,3). In the seven decades since Brooks’ paper, advancements in anesthesiology and intensive care, an increased knowledge of liver physiology, surgical hepatic anatomy, and resection techniques have encouraged hepatic resection in elderly patients, achieving improved surgical outcomes. Because of the high prevalence of liver cancers and aging of the world population, the elderly population considered for liver resection has increased (4,5). Also an effective multidisciplinary approach and better selection of elderly patients leads to reduced age-related perioperative morbidity and mortality (6). Moreover, the definition of “elderly patients” has been better defined so avoiding unnecessary confusion that has generated over the past years. Although advances in minimally invasive ablative techniques have increased the treatment options for patients with malignant hepatobiliary disease, liver resection remains the only treatment demonstrated to offer long-term survival (7–9). Also the past three decades have seen a dramatic decline in the mortality rate after liver resection in selected elderly patients, which is less than 5% in tertiary cancer care referral centers (2,6,10). Colorectal cancer has become a major public health problem that increasingly affects older people (11), and because the liver is the most common site of metastases, the number of elderly so affected is increasing (12). Liver resection is also successfully performed in aged patient suffering primary malignancies such as hepatocellular carcinoma (HCC) with results comparable to those seen in younger people. In this chapter, we highlight the main advances performed in liver surgery, taking into account all the issues that are still a matter of debate for elderly patients with primary or metastatic liver disease.

definition of “elderly patients” The age at which persons become “elderly” depends on social, environmental, and individual factors. Nowadays, after years 46

of arbitrary definition of “elderly,” in liver surgery the common practice is to identify as elderly a patient older than 70 years (6,13–18). This is due to the evidence of a rapid decrease of liver mass and portal blood flow from 70 years onward (17), which may affect liver function. A limited life expectancy in the elderly might argue against extending the indications for hepatectomy in these patients. However, life expectancy for people aged between 80 and 85 years is still 8 years, and 6 years for those over 85 years old. Moreover, the risk of cancer-related death diminishes with increasing age; it is estimated to be 40% for those aged between 50 and 70 years, falling to 10% for those over 90 years old (19). Recently, several studies reported comparable early and long-term results between young and aged patients undergoing liver resection. These studies highlighted that an age limit does not exist to contraindicate liver resection. After a careful evaluation of the operative risk, a similar chance of long-term survival can be offered also to well-selected elderly patients.

age-related liver changes The effects of aging on the human liver have not been clearly determined (20). In general, aging is characterized by a progressive decline of cellular functions and also the liver undergoes physiological changes. Although some recent studies have shown that aging itself does not affect liver function, the amount of hepatic tissue that can be safely removed, and the consequent capacity of liver regeneration are often difficult to be precisely assessed (14). Aging has been shown to be associated with multiple changes in hepatic function, however the clinically relevant biochemical parameters of liver function remain generally normal in the elderly. Thus abnormalities of these parameters should be evaluated for the presence of liver disease (21). As a matter of fact, the liver function seems to be quite well maintained in old age, but numerous age-related changes in hepatic structure have been described (22). However, there have been few comprehensive studies of liver morphology during aging, and most of these have been performed in rodents (20). The most frequently cited morphological change in the human liver is a decrease in size. In elderly men, liver weight declines by about 6.5% and in women it decreases by 14.3% (23), which may be attributable to decreased hepatic blood flow (24–26). The decrease in blood flow is about 45% in subjects over 75 years when compared to those under 40 years (26,27). The classic gross appearance of the liver in older persons is known as “brown atrophy.” The brown color is due to accumulation of lipofuscin (ceroid) within hepatocyte and also associated with major degree of steatosis (21). Alteration in the hepatocyte morphology has been also described (28). It has been reported that the liver in elderly humans has histologically fewer, but larger hepatocytes (29).

LIVER SURGERY IN ELDERLY PATIENTS In addition, hepatic clearance of many drugs is reduced in elderly persons (20,22). Traditional theories have attempted to attribute this observation to age-related reduction in liver mass and blood flow (24–26). More recently, it has been considered attributable to age-related changes in the sinusoidal endothelium and space of Disse, which may restrict the availability of oxygen and other substrates (30). Several other mechanisms have been described, among them the impaired enzymatic activities (31,32) due to oxidative protein damage sustained by free radicals (21). The rate of hepatic steatosis allowing safe liver surgery is not yet clearly defined, although a moderate to severe steatosis (involving more than 30% of the hepatocytes) seems to affect both postoperative morbidity and mortality (33,34). However, although it is impossible to exactly predict this feature before surgery without a liver biopsy specimen, this diagnostic tool should be considered when the presence of steatosis is suggested by imaging and a major resection is planned (14). All of these factors may reduce the functional reserve of the organ and therefore predisposing to postoperative liver failure (35). Thus in preoperative risk estimation prior to hepatic resection, it may be important to take into account the effect of aging upon liver function and structure, in addition to carrying out a qualitative and quantitative evaluation of liver parenchyma.

evaluation of the surgical risk The stress of liver resection may not be well-tolerated in the elderly (4). Liver surgery is not without complication and, before considering liver resection in elderly patients, the increased risks and costs of such surgery must be balanced against the potential improvement of life expectancy. Elderly patients are more likely to have decreased life expectancy with comorbidity, so the decision to perform major hepatectomy has to be carefully balanced against the likelihood of benefit before undertaking such resections. However, most studies record small numbers of cases or have not distinguished between major and minor resections, making interpretation of results difficult (32). Factors other than age should be considered in evaluating surgical risk in the elderly. It is well known that in elderly patients, a preoperative decline in cardiac and pulmonary functions, also combined with cerebrovascular disease can be frequently seen (2,36). To achieve better results in the elderly population, proper patient selection in terms of liver functional reserve and comorbidities conditions is mandatory. This necessitates a close collaboration between surgeons, anesthesiologists, cardiologists, pulmonary physicians, and geriatric physicians (6). A clear preoperative selection process should be undertaken to minimize perioperative risks (37). The majority of elderly may suffer from more than one comorbid disease or for many reasons do not have a good performance status. Cardiovascular and pulmonary disease have a prevalence among the elderly of 20% to 27% and 14%, respectively (38). Moreover, cardiovascular disease and diabetes mellitus were reported to be significant risk factors especially when associated with cirrhosis (39–41).

The most frequently reported causes of death in elderly patients with no underlying liver disease undergoing liver resection are hepatic insufficiency, myocardial infarction, pneumonia, and gastrointestinal bleeding (4,42,43). The evaluation of associated medical disease has been widely investigated focusing in particular on American Society of Anesthesiology (ASA) scores. Advanced ASA grading is known as one of the most reliable predictors of postoperative complications and mortality (4). ASA scores measure major comorbid diseases easily and with minimal expense and are able to predict outcomes after major surgical procedures (4,44). Some authors have considered an ASA score higher than II (i.e., a patient with mild to moderate systemic disease) as a contraindication for surgery for HCC or for major hepatectomies (42,45). In such patients procedures other than surgery (radiofrequency ablation or transarterial chemoembolization) could be considered (16). The exact determination of the ASA score is highly operatordependent and the reported experiences of postoperative deaths for causes unrelated to surgery (i.e., myocardial infarction) (42,46) in subjects with an unremarkable history of cardiac or pulmonary disease suggest that this score should be applied more selectively during the evaluation of elderly patients with underlying liver disease (14). Also in the elderly, the performance status, especially if they were physically active before surgery, has to be taken into account since a significant lower risk of postoperative complications have been recorded (47). Finally, the morphologic characteristics of the underlying liver pathology and number and size of malignancies have to be carefully evaluated prior to performing hepatectomy, aiming to avoid overextensive resections and to minimize intraoperative haemorrhage (6). One other factor having deleterious effects on early and late outcome is intraoperative blood loss. It is well known that hemorrhage and the need for transfusion are closely associated with worse prognoses (48), and this may be even worse in an aged liver.

colorectal liver metastases Colorectal cancer is a major public health problem. In western society, it is expected to increase in incidence by over 30% over the next 20 years because of ever-growing elderly (>70 years of age) population (49,50). The liver is the most common site of metastases and is involved approximately in half of patients (12). By the time of initial diagnosis of colorectal cancer, nearly a quarter of patients will have clinically detectable liver metastases (CRLM), despite increasing patient and clinician awareness of the disease. Of those who undergo apparently successful resection of the primary tumor, nearly half will develop liver metastases, usually within the first three years after colectomy (49,51,52). Currently, over half of all cancers are diagnosed in elderly patients, and 76% of all colorectal cancer patients are diagnosed between 65 and 85 years old (53,54). Encouraging results of surgery for CRLM in the elderly have been reported with 5-year survival rates between 21% and 44% (2,4,55–58). In elderly patients, liver resection for CRLM provides, as with younger patients, the only chance of cure, compared with untreated patients who have a median survival of 4.5 to

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 6.5 months (59,60), or patients treated by chemotherapy alone who have a median survival of 9.2 to 16.5 months (60,61). The only true contraindication for liver resection is the technical nonfeasibility of hepatectomy, independent of the presence of other poor prognostic factors (8,62). In 2005, the reported percentage of patients over 70 years of age undergoing liver resection for CRLM was 26.5%, which was dramatically higher when compared to 6% in the early 1990s (6). This improvement is mostly related to developments in liver surgery since resection for CRLM can be performed with a mortality rate below 5% (6,13), with 5-year survival rates ranging from 28% to 39% (4,7,63,64). Better results can now also be achieved because of the extensive use of chemotherapy in the elderly. Elderly patients can receive protocols similar to younger ones (65). In general, since the introduction of oxaliplatin into chemotherapy regimens, a prolonged survival and a delay of progression of disease has been reported (13,66,67). The main issue of the use of oxaliplatin is hepatotoxicity (sinusoidal congestion and thrombosis), which could also prove to be a problem, especially in case of impaired liver function (13,68). However, no significant postoperative complications have been reported in elderly patients who did or did not receive chemotherapeutic treatment (13). Further evidence for offering hepatic resection to well-selected older patients is the evidence of similar benefit provided by repeat hepatectomy to elderly and younger patients (6). Liver failure is a worrying but thankfully rare complication after liver resection. Some authors have found elderly patients to be more at risk of developing this complication than younger ones, resulting in a more conservative surgical selection policy (69,70). Severe postoperative liver dysfunction may be present in fewer than 10% of elderly patients who have undergone major liver resection for malignancy (71). Postoperative liver failure due to large resections or sepsis is the most frequent cause of death (71). In general, liver resection should be avoided in the presence of bilobar or need for extended resections, especially when associated to concomitant extrahepatic disease and in medically compromised patients. In those cases, the indication for surgery should therefore be very carefully considered only in selected cases (6,72). In view of these findings, it is advisable to consider limited resection whenever possible from the oncologic perspective rather than extended surgery. The existing surgical literature on surgery for CRLM in elderly patients (2,4,55–58) should be interpreted with caution because of the small patient numbers treated at single centers. Often these series describe less than 50 patients. Only recently a large cohort study, collecting data from more than 100 centers, has been published (6). This study highlighted the evidence that hepatic resection for CRLM can be performed safely in elderly patients provided they are fit for such a procedure. The difference in survival between elderly and younger patients could in part be explained by the more limited survival expectancy of the elderly population, also reflecting the higher prevalence of comorbidity.

hepatocellular carcinoma Primary tumors of the liver are among the most common solid tumours worldwide (4).

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The incidence of HCC is the fourth highest among all tumors (18), the number of patients affected has been increasing (73), and the age for detection of HCC is increasing in both men and women (17). Clarification of the optimal treatment strategy for extremely elderly patients with HCC has thus become an urgent necessity. Management of HCC with other modalities, such as percutaneous ethanol injection therapy (74), microwave therapy (75), and percutaneous radiofrequency ablation (RFA), may be an acceptable alternative to hepatic resection in the elderly, but the best treatment for patients in this age group remains controversial. Liver transplantation is theoretically the optimal treatment for HCC because it is the only method of treating both the tumor and the underlying liver cirrhosis. Replacement of the diseased liver is not only the best oncological treatment, but also the best method for preventing the development of new tumors and avoiding the life-threatening complications of cirrhosis. In patients with HCC and cirrhosis, transplantation based on the Milan criteria achieves a better outcome than hepatic resection with respect to both survival and disease recurrence (76–79). However, the limited availability of donor organs makes liver transplantation problematic (80,81) and as a consequence patients older than 70 years are excluded from transplantation programs (82). With advances in surgical treatment for HCC, hepatectomy for elderly HCC patients has become safer. There have been many reports of hepatectomies for elderly HCC patients (83–85). But because of the unclear data on long-term survival after local ablation of HCC, especially for large tumors, liver resection remains the preferred treatment, with 5-year survival rates ranging from 40% to 50% (86,87). Resection is considered to be a reasonable first-line treatment for patients with small tumors and underlying chronic liver disease, which may offer potential cure (80). Recent studies have shown the safety and feasibility of hepatectomy for HCC patients older than 70 years of age (88,89). It has been demonstrated that long-term outcome after resection of HCC is similar in older and younger patients (1,10,83,85). No operative mortality has been reported in a series of carefully selected octogenarians who underwent liver resection for HCC (45). Recent studies have identified some differences in the clinical pathological features of HCC between elderly and younger patients. Risk factors for HCC seem to be different in elderly people. A significant lower positive rate for HBsAg has been described among the elderly (88,90). Most HBV-related HCCs develop in patients in their early fifties. This may be the reason why there are few elderly HCC patients with HBV infection. On the other hand, HCV infection constitutes a major part of the etiology in elderly patients with HCC (17,91). Factors other than viral hepatitis infection, such as alcohol or genetic mutations, may contribute to the development of HCC in some elderly patients (88). Several studies have shown that elderly patients with HCC had good liver function and that only a small percentage of elderly patients with HCC had liver cirrhosis (90,92). It is possible that a large proportion of patients with cirrhosis and HCC die before reaching the age of 70 years, and those who survive have well-preserved hepatic function (93).

LIVER SURGERY IN ELDERLY PATIENTS Some studies have demonstrated a close relation between HCC and alcohol abuse, that is, individuals who abuse alcohol have a significantly higher relative risk of developing HCC than those who do not. Although data about the role of alcohol in the development of HCC are inconsistent, the mechanisms that have been proposed include the induction of tumorigenesis secondary to alcoholic cirrhosis, a direct tumorinitiating and promoting effect of ethanol through induction of various enzymes, alterations of DNA repair, dietary deficiencies, immune suppression, and depletion of hepatic antitumor factors (17). There is no general agreement about the relation between alcohol abuse and postoperative recurrence of HCC or survival, but there have been a few reports of an interaction between alcohol abuse and postoperative recurrence (94). The mechanism by which alcohol abuse is related to HCC recurrence and a lower survival rate remains to be elucidated. However, at least two possible reasons can be suggested for the higher postoperative recurrence rate in patients with alcohol abuse. First, these patients may be more susceptible to developing new primary tumors after hepatectomy because chronic alcohol abuse enhances hepatocarcinogenesis. Second, they might have a higher incidence of unrecognized intrahepatic metastases at the time of initial hepatectomy because chronic alcohol abuse seems to be related to the aggressiveness of HCC, including the rate of metastasis (17). Heavy alcohol abuse and HCV infection are two leading causes of cirrhosis (91). Preoperative severe liver dysfunction carried a high risk for postoperative hepatic failure, and cirrhosis is associated with increased postoperative mortality in general (71). Advanced age is still related to poor early outcome (42), with operative mortality rates of up to 42%, attributable to liver failure in patients with cirrhosis (95). The significance of AFP has still not been well-defined. Some authors found a lower frequency of raised AFP level, compared with younger patients (17). Various other predictors have been reported to be risk factors for poor prognosis of postoperative HCC patients, such as liver cirrhosis, Child–Pugh grading, tumor size, satellite nodules, and vascular invasion (18). Some authors found a significantly higher frequency of tumor encapsulation in elderly HCC patients when comparing the histological characteristics of the resected tumors. Tumor encapsulation has been reported as a favorable prognostic factor for HCC (96). Also a higher frequency of tumor encapsulation might be an indicator for less malignant degree of the elderly patients with HCC (18). Tumor diameter should not be considered a prognostic factor. Patients over 70 years of age with large tumors should be scheduled for surgery with expected favorable results (85). For the elderly patients with HCC, predictors of postoperative survival are not well known. So far, only a few papers revealed differing findings by multivariate analysis. Hanazaki et al. (83) reported that liver cirrhosis and vascular invasion were independent prognostic factors for the survival of postresectional elderly HCC patients. Zhou et al. (97) found that Child–Pugh grading, portal vein tumor thrombus, and

Edmondson–Steiner grading were prognostic factors. However, other authors failed to yield similar results. Postoperative recurrence of HCC is the most important factor affecting the survival of patients who underwent radical resection. Poor results in some series can be explained by a high proportion of patients with cirrhosis. If the amount of resected nontumors liver parenchyma is reduced, resection of the primary liver tumor is justified despite narrow surgical resection margins. A significant reduction in postoperative mortality, as well as morbidity can be achieved by this approach. When postoperative complications occur, they do not correlate with the amount of liver resected but with preoperative liver function and intraoperative haemorrhage (71). However, the prognosis following resection for HCC remains unsatisfactory because of the high incidence of recurrence in the liver remnant; the cumulative 5-year recurrence rates after curative hepatectomy are <70% (98). Therefore appropriate management of recurrent HCC is important to improve longterm outcomes after hepatectomy. Many studies have supported favorable results after repeat hepatectomy for recurrent HCC (89). Repeat hepatectomy is the first choice for patients with preserved liver function (18). Even for the elderly patients with recurrent HCC, repeated hepatectomy has been recommended to achieve better survival if these tumors were resectable (83). Patients with recurrent HCC are older than those with primary HCC. Repeat hepatectomy for recurrent HCC is safe even for patients aged more than 75 years, especially when they underwent limited hepatectomies (89). Recently, an alternative strategy of primary hepatectomy followed by liver transplantation for recurrent HCC (salvage liver transplantation) has been proposed (29). Percutaneous ablation therapy may also be a preferable therapeutic modality for small-sized or small-volume HCC; however, there have been only a few studies on ablation therapies for recurrent HCC, and the overall 3-year survival rate after ablation therapy was 43% to 48%, which is less than the survival rates obtained after repeat hepatectomies (>70%) in certain centers (89). Not only younger patients but also elderly patients with early-stage HCC might benefit from this modality, which is less invasive than hepatectomy. Selection criteria for elderly patients with recurrent HCC who are good candidates for repeat hepatectomy remain to be determined, and the age limitations for such an aggressive operative approach are not clear at present. Nevertheless, advanced age by itself does not have an adverse effect on operative outcomes, including postoperative complications and long-term prognosis, after repeat hepatectomies on patients with recurrent HCC. Repeat hepatectomy may therefore be justified for treating recurrent HCC in selected elderly patients. In conclusion, both the short-term and long-term outcome of resection of HCC seems similar to the younger in carefully selected elderly patients, even though elderly have a higher incidence of associated diseases. HCC in the elderly is less HBVassociated, less advanced, and less aggressive. Elderly patients with preoperative alcohol abuse should be followed up very closely, even after R0 surgery, since alcohol abuse is strongly correlated with postoperative recurrence and poor survival.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Hepatectomy is safe for the elderly HCC patients without preoperative comorbidities or with well-controlled preoperative comorbidities.

financial cost In the current climate of scarce health care resources, treatment for elderly patients has been under close scrutiny. Several studies have shown that elderly patients have benefited from liver resection for malignancy with results comparable to those younger than 70 years of age. The use of health care resources in terms of intensive care unit and in-hospital stays is no different than in the younger population, and some of this costsaving can be attributed to better support in terms of anesthesia and community nursing (32). Therefore careful selection of patients using the ASA grade and meticulous surgical technique are essential to achieve better outcomes after hepatic resection in patients over the age of 70 years.

conclusions Age alone should not be considered a contraindication for liver resection: hepatectomy is safe, effective, and a curative therapy in the elderly. Major hepatectomies are the feasible procedure in patients older than 70 years who have preserved liver function and controllable medical conditions, yielding close to 0% operative mortality and low morbidity rates in specialized tertiary centers.

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LIVER SURGERY IN ELDERLY PATIENTS 44. Cullen DJ, Apolone G, Greenfield S, Guadagnoli E, Cleary P. ASA Physical Status and age predict morbidity after three surgical procedures. Ann Surg 1994; 220(1): 3–9. 45. Wu CC, Chen JT, Ho WL, et al. Liver resection for hepatocellular carcinoma in octogenarians. Surgery 1999; 125(3): 332–8. 46. Yanaga K, Kanematsu T, Takenaka K, et al. Hepatic resection for hepatocellular carcinoma in elderly patients. Am J Surg 1988; 155(2): 238–41. 47. Seymour DG, Pringle R. Post-operative complications in the elderly surgical patient. Gerontology 1983; 29(4): 262–70. 48. 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(4): 698–708; discussion 709–10. 49. Poston GJ. Surgical strategies for colorectal liver metastases. Surg Oncol 2004; 13(2–3): 125–36. 50. Primrose JN. Treatment of colorectal metastases: surgery, cryotherapy, or radiofrequency ablation. Gut 2002; 50(1): 1–5. 51. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet 1994; 343(8910): 1405–10. 52. Sugarbaker PH. Surgical decision making for large bowel cancer metastatic to the liver. Radiology 1990; 174(3 Pt 1): 621–6. 53. Quaglia A, Capocaccia R, Micheli A, Carrani E, Vercelli M. A wide difference in cancer survival between middle aged and elderly patients in Europe. Int J Cancer 2007; 120(10): 2196–201. 54. Petrowsky H, Clavien PA. Should we deny surgery for malignant hepatopancreatico-biliary tumors to elderly patients? World J Surg 2005; 29(9): 1093–100. 55. Zacharias T, Jaeck D, Oussoultzoglou E, Bachellier P, Weber JC. First and repeat resection of colorectal liver metastases in elderly patients. Ann Surg 2004; 240(5): 85 8–65. 56. Brunken C, Rogiers X, Malago M, et al. [Is resection of colorectal liver metastases still justified in very elderly patients?]. Chirurg. 1998; 69(12): 1334–9. 57. Zieren HU, Muller JM, Zieren J. Resection of colorectal liver metastases in old patients. Hepatogastroenterology 1994; 41(1): 34–7. 58. Figueras J, Ramos E, Lopez-Ben S, et al. Surgical treatment of liver metastases from colorectal carcinoma in elderly patients. When is it worthwhile? Clin Transl Oncol 2007; 9(6): 392–400. 59. Moreaux J. [Hepatic metastases of colorectal cancer. Natural history and surgical treatment by excision]. Chirurgie 1985; 111(7): 528–37. 60. Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998; 352(9138): 1413–8. 61. Scheithauer W, Kornek GV, Raderer M, et al. Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as firstline treatment in advanced colorectal cancer. J Clin Oncol 2002; 20(1): 165–72. 62. Minagawa M, Makuuchi M, Torzilli G, et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results. Ann Surg 2000; 231(4): 487–99. 63. Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer 1996; 77(7): 1254–62. 64. Iwatsuki S, Dvorchik I, Madariaga JR, et al. Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J Am Coll Surg 1999; 189(3): 291–9. 65. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006; 24(25): 4085–91. 66. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22(1): 23–30. 67. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18(16): 2938–47.

68. Pawlik TM, Choti MA. Surgical therapy for colorectal metastases to the liver. J Gastrointest Surg 2007; 11(8): 1057–77. 69. Kimura F, Miyazaki M, Suwa T, Kakizaki S. Reduction of hepatic acute phase response after partial hepatectomy in elderly patients. Res Exp Med (Berl) 1996; 196(5): 281–90. 70. Aalami OO, Fang TD, Song HM, Nacamuli RP. Physiological features of aging persons. Arch Surg 2003; 138(10): 1068–76. 71. Koperna T, Kisser M, Schulz F. Hepatic resection in the elderly. World J Surg 1998; 22(4): 406–12. 72. Wanebo HJ, Chu QD, Vezeridis MP, Soderberg C. Patient selection for hepatic resection of colorectal metastases. Arch Surg 1996; 131(3): 322–9. 73. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004; 127(5 Suppl 1): S27–34. 74. Kotoh K, Sakai H, Sakamoto S, et al. The effect of percutaneous ethanol injection therapy on small solitary hepatocellular carcinoma is comparable to that of hepatectomy. Am J Gastroenterol. 1994; 89(2): 194–8. 75. Seki T, Wakabayashi M, Nakagawa T, et al. Ultrasonically guided percutaneous microwave coagulation therapy for small hepatocellular carcinoma. Cancer 1994; 74(3): 817–25. 76. Figueras J, Jaurrieta E, Valls C, et al. Resection or transplantation for hepatocellular carcinoma in cirrhotic patients: outcomes based on indicated treatment strategy. J Am Coll Surg 2000; 190(5): 580–7. 77. Michel J, Suc B, Montpeyroux F, et al. Liver resection or transplantation for hepatocellular carcinoma? Retrospective analysis of 215 patients with cirrhosis. J Hepatol 1997; 26(6): 1274–80. 78. Sarasin FP, Giostra E, Mentha G, Hadengue A. Partial hepatectomy or orthotopic liver transplantation for the treatment of resectable hepatocellular carcinoma? A cost-effectiveness perspective. Hepatology 1998; 28(2): 436–42. 79. 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(11): 693–9. 80. Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 2002; 122(6): 1609–19. 81. Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis 1999; 19(3): 311–22. 82. Figueras J, Ibanez L, Ramos E, et al. Selection criteria for liver transplantation in early-stage hepatocellular carcinoma with cirrhosis: results of a multicenter study. Liver Transpl 2001; 7(10): 877–83. 83. Hanazaki K, Kajikawa S, Shimozawa N, et al. Hepatic resection for hepatocellular carcinoma in the elderly. J Am Coll Surg 2001; 192(1): 38–46. 84. Yeh CN, Lee WC, Jeng LB, Chen MF. Hepatic resection for hepatocellular carcinoma in elderly patients. Hepatogastroenterology 2004; 51(55): 219–23. 85. Ferrero A, Vigano L, Polastri R, et al. Hepatectomy as treatment of choice for hepatocellular carcinoma in elderly cirrhotic patients. World J Surg 2005; 29(9): 1101–5. 86. Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 2000; 32(6): 1224–9. 87. Vivarelli M, Guglielmi A, Ruzzenente A, et al. Surgical resection versus percutaneous radiofrequency ablation in the treatment of hepatocellular carcinoma on cirrhotic liver. Ann Surg 2004; 240(1): 102–7. 88. Oishi K, Itamoto T, Kobayashi T, et al. Hepatectomy for hepatocellular carcinoma in elderly patients aged 75 years or more. J Gastrointest Surg 2009; 13(4): 695–701. 89. Tsujita E, Utsunomiya T, Ohta M, et al. Outcome of repeat hepatectomy in patients with hepatocellular carcinoma aged 75 years and older. Surgery 2009; 147: 696–703. 90. Tsukioka G, Kakizaki S, Sohara N, et al. Hepatocellular carcinoma in extremely elderly patients: an analysis of clinical characteristics, prognosis and patient survival. World J Gastroenterol 2006; 12(1): 48–53. 91. Dohmen K, Shirahama M, Shigematsu H, Irie K, Ishibashi H. Optimal treatment strategy for elderly patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2004; 19(8): 859–65. 92. Nakamuta M, Morizono S, Kohjima M, Kotoh K, Enjoji M. Baseline characterization of patients aged 70 years and above with hepatocellular carcinoma. World J Gastroenterol 2005; 11(47): 7512–4.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 93. Namieno T, Kawata A, Sato N, Kondo Y, Uchino J. Age-related, different clinicopathologic features of hepatocellular carcinoma patients. Ann Surg 1995; 221(3): 308–14. 94. Kubo S, Tamori A, Nishiguchi S, et al. Effect of alcohol abuse on polyamine metabolism in hepatocellular carcinoma and noncancerous hepatic tissue. Surgery 1998; 123(2): 205–11. 95. Yamamoto K, Takenaka K, Matsumata T, et al. Right hepatic lobectomy in elderly patients with hepatocellular carcinoma. Hepatogastroenterology. 1997; 44(14): 514–8.

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96. Nagao T, Inoue S, Goto S, et al. Hepatic resection for hepatocellular carcinoma. Clinical features and long-term prognosis. Ann Surg 1987; 205(1): 33–40. 97. Zhou L, Rui JA, Wang SB, et al. Clinicopathological features, post-surgical survival and prognostic indicators of elderly patients with hepatocellular carcinoma. Eur J Surg Oncol 2006; 32(7): 767–72. 98. Sugimachi K, Maehara S, Tanaka S, Shimada M. Repeat hepatectomy is the most useful treatment for recurrent hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 2001; 8(5): 410–6.

6

Small solitary hepatic metastases: when and how? David L. Bartlett and Yuman Fong

introduction The management of patients with small hepatic metastases from colorectal cancer and other histologies requires the consideration of many diverse patient- and tumor-related factors. These factors include the natural history of the tumor type, the expected cure rate after surgical treatment, effectiveness of alternative treatments, and the morbidity of surgical resection. In general, the indications for any major surgical procedure include the potential for cure, prolongation of survival, and palliation of symptoms. For metastatic tumors to the liver in selected cases, the cure rate may be over 50% for colorectal cancer (1), but will be exceedingly rare for other histologies such as gastric cases, and melanoma and sarcoma. Small metastases to the liver generally do not cause symptoms (except for hormone secreting neuroendocrine tumors) and, therefore, palliation of symptoms is not a common indication for management of these lesions. Nevertheless, many issues remain unresolved. Does resection of a small solitary hepatic metastasis prolong survival in cases where the patient is likely to develop widespread metastases in the future? Is there any harm in allowing a tumor to go untreated for a period of time, knowing that with close follow-up the resection option may still be possible in the future? Do metastases metastasize such that a delay in management may obviate the curative option? Unfortunately, all of these difficult issues are only addressed by sparse data in the literature. The risk and extent of the surgical procedure plays a significant role in the decision making for management of small hepatic metastases. It is more reasonable to excise an enlarged subcutaneous lymph node for metastatic cancer than it is to perform a hepatic lobectomy when the chance of benefit is low in both cases. As other less invasive ablative options become routine therapy, it may be reasonable to consider these options in cases where surgical resection is unreasonable. These alternative options include percutaneous approaches at ablation such as radiofrequency ablation and percutaneous alcohol injection (2). Laparoscopic procedures may also be an alternative for the management of small hepatic metastases, including laparoscopic resection of tumors and laparoscopically directed ablation such as cryotherapy. If the risks, discomfort, and hospital stay are truly minimal, then it becomes reasonable to consider local treatment of these lesions, even with a small chance of overall benefit to the patient. This chapter will provide an overview of the data on survival benefit after resection of hepatic metastases and the techniques of surgical management. A brief discussion of minimally invasive and percutaneous procedures for management of small solitary hepatic metastases will follow. In addition, a discussion of the role for adjuvant therapy after resection or ablation of the hepatic metastases will be included.

survival results for hepatic metastasectomy While the purpose of this chapter is not to provide an in-depth review of the results of hepatic metastasectomy, a general sense of expected cure rate and prolongation of survival after hepatic metastasectomy for various histologies is required in order to make an informed decision regarding resection of small hepatic metastases. Colorectal Metastases Colorectal cancer, compared to other histologies, is more likely to present as disease isolated to the liver. The natural history of unresected solitary hepatic metastases from colorectal cancer was described by Wagner et al. where 39 patients with solitary metastases did not undergo therapy and the median survival was 24 months (3). Wood et al. described 15 patients with solitary hepatic metastases left untreated with a mean survival of 17 months (4). There is a considerable body of literature on the results of hepatic metastasectomy for colorectal cancer. The overall 5-year survival ranges from 22% to 39% (5). In many studies, low number and small size are associated with improved prognosis such that a small solitary metastasis from colorectal cancer has a greater than 50% of 5-year survival. Nuzzo et al. report 56% actuarial 5-year survival in patients with solitary metachronous hepatic metastases from colorectal cancer less than 4 cm in size (1). Table 6.1 reviews the results of the largest series for solitary metastasectomy. After resection of solitary metastases from colorectal cancer, 5-year survival ranges from 30% to 47% (6–10). These reports do not consider the small solitary metastases separately from the entire group of solitary metastases. The size of the lesion is expected to affect prognosis and, therefore, the actual results for small solitary hepatic metastases may be even better than the numbers reported in Table 6.1. Liver resection for hepatic colorectal metastases is, therefore, safe and effective, and may be curative. Neuroendocrine Metastases For cancers of other than colorectal origin, patients with hepatic metastases from neuroendocrine tumors have been thought to be the most likely to benefit from surgical resection. Certainly, if the tumor were symptomatic for either hormonal or physical reasons, resection should be considered even though cure is unlikely. Because of the indolent nature of these tumors, durable palliation can be achieved with cytoreduction. Fiveyear survival rates for untreated hepatic metastases from neuroendocrine tumors have ranged from 13% to 54% (11–15). In patients with no symptoms, the case for surgical resection, or any treatment for that matter, is less clear. We and others (16) have adopted a very aggressive approach even for asymptomatic tumors based only on retrospective data.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Chen et al. compared liver resection for neuroendocrine tumors with a retrospectively matched cohort who did not undergo resection, demonstrating improved survival after resection (17). The general recommendation is for aggressive surgical management of neuroendocrine metastasis (18). We acknowledge that the variable growth rate and sometimes indolent nature of these tumors make firm conclusions based on retrospective data without a nontreated control group suspect. The rarity of these tumors, however, does not allow for random assignment trials. Certainly for small hepatic metastases, aggressive surgical resection is indicated, while it is acknowledged that definitive proof of its benefit may never be achieved. Noncolorectal, Nonneuroendocrine Metastases For histologies other than colorectal or neuroendocrine cancer, the utility of hepatic metastasectomy is not as obvious. For these tumors, the liver is rarely the sole site of disease; liver metastases are rarely the ultimate cause of death, nor does it contribute significantly to symptoms prior to death. Nevertheless, selected cases of disease isolated to the liver after a long disease-free interval raise the possibility of a single site of metastatic disease that could be cured with surgical therapy.

Table 6.1 Survival After Hepatic Resection for a Solitary Colorectal Metastasis

Author

Date

N

Actuarial 5-year survival (%)

Hughes et al. (6) Rosen et al. (7) Scheele et al. (8) Taylor et al. (9) Fong et al. (10)

1988 1992 1995 1997 1997

509 185 180 A077 240

37 30 36a 47 47

Median survival (months) – – 45 54 –

a

Actual 5-year survival.

Table 6.2 reviews the largest series for hepatic metastasectomy with a variety of histologies. Breast cancer Many reviews have been published on hepatic metastasectomy for breast cancer. Due to the high incidence of breast cancer and the frequency of liver metastases for this histology, the first site of metastases is frequently observed to be hepatic. In highly selected patients, favorable results of section of such liver metastases have been reported. Raab et al. reported a 5-year survival of 18.4% in 34 patients after hepatic metastasectomy for breast cancer (19). Elias et al. reported 9% 5-year survival after resection in 21 patients (20). The relatively few patients in these reports compared to the total number of breast cancer patients in each institution during the study period reflect the degree of patient selection for surgery. The survival rates reported are actuarial survival rates and the actual cure rate is much lower. At most, hepatic metastasectomy for breast cancer should be considered cytoreductive. It may delay the development of symptoms and prolong survival, but it has very little chance of curing the disease. Sarcoma Similarly, hepatic resection for sarcoma metastases may be associated with long-term survival in highly selected patients, but it is unlikely to result in cure. In a series of 14 hepatic resections for metastatic sarcoma, recurrence was found in all patients during follow-up, and 11 of 14 failed in the liver (21). The median survival in that series was 30 months. Melanoma Metastatic cutaneous melanoma to the liver has been resected with long-term survival, but these tumors also ultimately recur (22). The erratic behavior of melanoma makes conclusions regarding the benefit of hepatic metastasectomy difficult.

Table 6.2 Survival Following Hepatic Metastasectomy for Noncolorectal Histologies Author Chen et al. (17) Que et al. (57) Harrison et al. (26) Jaques et al. (21) Harrison et al.26 Elias et al. (20) Raab et al.19 Ochiai et al. (24) Bines et al. (25) Harrison et al. (26) a

Histology Neuroendocrine Neuroendocrine Genitourinaryb Sarcoma Breast/melanoma/sarcoma Breast Breast Gastric Gastric Gastrointestinale

4-year survival. Includes renal (5), testicular (9), adrenal (7), ovary (7), uterine (4), cervix (2). 4 of 21 actual 5-year survivors. d 1 of 7 actual 5-year survivors. e Includes gastric (5), pancreatic (2). NR: not reached. b c

54

N 15 74 34 14 41 21 34 21 A07 A07

Actuarial 5-year survival (%)

Median survival (months)

73 73a 60 A00 26 A09 18 19c 14d A00

NR NR NR 30 32 26 27 18 15 25

SMALL SOLITARY HEPATIC METASTASES: WHEN AND HOW? Only in highly selected cases is it appropriate to consider resection of cutaneous melanoma. Ocular melanoma, on the other hand, has a unique natural history. Ocular melanoma preferentially metastasizes to the liver and the majority of patients die of liver failure as a direct result of tumor progression. Anecdotal reports exist of long-term survival after metastasectomy for ocular melanoma (23), although these tumors are also almost always multifocal and resection of what appears to be a solitary metastasis is most often associated with liver recurrence. These hepatic metastases may show up many years after the treatment of the primary tumor. A long disease-free interval reflects a slow tumor doubling time, and suggests resection may achieve durable palliation. Usually in this disease, however, the appearance of a solitary liver metastasis is merely a precursor of the later appearance of multiple metastases. Other gastrointestinal cancers In general, hepatic metastasectomy for gastrointestinal primaries other than colorectal is not associated with prolonged survival. For tumors such as esophageal, gastric, small bowel, and pancreatic cancer, the pattern of spread includes regional lymph nodes, the peritoneal cavity, and lung metastases in addition to liver metastases. It is unlikely that these patients will die of liver failure as a result of progression of hepatic metastases, but instead, suffer other gastrointestinal sequelae from extrahepatic tumor progression. A major operative procedure can be of significant detriment to these patients with aggressive cancers where survival is expected to be of the order of weeks to months. Nevertheless, even for these tumors, selected cases exist where one might consider resection, and the literature contains anecdotal reports of long-term survivors after liver resection (24,25). Genitourinary tumors For noncolorectal, nonneuroendocrine tumors, metastases from genitourinary primaries seem to have the best prognosis following hepatic metastasectomy. In a recent review by Harrison et al., 34 patients underwent hepatic resections for genitourinary primaries (including testicular, adrenal, ovary, renal, uterine, and cervix) with a 5-year actuarial survival of 60% (26). Other investigators have reported prolonged survival after resection for renal cell cancer (27) and adrenal cancer (28). While the natural history of genitourinary tumors contributes to these remarkable results, it does suggest a survival benefit to resection in selective cases.

do metastases metastasize? For small solitary hepatic metastases, where many months of growth would still not preclude resection, the question is whether a waiting period would allow for further spread of the tumor from the metastatic deposit itself. If metastatic tumors were unable to further metastasize, waiting for the first sign of progression prior to initiating treatment and allowing other metastatic disease to declare itself would seem a reasonable approach. If, however, metastases are able to spread during that waiting period, then the chance of potential cure may be adversely affected by the delay in

definitive treatment. Unfortunately, it is clear that metastatic tumors do have the potential to metastasize themselves, and this must be considered when recommending observation alone. Experimental evidence suggests that cells from spontaneous metastases are more likely to metastasize than cells populating the parent neoplasm (29). Clinically, the most obvious examples of metastases from metastatic colorectal cancer deposits are in the cases of perihepatic lymph node metastases (30) and satellite-tumor formation (31). Published data would indicate that metastases to periportal lymph nodes occur in 10% to 20% of cases of hepatic colorectal metastases (30). The presence of lymph node metastases portends a poor prognosis. Therefore, excision of liver tumors before they spread to regional lymph nodes would be advantageous. A recent paper examined the incidence of satellite micrometastasis in colorectal liver metastases by careful histologic examination of resection specimens and found that 56% of specimens had micrometastases as far as 3.8 cm away from the tumor being resected (31). In some cases, these satellites could be traced to the original metastasis by a trail of cells, suggesting spread from the original metastasis. As discussed previously, the presence of satellitosis is an important independent poor prognostic factor. It may be that a delay in resection allows for the development of satellitosis, which negatively impacts on prognosis. On the other hand, the presence of satellitosis may be an indicator of biologic aggressiveness, which portends a poor prognosis regardless of when the tumor is resected.

patient selection Colorectal Metastases In order to decide when surgical resection is reasonable for small solitary hepatic metastases, it is important to review prognostic factors that are independent of size and number, which may influence the decision regarding management of these tumors. Many studies have examined data on prognostic factors for outcome after hepatic resection for colorectal metastases. The time to development of liver tumor after resection of the primary, pathologic margin, stage of the primary tumor, tumor number, carcinoembryonic antigen levels, satellitosis, extrahepatic disease, and positive surgical margin have all been shown to predict survival after hepatic resection for colorectal metastases independent of size (7,8,10,32). Extrahepatic disease is considered a contraindication to hepatic resection. Even the presence of perihepatic lymph nodes portends a poor prognosis and generally is felt to be a contraindication to resection. Particularly in the cases of small solitary hepatic metastases with extrahepatic disease, there would be no advantage to resection or ablation of the liver tumor because systemic disease will likely be the ultimate cause of death regardless of what is done with the liver metastases. Of the other various factors that are prognostic for outcome, surgical margin, and satellitosis are the least useful in patient selection. No one would subject a patient to surgical resection expecting a positive margin. Satellitosis cannot be easily assessed preoperatively and therefore is a poor selection criterion for surgery.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS We analyzed our recent data on factors prognostic for outcome after resection of hepatic metastases from colorectal cancer (33). In data derived from our last 1001 liver resections for this disease, the seven factors found to be independent predictors of poor long-term outcome were 1. node positive outcome, 2. presentation of liver disease within 12 months of the primary cancer, 3. CEA > 200 ng/dl, 4. number of liver tumors > 1, 5. size > 5 cm, 6. positive margin, and 7. extrahepatic disease. From this, we formulated a clinical risk score (CRS) based on the first five of these factors for use in patient selection for surgery and for stratification of patients for clinical studies. Using one point for each criterion, a summed score of 0–2 puts patients in a low-risk group and is a strong indication for hepatectomy. In the patients with small tumors, a maximum score of 4 is possible. The 5-year survival of patients with small tumors and 0–2 points on the CRS is 47% and the median survival is 56 months (33). Patients with a score of 3–4 are in a high-risk group, with a median survival of 32 months and 5-year survival of 24% (Fig. 6.1). In these high-risk patients, a period of observation with no therapy or systemic chemotherapy allowing for the extent of metastases to declare themselves is reasonable. Improved imaging techniques such as fluorodeoxyglucose positron emission tomography (FDG PET) scanning should be considered and may help discover extrahepatic disease noninvasively in these patients at high risk for additional cancer (34). Finally, these patients should be considered for clinical studies of aggressive adjuvant chemotherapy after liver resection. 1.0

Survival

0.8

0.6

0.4

0.2

0.0 0

12

24

36

48

60

Months Figure 6.1 Prediction of long-term outcome for small (<3 cm) (N = 293) metastatic deposits based on clinical risk score (CRS). CRS is based on the following five criteria: (1) node positive primary cancer, (2) disease-free interval <12 months, (3) number of liver tumors >1, (4) size of liver tumor >5 cm and (5) CEA > 200 ng/dl. For score = 0–2 (N = 236) (open box), the median survival was 56 months and the 5-year survival 47%. For score = 3–4 (N = 57) (filled triangles), the median survival was 32 months and the 5-year survival 24%.

56

Neuroendocrine Tumors Patients with symptomatic neuroendocrine tumors should be considered for resection or ablation. For the small tumor, symptoms are most likely derived from hormonal secretion by the tumors, and such hormone levels will also provide a marker for effectiveness of the ablation or resection. For asymptomatic tumors, a period of observation to allow assessment of the pace and aggressiveness of the tumors is reasonable when the tumors are small. At the first signs of progression, resection or ablation should be considered. Noncolorectal, Nonneuroendocrine Tumors Harrison et al. defined prognostic factors involved in the resection of noncolorectal, nonneuroendocrine hepatic metastases (26). In this study, 96 patients underwent liver resection. The prognostic factors of significance on multivariate analysis included the disease-free interval (>36 months), curative resection (versus palliative incomplete resection), and primary tumor type. Their conclusions would suggest that regardless of histology, with a long disease-free interval patients may benefit from surgical resection.

resection techniques For small solitary metastases to the liver, the goal of resection is to completely excise the tumor while preserving the maximum normal hepatic parenchyma. Preserving parenchyma facilitates postoperative recovery and also provides flexibility for further resections should intrahepatic recurrences occur (35). Small surface-oriented metastases can be excised using a nonanatomic wedge resection, whereas deeper lesions require formal segmentectomies or sectorectomies. A goal of at least a 1 cm margin is reasonable (36). The use of intraoperative ultrasound is important to rule out other small hepatic metastases, which may not be evident on preoperative scans and in defining the intersegmental planes for designing the approach to segmentectomy. Even for wedge resections, ultrasound is beneficial in defining the vascular anatomy around the lesion, which may help minimize blood loss. Wedge Resections Wedge resections must be performed meticulously to avoid inadvertently leaving a positive margin. Large chromic liver sutures can be placed and used for retraction during dissection. The parenchymal dissection should be performed along the lines used for other forms of liver resection. We prefer the Kelly clamp technique where the clamp is used to crush the normal parenchyma, exposing vessels that are then clipped, tied, suture ligated, or stapled using a vascular stapling device (37). The Pringle maneuver is used intermittently for 5 minutes at a time followed by reperfusion of the parenchyma, during which time the argon beam coagulator is used to coagulate small bleeding vessels on the surface. This technique is superior to the simple use of electrocautery for the dissection, which is often attempted for what seems to be routine wedge resections. The char effect of the electrocautery prevents adequate visualization of the anatomy, making it quite easy to stray into large vessels or into the tumor.

SMALL SOLITARY HEPATIC METASTASES: WHEN AND HOW? The most difficult margin in performing a wedge resection is the deep margin of dissection. Using intraoperative ultrasound, the depth of dissection should be measured prior to the initiation of parenchymal dissection, including at least a 1-cm margin deep to the tumor. The dissection should be carried down perpendicular to the liver surface to the predetermined depth. At this point, the tumor can be lifted up and dissection can proceed horizontally across the base of the wedge. The tendency to resect with a “V-shaped approach” is more likely to be complicated by a positive deep margin. At the end of the dissection, the Pringle maneuver is removed and the argon beam coagulator is used to control bleeding vessels. Careful examination is made for any evidence of a bile leak, which is controlled with suture ligature. For larger lesions where it is especially difficult to achieve the deep margin safely, a cryoassisted wedge resection can be performed (38). The cryotherapy probe is inserted into the tumor and freezing is begun with real time ultrasound imaging. When the zone of freezing is confirmed by ultrasound to be at least 1 cm beyond the tumor, wedge resection is performed using the freeze margin as the margin of resection. The cryotherapy probe makes a ready retracting device and the parenchyma is usually easy to dissect at the margin of the ice-ball. Freezing must continue intermittently during dissection to ensure that the ice-ball does not retract and expose the tumor.

clamped at its junction with the vena cava during parenchymal transection to further minimize blood loss. When the solitary metastases lie near an intersegmental plane, two segments can be removed. This is most easily done as a formal sector such as the left lateral sectorectomy (segments II and III) and right posterior sectorectomy (segments VI and VII). The caudate lobe (segment I) can be resected as an isolated segmentectomy when the tumor is confined to this lobe (42). This requires a more extensive dissection, including complete division of all the perforating caudate veins draining directly into the vena cava as well as the numerous small portal triads extending off the main left pedicle at the base of the umbilical fissure. Figure 6.2 demonstrates a case of a small, solitary segment of hepatic metastasis for colorectal cancer, which was detected on an MRI scan used for screening because of a rising CEA. Although this was a surface lesion, intraoperative ultrasound revealed the segment VI triad immediately adjacent to the tumor. The segment VI triad was located by ultrasound and ligated at its origin with minimal parenchymal dissection. The intersegmental planes were then marked by electrocautery and a formal segmentectomy was performed with negative margins. While an aggressive resection was indicated and performed, the patient can still undergo a formal left or right hepatic lobectomy in the future if indicated. No dissection of the vena cava or porta hepatis was required.

Segmental Resections For all but the most superficial lesions, we prefer a segmental approach for the resection of tumor (39). Segmental resections have a significantly lower rate of pathologic positive margins, and this translates into improved long-term survival (40). Small, deep solitary metastases and surface lesions adjacent to major vascular structures lend themselves particularly well to segmentectomies or sectorectomies. The intersegmental planes can be identified intraoperatively using vascular landmarks with the aid of intraoperative ultrasound. Using these planes for parenchymal dissection will minimize blood loss and help ensure a safe margin. Inflow occlusion for the segment can almost always be performed first, thereby producing demarcation of the segmental planes to further enhance the dissection. The portal triad to segments II, III, and IV can be identified and controlled within the umbilical fissure with little parenchymal dissection (37). The right posterior sectoral pedicle can be found by dividing the parenchyma along a horizontal cleft (fissure of Gans) present on the inferior surface of the right lobe of the liver. The pedicle can be traced to its bifurcation to segments VI and VII for control of the individual segmental portal triads. The anterior sectoral pedicle can be dissected from an inferior or anterior approach. The major hepatic veins lie within the intersegmental planes and can be a source of significant blood loss during the parenchymal transection phase of a segmentectomy. The use of low central venous pressure (0–5 mmHg) during parenchymal dissection can decrease back bleeding in these veins (41). Extrahepatic control of the left, middle, and right hepatic veins can also be achieved and the vein of concern temporarily

Morbidity and Mortality The mortality rates for major hepatic resection have decreased significantly over time to a common reporting of mortality in the 1% to 4% range (43). These values are even lower for wedge resections and segmentectomies. In a recent report of 270 wedge or segmental resections, the operative mortality was 0.5% (40). This low mortality is not surprising considering that the main cause of death in studies of liver resection is liver failure secondary to inadequate residual normal parenchyma, an unlikely event for resection of small solitary hepatic metastases where minimal normal parenchyma is sacrificed. While mortality rates are low, the complication rate for major hepatic resection is still relatively high, ranging from 20% to 50% (5). Bile leaks, perihepatic abscess, hemorrhage, cardiopulmonary complications, pleural effusions, pneumonia, and pulmonary embolism are among the most common complications (43). Many of these could be expected after segmentectomy and wedge resections as well as major hepatic resections. Even though these complications do not translate into a high mortality rate, they may affect recovery time and quality of life. While this is not a significant issue for patients expected to undergo a long-term disease-free interval or cure, it may be significant for patients whose survival is expected to be of the order of months. For those patients with aggressive tumors who are likely to fail outside the liver in the near future, less invasive techniques which are associated with a lower complication rate and quicker recovery time are more appealing. Ablative Techniques Other minimally invasive techniques include local ablative therapies such as laparoscopically directed cryotherapy (44) or

57

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A)

(B)

(C)

(D)

Figure 6.2 An example of a small, solitary colorectal metastasis to segment VI. (A) MRI reveals subtle abnormality not seen on CT scan. (B) Intraoperative ultrasound reveals the tumor and adjacent segment VI portal vein. (C) Intersegmental planes have been marked on the liver capsule with electrocautery and parenchymal dissection begun. (D) Resected segment with tumor (microscopic negative margins). (Special thanks to Dr Peter Choyke for MRI scan.)

radiofrequency ablation (45). These techniques will be discussed further in chapter 8. They provide ideal alternatives to laparotomy and major liver resection for the treatment of small solitary hepatic metastases, since the small tumor is the most likely to be completely treated by ablation techniques. Furthermore, treatment by ablative techniques does not preclude future resection. Percutaneous approaches to tumor ablation are even more attractive than laparoscopic procedures. Local injection of toxic agents such as ethanol has been shown to be effective for hepatocellular cancers, however these agents have not been proven for other histologies and are known to be poorly effective for colorectal cancer (2). Radiofrequency ablation can be performed percutaneously under ultrasound guidance with local anesthesia. Figure 6.3 demonstrates a case of a metastatic pancreatic cancer 2 years after a dramatic primary response to gemcitabine and radiation therapy. Because the patient will likely begin to fail in multiple sites in the near future with limited survival potential, a laparotomy and hepatic resection was not considered reasonable. She was treated with percutaneous radiofrequency ablation, achieving a good zone of necrosis encompassing the mass, and she spent only one day in the hospital with very minimal discomfort. How such procedures, which have low morbidity and which maintain quality of life, will factor

58

in the treatment of patients with small hepatic metastases must be addressed by studies with sufficient follow-up to define the local recurrence rate.

adjuvant chemotherapy The role for adjuvant systemic chemotherapy after the removal of small solitary hepatic metastases is not well defined. Even for hepatic colorectal metastases, which are commonly treated with surgery, data on adjuvant chemotherapy after liver resection is sparse. Two retrospective studies have suggested a benefit of adjuvant systemic chemotherapy after metastasectomy, but others have not supported this (6,46–48). Use of systemic chemotherapy after resection of hepatic colorectal metastases is based mainly on data demonstrating adjuvant 5-fluorouracil (5-FU) and levamisol or 5-FU and leucovorin to decrease recurrence rate and improve survival when used after resection of the primary tumor (49). It is hoped that a similar benefit will be seen when 5-FUbased chemotherapy is used after metastasectomy. Current practice is to offer adjuvant 5-FU-based chemotherapy after hepatic resection to patients who have had no previous chemotherapy. There are currently no data to support the use of irinotecan and oxaliplatin in an adjuvant setting, although studies are in progress.

SMALL SOLITARY HEPATIC METASTASES: WHEN AND HOW?

(A)

(B)

(C) Figure 6.3 An example of a small, solitary pancreatic cancer metastasis treated with percutaneous radiofrequency ablation. (A) Pretreatment CT scan reveals hypodense 3 cm right lobe liver metastasis. (B) Ultrasound hoto with radiofrequency probe inserted into tumor. (C) Post-treatment scan (3 weeks) reveals large zone of necrosis replacing prior tumor. (Special thanks to Dr Thomas Shawker for ultrasound photo.)

For patients with hepatic colorectal metastases, the most common site of tumor recurrence after liver resection is the remnant liver (50). In the treatment of patients with small hepatic metastases, there is particular concern that even smaller undetected metastases may subsequently present as a liver tumor recurrence. Regional chemotherapy to treat the liver site is therefore a theoretically attractive option for adjuvant care. Data addressing the utility for such hepatic arterial infusional (HAI) chemotherapy had been sparse, consisting only of four small single-arm studies (51–53) and a single, small, randomized trial consisting of 36 patients (54). These preliminary studies demonstrated safety of such an approach, but efficacy data were insufficient to support the routine use of adjuvant intraarterial chemotherapy. Two large randomized trials examining adjuvant HAI have been completed. In the first trial (55), 224 patients from 25 centers were randomized to either no adjuvant therapy or adjuvant HAI 5-FU + systemic folinic acid. Although no difference was found between the groups, technical factors compromised this study such that only 34 of the 114 patients randomized to chemotherapy completed the adjuvant treatments. In another study, Kemeny et al. randomized 156 patients to either systemic 5-FU + leucovorin or HAI floxuridine (FUDR) + systemic 5-FU after complete resection of tumor (56). There was a significant survival advantage to HAI that is most likely related to local liver tumor control. We believe HAI chemotherapy is effective and

should be considered as an adjuvant to resection of hepatic colorectal metastases. For noncolorectal, nonneuroendocrine histologies metastatic to the liver, the most likely cause of death will be related to the disease outside the liver, regardless of how the liver is managed. For patients who are likely to develop systemic metastases in the near future, it may be reasonable to offer chemotherapy prior to resection. If the tumor responds, then a resection will be performed with confidence that other micrometastatic disease may be effectively treated with chemotherapy. If the tumor does not respond and the liver remains the only site of metastatic disease, resection is performed with increased confidence conferred by the longer period of observation. If the patient advances systemically during chemotherapy, then it is very unlikely that a resection would have been of benefit and the patient will have avoided the potential morbidity, pain, discomfort, and recovery time of an hepatic resection. That patient can go on to obtain second-line chemotherapy, investigational chemotherapy, or have no additional treatment.

conclusions Algorithms for the management of small solitary hepatic metastases are shown in Figure 6.4. Both patient and tumor characteristics must be considered in making management decisions. The most important tumor-related characteristic is

59

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Colorectal metastases

High CRS (3–4)

Low CRS (0–2)

Observation or chemotherapy

Resection

No extrahepatic progression

Extrahepatic progression

Resection or ablation

Chemotherapy

Ablation

Resection

Adjuvant therapy protocol

Adjuvant therapy protocol

(A) Neuroendocrine metastases

Symptomatic

Non-colorectal non-neuroendocrine Asymptomatic Long disease-free interval

Resection

Ablation

Short disease-free interval

Observation Resection Progression

No progression

Resection or ablation

Observation

(B)

Effective chemotherapy (>20% response)

No effective chemotherapy

Trial of chemotherapy

Ablation vs observation

(C)

Figure 6.4 Algorithms for the management of small hepatic metastases. (A) Algorithm for colorectal metastases (CRS, clinical risk score). (B) Algorithm for neuroendocrine metastases. (C) Algorithm for non-colorectal, non-neuroendocrine metastases.

histology. For patients with colorectal cancer (Fig. 6.4A), the prognostic factors for tumor recurrence after resection are well defined. Using the clinical risk score (CRS) as selection criterion, patients with CRS = 0–2 are ideal candidates for resection. Those with CRS = 3–4 should consider observation or chemotherapy prior to a definitive hepatic procedure. Immediate ablation or resection should be performed in the setting of a clinical trial, and most appropriately a trial examining adjuvant therapy. For neuroendocrine cancers (Fig. 6.4B), symptomatic tumors should be treated with resection and/or ablation when possible. When the cancer is found in an asymptomatic patient, a period of observation is not unreasonable because of the often indolent nature of these tumors. At resection, the principle should be to leave as much normal liver behind in order to minimize the risk of liver failure and in order to allow for

60

repeat anatomic liver resections in the future for recurrent disease. Enucleation with positive margins is acceptable for treatment of this histology because resection is almost never curative, and such cytoreduction can provide significant and durable palliation with minimum risk. For patients with small, solitary, noncolorectal nonneuroendocrine tumors, the most significant factor in terms of prognosis seems to be the disease-free interval (Fig. 6.4C). For patients with a long disease-free interval from primary resection a curative surgical resection is indicated as the most effective means of therapy. While it may be still unlikely that these patients can be cured, they must be given the benefit of the doubt and the most optimal procedure performed. The definition of “long” has been arbitrarily set at 36 months by Harrison et al. (26), but in reality it must vary according to histology. For gastric cancer, 12–24 months would be

SMALL SOLITARY HEPATIC METASTASES: WHEN AND HOW? considered long, whereas for ocular melanoma, 3–5 years would be more reasonable. Patients with a short disease-free interval from a tumor with a poor prognosis should undergo a trial of chemotherapy if there is a known effective agent. If no effective agent exists (as is the case for most solid malignancies), then these patients are ideal for an experimental, minimally invasive, local ablative therapy. This provides an advantage to observation alone, given the low but definite risk of the metastases spreading during the observation period. It will be psychologically more comforting to the patient to know that the lesion has been ablated, and risk, pain, and recovery duration are minimal. Observation alone is also quite reasonable, but it is often not accepted by patients. Patient-related factors must also be taken into consideration. Patients who have concomitant illnesses that make them poor operative candidates may be better served with a minimally invasive or percutaneous technique, even in the case of potentially curable metastases from colorectal cancer. Because of improvements in diagnostic techniques and the routine use of serum tumor markers, the detection of small solitary hepatic metastases from various tumors will likely increase in the future. A uniform approach to these patients such as that which is outlined in the treatment algorithm should be considered.

key points Factors that determine management ● ● ● ●

Natural history of tumor type Expected cure rate after surgical treatment Effectiveness of alternative treatment strategies Morbidity of surgical resection

Survival rates following hepatic resection ●

●

Good evidence for long-term survival Colorectal metastases Neuroendocrine metastases Survival possible in highly selected cases Breast cancer Sarcoma (especially gastrointestinal stromal tumors) Melanoma

Patient selection factors in colorectal metastases ●

●

Contraindications Extrahepatic disease (except solitary pulmonary metastases) Positive hilar lymph nodes Relative contraindications Presentation within 12 months of resection of primary tumor CEA >200 ng/dl >1 liver tumor Tumor >5 cm in size Positive resection margin

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 27. Fujisaki S, Takayama T, Shimada K, et al. Hepatectomy for metastatic renal cell carcinoma. Hepato-gastroenterology 1997; 44: 817–9. 28. Iwatsuki S, Shaw BW, Starzl TE. Experience with 150 liver resections. Ann Surg 1983; 197: 247. 29. Talmadge JE, Fidler IJ. Enhanced metastatic potential of tumor cells harvested from spontaneous metastases of heterogeneous murine tumors. J Natl Cancer Inst 1982; 69: 975–80. 30. Elias D, Saric J, Jaeck D et al. Prospective study of microscopic lymph node involvement of the hepatic pedicle during curative hepatectomy for colorectal metastases. Br J Surg 1996; 83: 942–5. 31. Nanko M, Shimada H, Yamaoka H et al. Micrometastatic colorectal cancer lesions in the liver. Jpn J Surg 1998; 28: 707–13. 32. Hughes KS, Simon R, Songhorabodi S, Adson MA. Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery 1986; 100: 278–84. 33. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230(3): 309–18. 34. Delbeke D, Vitola JV, Sandler MP et al. Staging recurrent metastatic colorectal carcinoma with PET. J Nucl Med 1997; 38: 1196–201. 35. FernE1ndez-Trigo V, Shamsa F, Sugarbaker PH. Repeat liver resections from colorectal metastasis. Surgery 1995; 117: 296–304. 36. Shirabe K, Takenaka K, Gion T et al. Analysis of prognostic risk factors in hepatic resection for metastatic colorectal carcinoma with special reference to the surgical margin. Br J Surg 1997; 84: 1077–80. 37. Blumgart LH. Liver resection—liver and biliary tumours. In: Blumgart, LH ed. Surgery of the Liver and Biliary Tract. New York: Churchill Livingstone, 1994: 1495–538. 38. Polk W, Fong Y, Karpeh M, Blumgart LH. A technique for the use of cryosurgery to assist hepatic resection. J Am Coll Surg 1995; 180: 171–6. 39. Billingsley KG, Jarnagin WR, Fong Y, Blumgart LH. Segment-oriented hepatic resection in the management of malignant neoplasms of the liver. J Am Coll Surg 1999; 187: 471–81. 40. DeMatteo RP, Palese C, Jarnagin WJ, Sun RL, Blumgart LH, Fong Y. Anatomic segmental hepatic resection is superior to wedge resection as an oncologic operation for colorectal liver metastases. J Gastrointest Surg 2000; 4(2): 178–84. 41. Cunningham JD, Fong Y, Shriver C. One hundred consecutive hepatic resections: blood loss, transfusion and operative technique. Arch Surg 1994; 129: 1050–6. 42. Bartlett D, Fong Y, Blumgart LH. Complete resection of the caudate lobe of the liver: technique and results. Br J Surg 1996; 83: 1076–81.

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43. Fong Y, Blumgart LH. Hepatic colorectal metastasis: current status of surgical therapy. Oncology 1998; 12: 1489–94. 44. Lezoche E, Paganini AM, Feliciotti F, et al. Ultrasound-guided laparoscopic cryoablation of hepatic tumors: preliminary report. World J Surg 1998; 22: 829–36. 45. Siperstein AE, Rogers SJ, Hansen PD, Gitomersky A. Laparoscopic thermal ablation of hepatic neuroendocrine tumor metastases. Surgery 1997; 122: 1147–55. 46. Fortner JG, Silva JS, Golbey RB. Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer: I. Treatment by hepatic resection. Ann Surg 1984; 196: 306–16. 47. Butler J, Attiyeh FF, Daly JM. Hepatic resection for metastases of the colon and rectum. Surg Gynecol Obstet 1986; 162: 109–13. 48. Pagana TJ. A new technique for hepatic infusional chemotherapy. Semin Surg Oncol 1986; 2: 99–102. 49. Moertel CG, Fleming TR, Macdonald JS et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322: 352–8. 50. Blumbart LH, Fong Y. Surgical management of colorectal metastases to the liver. Curr Prob Surg 1995; 5: 333–428. 51. Goodie DB, Horton MD, Morris RW, Nagy LS, Morris DL. Anaesthetic experience with cryotherapy for treatment of hepatic malignancy. Anaes Int Care 1992; 20: 491–6. 52. Moriya Y, Sugihara K, Hojo K, Makuuchi M. Adjuvant hepatic intra-arterial chemotherapy after potentially curative hepatectomy for liver metastases from colorectal cancer: a pilot study. Eur J Surg Oncol 1991; 17: 519–25. 53. Curley SA, Roh MS, Chase JL, Hohn DC. Adjuvant hepatic artery infusion chemotherapy after curative resection of colorectal liver metastases. Am J Surg 1993; 166: 743–8. 54. Kemeny MM, Goldberg D, Beatty D et al. Results of a prospective randomized trial of continuous regional chemotherapy and hepatic resection as treatment of hepatic metastases from colorectal primaries. Cancer 1986; 57: 492–8. 55. Lorenz M, Muller HH, Schramm H et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. Ann Surg 1998; 228: 756–62. 56. Kemeny N, Huang Y, Cohen AM et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl Med 1999; 341(27): 2039–48. 57. Que FG, Nagorney DM, Batts KP, Linz LJ, Kvols LK. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg 1995; 169: 36–43.

7

Managing complications of hepatectomy Fenella K. S.Welsh, Timothy G. John, and Myrddin Rees

introduction The safety of elective liver surgery has improved dramatically in the past 30 years. A multicenter American series comprising 621 liver resections published in the late 1970s reported a 13% mortality (1). By contrast, recent large published series describe posthepatectomy mortality rates of 0% to 4.4%, with 19.6% to 45% morbidity (2–8) (Table 7.1). Furthermore, individual units have demonstrated a significant reduction in morbidity and mortality over time, despite ever-widening the indications for hepatectomy (6,8). This dramatic improvement in immediate postoperative outcome can be explained by increased specialization of liver surgery in high-volume centers (9), better selection of patients in terms of hepatic functional reserve and comorbid conditions, advances in surgical technique, including greater understanding of hepatic segmental anatomy and improved instrumentation for the parenchymal transection. Furthermore, anesthesia and critical care has improved enormously, the routine use of low central venous pressure (CVP) anesthesia being a particular advance. However, even a 20% complication rate remains significant, particularly if the indication for hepatectomy is for livingdonor transplantation. Furthermore, postoperative morbidity can also adversely affect disease-specific and disease-free survival (10–12). Thus the short- and long-term consequences of postoperative morbidity, coupled with increasing litigation, and limited health care resources, has renewed the drive to further improve the immediate outcome from liver resection, with emphasis on prevention of and improved management of complications, when they occur. The precise definitions of the specific complications such as bleeding, bile leak, and hepatic insufficiency are still without consensus. Moreover, the stratification of the severity of each complication is still unclear. Standardized definitions, grading, and reporting of the complications of hepatectomy are needed to allow an objective, quality assessment of outcome data from different units and further improve results. The system proposed and validated by Clavien, focusing on the therapeutic consequences of complications in order to rank their severity, is currently the best available (13). However, it is still not universally adopted within the surgical community. A number of studies have attempted to identify the risk factors associated with complications and death from hepatectomy, three of which are detailed in Table 7.2. From these studies, there is consensus that the estimated blood loss or blood transfusion rate, the extent of hepatic resection, and an additional extrahepatic procedure are all independent predictors of morbidity and mortality. In addition, medical comorbidity, an elevated preoperative creatinine, preoperative thrombocytopenia, or hypoalbuminemia also appear to increase the operative risk. However, in the Hong Kong study (8), while cirrhosis per se was associated with increased

postoperative morbidity and mortality on an initial univariate analysis, it failed to independently predict outcome on subsequent multivariate analysis. Similarly, Belghiti’s group found that the in-hospital mortality rate was significantly higher in those patients with cirrhosis (8.7%) compared to those without underlying liver disease (1%, p < 0.001), but this was not subjected to multivariate analysis (7). Thus while liver resection in cirrhotic patients is technically more challenging than resecting normal liver, with a higher incidence of bleeding, septic complications, and postoperative liver failure (14), these two studies would suggest that in experienced high-volume centers, liver resection can be safely performed in patients with early cirrhosis. The common complications of hepatectomy may be classified as specific to the procedure or of a more general nature (Table 7.3). This chapter will deal with these complications in turn, focusing on their definition, incidence, predisposing factors, prevention, presentation, investigation, and treatment.

bleeding Incidence Bleeding is the most feared complication of hepatectomy, both on the operating table and in the immediate aftermath of surgery. In the 1960s and 1970s, it was the cause of major morbidity and mortality. The 1974 Liver Tumor Survey was a multicenter series of 621 hepatic resections performed in 98 U.S. centers, published in 1977. It reported a 13% mortality, with 15 of the 82 deaths (18%) due to exsanguinating hemorrhage in the operating room and bleeding being the documented primary cause of death in 26 of the 76 patients (34%), where the cause of death could be determined (1). However, bleeding is now relatively rare, with the median estimated blood loss for an elective hepatectomy being 345 to 600 ml (3,6) and the need for perioperative blood transfusion now being the exception rather than the rule. Indeed, the incidence of major hemorrhagic complications is rare, 0.7% (7/1005) in our own series (3). Of these seven cases, there were no on-table deaths, five patients were treated nonoperatively and two underwent reexploration for bleeding from a hepaticojejunal anastomosis and a left caudate branch of the portal vein respectively. In the Sloan-Kettering series of 1803 patients, the incidence is similar (1%) (6). Prevention Prevention remains the key to the management of bleeding. In the preoperative assessment, a careful drug history should be taken. If the patient is on drugs such as aspirin, clopidogrel, or warfarin, the indication for the treatment should be reviewed, and the drugs stopped where possible. Patients on warfarin as prophylaxis for thromboembolic events can be managed with an inferior vena cava (IVC) filter, placed preoperatively. It is

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 7.1 Morbidity and Mortality from Hepatic Resection in Recent Large Case-Series Reference

Years of study

No of centers

No of resections

Imamura et al. Rees et al. Wei et al. Malik et al. Jarnagin et al.

1994–2002

1

1056

1987–2005 1992–2002 1993–2006 1991–2001

1 2 1 1

1005 423 687 1803

Belghiti et al.

1990–1997

1

747

Poon et al.

1989–2003

1

1222

Case-mix 50% HCC 29% cirrhotic 100% CRLM 100% CRLM 100% CRLM 62% CRLM 10% HCC Elective & emergency. 35% benign 28% HCC 17% CRLM 32% cirrhotic 60% HCC 33% cirrhotic

Mortality

Morbidity

0%

39%

1.5% 1.7% 3.0% 3.1%

25.9% 19.6% 29.5% 45.0%

4.4% all 3.9% elective 8.7% cirrhotic 25.0% emergency 4.9%

22.0%

32.4%

Abbreviations: CRLM, colorectal liver metastases; HCC, hepatocellular carcinoma.

Table 7.2 Three Studies Reporting the Independent Predictors of Morbidity and Mortality after Hepatic Resection Reference Jarnagin et al.

Years of study 1991–2001

No of resections 1803

Belghiti et al.

1990–1997

478 elective resections, no cirrhotics

Poon et al.

1989–2003

1222

Predictors of morbidity Estimated blood loss Extent of resection + EH procedure ↑ preoperative creatinine Hypoalbuminemia Medical comorbidity Male gender ASA score Extent of resection Steatosis Blood transfusion + EH procedure Thrombocytopenia Blood transfusion + EH procedure

Predictors of mortality Estimated blood loss Extent of resection + EH procedure ↑ preoperative bilirubin Thrombocyt openia Age + EH procedure (in patients with malignancy)

Hypoalbuminemia Thrombocytopenia ↑ preoperative creatinine Major resection Blood transfusion

Abbreviation:+EH Procedure, additional extra-hepatic procedure.

important to identify patients with tricuspid regurgitation or right heart disease, where the anesthetist may encounter difficulties in lowering the CVP, as this may influence the extent of resection. Careful evaluation and correction of coagulation abnormalities should be performed pre- and perioperatively, particularly in the cirrhotic patient. Two key maneuvers are used to prevent bleeding during hepatic transection: portal triad clamping and low CVP anesthesia. Portal triad clamping, first described by Pringle in 1908, reduces hepatic arterial and portal venous bleeding (15,16). Although a European survey demonstrated that the use of inflow occlusion is not universal, it did confirm that most hepatic surgeons resort to it in difficult cases and that experienced surgeons are more likely to use it routinely (17). However, a recent systematic review and meta-analysis of the effect of inflow occlusion on postoperative morbidity and mortality failed to demonstrate any significant outcome

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benefit (18). This is confirmed by another systematic review published in 2009, which compared 166 patients with vascular occlusion to 165 patients with no vascular occlusion (19). However, despite the small numbers involved, this later study showed that blood loss was significantly lower in those patients who had vascular occlusion. A low CVP reduces back bleeding from hepatic veins during the transection (20–22) and is now accepted practice during liver resection worldwide. Indeed, following the introduction of low CVP anesthesia in our own unit, the mean blood loss was significantly reduced from 2116 to 426 ml (3). However, these techniques can test the patients’ cardiovascular reserve. Obstructing the portal blood flow causes venous congestion of bowel and in combination with warm ischemic liver injury, releasing a flush of anerobic metabolites and cytokines back into the circulation on release of the clamp (23). Low CVP anesthesia relies on patients being maintained in a

MANAGING COMPLICATIONS OF HEPATECTOMY Table 7.3 Complications of Hepatectomy General complications Immediate (on table) Early (days)

Late (weeks/ months)

Specific complications

• Hypothermia

• Bleeding

• Respiratory— atelectasis, pleural effusion, pneumonia • Cardiovascular— DVT, PE, MI, arrhythmias, CVA • Renal failure • Wound infection • Pain • Incisional hernia

• • • •

Bleeding Bile leak Hepatic insufficiency Intra-abdominal abscess

Investigation and Treatment The hemoglobin concentration and clotting screen should be performed urgently, ensuring that the patient has an up-todate cross match. Any coagulopathy should be corrected. If the patient remains shocked, appropriate investigations may include endoscopy and mesenteric arteriography. Ultimately, as in our own series, small number of patients may need to return to the operating theatre for surgical control of hemorrhage.

biliary complications • Biliary stricture

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolus; MI, myocardial infarction; CVA, cerebrovascular accident.

hypovolemic state until liver resection has been completed (20,21). This is in contrast to most other major surgical procedures, where patients have large volumes of crystalloid and colloid perioperatively. While a recent meta-analysis has confirmed that the use of the antifibrinolytic agent aprotinin can significantly reduce transfusion requirements during liver transplantation (24), there is no evidence for its routine use during liver resection (25). In contrast, a prospective double-blind randomized trial of tranexamic acid, another antifibrinolytic agent, has shown that its use perioperatively significantly reduced the blood loss and transfusion requirements in elective liver resection (26). Two prospective randomized controlled trials have failed to show any benefit of using recombinant factor VIIa in either noncirrhotic (27) or cirrhotic (28) patients undergoing hepatectomy. Since the early 1990s, the use of fibrin sealants has become a popular aid hemostasis at the hepatic parenchymal transection site. Two early randomized trials suggested some benefit in achieving hemostasis (29) and reducing postoperative blood loss (30), although the numbers involved were small. A more recent trial of a carrier-bound fibrin sealant (TachoSil®) suggested it was quicker and more effective hemostasis compared to argon beam coagulation (31). However, the numbers involved were again small (<65 patients in each group). A larger prospective randomized trial of fibrin glue versus control involving 300 patients undergoing hepatic resection was published in 2007 (32). This showed no difference in blood loss, blood transfusion, or overall morbidity between those who received the fibrin glue and those who did not. This study provides the best evidence to date that the routine use of such topical hemostats is not justified, although it is our own personal bias that fibrin glue needs to be combined with a collagen matrix to be effective. Presentation Postoperatively, patients who are bleeding may present with classical signs of shock, persistent blood loss in an abdominal drain, a drop in hemoglobin, or gastrointestinal bleeding.

Incidence and Definition of a Bile Leak Bile leak remains a persistent problem after hepatectomy, with a reported incidence of 1% to 12% (3,33). In addition, it appears to be the most common complication after living donor hepatectomy, with an incidence of 7.5% in the 731 donors in one Japanese series (34) and 9% in 381 donors in an American series (35). The variable incidence may be explained by the different patient populations analyzed and the lack of consensus regarding the definition. The Amsterdam group has defined bile leakage as one or more of the following criteria: the presence of persisting bile-stained effluent from an abdominal drain, leakage detected on radiological imaging, and occurrence of a bile collection drained percutaneously or found during relaparotomy (36). This definition of a bile leak, used in conjunction with Clavien’s severity grading (13), could be widely applied in clinical practice. Prevention Meticulous technique during the parenchymal transection, ensuring that both small and large bile ducts are adequately secured with clips, ties, or sutures, is vital for the prevention of bile leakage. Inspection of the cut surface and application of a clean white-gauze swab is usually enough to reveal a bile leak, which must then be sutured. Methods for testing for bile leakage have previously been advocated and include injection of the biliary system (usually via the cystic duct stump) with saline solution or methylene blue, or formal direct cholangiography after the transection has been completed. However, the only prospective randomized study has shown no evidence that such maneuvers reduce the bile-leak rate (37) and thus this technique cannot be recommended as a routine. While one study has show that topical fibrin glue significantly reduces the bile-leak rate following hepatectomy (38), other studies have failed to show any benefit (29,39). Thus there is no clear evidence that topical hemostatic agents used after the liver resection on the parenchymal surface reduce the bile-leak rate (33). Risk Factors for a Bile Leak There is consensus in the literature that extended hepatic resections are associated with an increased risk of bile leak (36). An Italian series of 610 liver resections without a concurrent hepaticojejunostomy reported a 3.6% incidence of postoperative bile leakage (38). On multivariate analysis, they found that resection of a peripheral cholangiocarcinoma (relative risk 5.5) and hepatectomies including segment 4 (relative risk 3.1) were the only independent risk factors for a bile leak.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Other risk factors reported include a large transection area and operations, which expose the major Glissonian sheath around the hepatic hilum (major central resections including segments 4b, 5, or the caudate), with subsequent unrecognized injury to the bile duct (40). Gertsch and coworkers showed that patients who had postoperative ischemia of part of the remnant liver had a higher incidence of bile leakage (18.4%) compared to those with no ischemia (2.7%) (41). In addition, any hepatic resection, which includes resection of the extrahepatic biliary tree with concomitant hepaticojejunostomy has a significantly higher bile leak rate (36,40,42). The presence of cirrhosis appears to be associated with a lower risk of a bile leak, possibly because of a less aggressive surgical approach in these patients (38). Presentation of a Postoperative Bile Leak A bile leak can present as bile-stained effluent from an abdominal drain. Other patients will show signs of intra-abdominal sepsis, with a fever, abdominal pain, or right-sided chest signs, and leak bile into a secondarily placed drain. Management of a Postoperative Bile Leak Minor bile leaks may often resolve with no requirement for further intervention. In their case series, Vigano and coworkers found that 77% of bile leaks settled spontaneously. However, a drainage output greater than 100 ml on postoperative day 10 was the only independent risk factor for failure of conservative management (43). Percutaneous tube drainage should then be the intervention of choice. If percutaneous drainage fails because of persistent or recurrent bile leakage, endobiliary stenting should be undertaken, to reduce the intrabiliary pressure and promote rapid resolution of the bile leak (44,45). Clearly this can only be successful if there is communication between the leaking bile duct and the main biliary tree. In the face of failure of percutaneous and endoscopic approaches, relaparotomy should be undertaken, with a view to optimizing drainage, a further hepatic resection, or formation of a biliary enteric anastomosis. The precise intraoperative decision will depend on the volume of the liver remnant and functional liver reserve as well as the extent of local sepsis. We have had to perform a biliary enteric anastomosis for a persistent bile leak in one patient out of our entire cohort of liver resections (1/1600). The patient had undergone an extended left hepatectomy. Following an initially uncomplicated postoperative course with discharge home on day 4, she was readmitted three weeks later with intra-abdominal sepsis. After initial percutaneous drainage of a large bile collection, the leak failed to resolve with endoscopic biliary drainage. A laparotomy was therefore performed and the area of bile leakage identified at the resection edge, but no actual bile duct seen. A Roux-en-Y jejunal loop was therefore anastomosed to the resection edge with a successful outcome. Consequences of a Bile Leak The direct consequences of a postoperative bile leak include prolonged hospital stay and increased morbidity and mortality (39). Patients with persistent bile leakage are at risk of

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developing intra-abdominal sepsis, with the attendant risk of liver failure and death (46). Incidence of Biliary Stricture after Hepatectomy A biliary stricture is an uncommon, late complication of hepatectomy, with an incidence of 0.2% (4/1803) in the SloanKettering series (6). It is caused by unrecognized intrahepatic injury to the bile ducts, either directly or due to isolated devascularization of the biliary tree. A distal biliary stricture may be responsible for a persistent proximal bile leak. Management of Biliary Stricture After Hepatectomy A biliary stricture after hepatectomy should be managed in the same way as any iatrogenic biliary stricture. This will include radiological and/or endoscopic assessment of the level of the stricture and its relationship to the remaining biliary tree, together with an estimate of the volume and function of the hepatic remnant. Avoidance of sepsis or cholangitis is paramount, as is attention to the nutritional status of the patient. Potential treatments include endobiliary stenting, biliary reconstruction, or a further hepatic resection tailored to the individual circumstances.

hepatic insufficiency Definition and Incidence There is currently no internationally accepted definition of postoperative liver failure or hepatic insufficiency. Belghiti’s group have proposed the “50-50 criteria,” which are a prothrombin index <50% of normal (corresponding to an International Normalized Ratio (INR) of 1.7 or more) and a serum bilirubin > 50 µmol/L on postoperative day 5, as a simple, accurate predictor of liver failure and death (47). On the fifth postoperative day, both prothrombin time and bilirubin should have returned to normal values. They found that the persistence of the “50-50 criteria” at this time indicated a significant impairment of liver function and was associated with a 59% risk of early postoperative mortality, compared with a 1.2% risk if the criteria were not met. They recently prospectively evaluated these criteria in a cohort of 436 elective hepatectomies and found that the “50-50 criteria” on postoperative days 3 and 5 were accurate predictors of death on multivariate analysis (48). The MD Anderson group reviewed data from 1059 noncirrhotic patients who underwent a major hepatectomy and found that a peak bilirubin of more than 120 µmol/L (7.0 mg/d/L), accurately predicted liver-related death and suggested that this be used as a definition (49). By this definition, the incidence of postoperative liver failure with or without multiorgan failure resulting in death in their series was 2.8%. In the French multicenter series of 1568 hepatectomies, the incidence of liver failure was 43/1568 (2.7%), however this was responsible for death in 7/43 (16%) of those patients (50). In the Hong Kong series (8), postoperative liver failure occurred in 47 out of the 1222 hepatic resections (3.8%), but again, it is not defined. This series had a higher incidence of patients (59.2%) with cirrhosis or chronic hepatitis compared to most Western case series. Overall, the reported incidence in the literature ranges from 0.7% to 9.1% (51).

MANAGING COMPLICATIONS OF HEPATECTOMY Prevention The incidence of postoperative liver failure is related to the volume and quality of the remnant liver, the amount of blood lost during surgery (52,53), and the presence of comorbid conditions such as diabetes mellitus (51,52). As treatments are limited and the consequences life-threatening, preoperative assessment of the individual patient’s risk is vital and will affect the operative approach (54). Assessment of liver function can be achieved using liver biochemistry, coagulation studies, and the Child–Pugh classification (55). However, because of the limits of the Child–Pugh scoring system, surgeons have looked for other tests of hepatic function to help identify patients at risk of postoperative liver failure. The indocyanine green (ICG) retention test is the most widely used in clinical practice. ICG is a dye that is removed from plasma by the liver and rapidly excreted unchanged into bile. The ICG retention rate at 15 minutes (ICGR-15) provides a measure of hepatic function, with clearance said to be impaired when 15% or more of the ICG remains within the plasma at 15 minutes (56). Makuuchi’s group has successfully incorporated the ICGR-15 in their preoperative work-up of Child–Pugh class A patients to guide the extent of resection (54). The Hong Kong group also uses it in their preoperative assessment of patients with HCC, because of their high incidence of chronic liver disease. They use an ICGR of <20% as a cut-off for a major resection in cirrhotic patients (57). There is a close relationship between liver function and volume. The volume of the future liver remnant (FLR) may be assessed by computed tomography (CT) volumetry. Vauthey and colleagues reported the value of residual liver volume using CT as a predictor of hepatic dysfunction, noting a critical value of 25% below which they found a significant risk of hepatic dysfunction in patients with no underlying liver disease (58). These data have been confirmed by two other groups, who defined a critical FLR of 26.6% (53) and 26.5% (59), respectively. In patients with underlying liver disease, such as chemotherapy-associated steatohepatitis or cirrhosis, the FLR should be greater (59), with Vauthey’s group suggesting it should be at least 30% if the patient has received extensive preoperative chemotherapy and 40% if they have cirrhosis (60). A recent systematic review (61) looked at the association between chemotherapy type, liver injury, and the impact of liver injury on outcome following liver resection. This study found a significant association of irinotecan with steatohepatitis, especially in obese patients. These patients had a higher 90-day mortality rate compared to patients who did not have steatohepatitis (15% vs. 2%, p = 0.001) and a significantly higher risk of death from postoperative liver failure (6% vs. 1%, p = 0.01), highlighting that irinotecan appears to impair the functional reserve and regenerative capacity of the liver (60). Chemotherapy-associated hepatotoxicity and its impact on outcome after hepatectomy are covered in more detail in chapter 17. The use of portal vein embolization (PVE) to improve volume of the FLR and as a functional test of hepatic reserve PVE can be used to induce hypertrophy of the FLR and reduce the incidence of postoperative complications, including liver failure, in patients with a marginal FLR (62–65). PVE may also

provide an important functional test of hepatic reserve in patients with a borderline FLR, with the degree of hypertrophy predicting outcome from hepatectomy (63). Certainly, if patients with borderline FLR remnants do not exhibit hypertrophy following PVE, they should not undergo hepatic resection because of the risk of postoperative liver failure—the so-called “trial of PVE.” A recent consensus statement suggests that PVE is indicated when the FLR is <20% in patients with normal liver, <30% in patients who have had chemotherapy, and <40% in patients with well-compensated cirrhosis (66). Optimization of Venous Drainage A key aspect of maximizing the function of the remnant liver and prevention of hepatic insufficiency is to preserve and optimize its venous drainage. Belghiti showed that following a right hepatectomy, left hepatic venous outflow was impaired if the left liver was not fixed in the anatomical position (defined as the position where the falciform ligament was in its strict medial position) (67). The consequent venous congestion could result in bleeding from the resection surface in the short-term and impaired function and regeneration of the liver remnant in the ensuing few days or weeks. The venous drainage on preoperative imaging should be carefully evaluated when planning any resection, therefore allowing optimization of the venous drainage of the future liver remnant. For example, preserving the umbilical vein when performing a right hepatectomy extended to segment 4a will allow adequate drainage of segment 4b. Belghiti’s group has demonstrated the importance of this, using the living donor hepatectomy as a model (68). They showed that 84% of donors who underwent right liver harvesting to include the middle hepatic vein, developed venous congestion of segment 4 postoperatively, compared to none of the donors who had right liver harvesting without including the middle hepatic vein. Furthermore, this was associated with impaired postoperative liver function and regeneration. Treatment of Postoperative Hepatic Insufficiency As emphasized above, the mainstay of management of operative hepatic insufficiency is prevention. However, should it occur, there are a number of important strategies to employ. Patients should be receiving best supportive care, to optimize other organ functions, in a minimum level 1 environment, with intensive escalation of care as required. It is important to avoid secondary septic insults such as pneumonia or intraabdominal sepsis, as any second “hit” will increase the risk of death. Liver failure and sepsis appear to be closely linked. Schindl and coworkers have reported a direct correlation between the extent of liver resection and the incidence of infective complications (53). This risk is further increased in the presence of cirrhosis or liver failure (53). Thus in a patient developing liver failure, infectious complications should be actively excluded by clinical assessment and radiological and bacteriological investigations. Infectious complications should be aggressively treated with appropriate antibiotics and drainage or reoperation as required. Other management strategies to combat posthepatectomy liver failure include dietary sodium restriction (<90 mmol

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS sodium per day), to reduce the sodium retention that can occur as a result of decreased renal excretion and enhanced sodium resorption (69). Some patients will develop hyponatremia and worsening ascites due to water retention. It is our practice to moderately restrict fluid for such patients to 1.5 to 2 L per day. If the serum sodium is > 126 mmol/L, patients should be commenced on spironolactone, an aldosterone antagonist, which acts on the distal tubules to increase natriuesis and conserve potassium. The initial dose should be 50 to 100 mg per day, increased up to 400 mg per day and limited by the development of hyperkalemia. The additional use of frusemide, a loop diuretic, at a dose of 40 mg per day, can enhance its natriuretic effect. In patients with a serum sodium 121 to 125 mmol/L, clinicians should consider stopping diuretics, particularly if there is evidence of renal impairment. In this scenario, patients should be given volume expansion, ideally with 20% salt-poor albumin. Other volume expanders such as Gelofusine® and 4.5% albumin solutions contain high concentrations of sodium (154 mmol/L) and their use will potentially worsen patients’ sodium retention. The management of patients with a serum sodium < 120 mmol/L is difficult and controversial. In this scenario, all diuretics should be stopped and patients should undergo volume expansion with colloid or saline. It is important that these patients are not taking nonsteroidal antiinflammatory drugs (NSAIDs), as these can also inhibit salt and water excretion and compound the problem (70,71). Hypoglycemia and hypophosphatemia should be aggressively corrected. These recommendations from the evolution of our own practice are reinforced by the current U.K. guidelines on the management of ascites in cirrhosis (69). A few small case series suggest that artificial liver support systems such as the molecular-adsorbent recirculating system (MARS) may be of value in treating posthepatectomy liver failure (72). However, a recent systematic review showed that there is currently insufficient evidence to support their use in these patients (73).

intra-abdominal infection Importance and Incidence Posthepatectomy infections are important as they can precipitate liver failure and death, as discussed earlier. The incidence of infected perihepatic collections ranges from 2.7% to 6.1% in modern case series (6,8), but is higher (12.8%) in older series (74). The incidence of infected ascites is less than 1% (8). Factors Affecting the Incidence of Intra-abdominal Infection The decreasing incidence of intra-abdominal infections over time is a reflection of the evolution of liver surgery in the past 30 years. In Yanaga’s series of 149 liver resections performed between 1973 and 1984, 19 patients (12.8%) developed intraperitoneal septic complications, of whom 13 patients died of liver failure (74). They identified five risk factors for this, which were: (1) right or extended right hepatectomy, (2) age > 65 years, (3) operation time > 5 hours, (4) blood loss > 3L, and (5) postoperative bleeding, which required a laparotomy to achieve hemostasis. A further Japanese case series of 535 hepatectomies performed between 1992 and 2005 reported that advanced age, diabetes mellitus, the use of silk sutures, and bile

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leakage were all associated with postoperative infective complications (75). They show a reduction in their postoperative infection rate from 44.7% at the start of the study to 9.2% by the end, with improvements in clinical practice such as early enteral nutrition and aggressive management of bile leaks. There is no evidence that the use of postoperative systemic antibiotics reduces postoperative infective complications. In a prospective randomized trial, Wu and coworkers showed that postoperative systemic antibiotics after liver resection did not influence the incidence of infective complications, which was 23% in each group (76). Another prospective randomized trial investigated whether omentoplasty to the hepatic parenchymal transection surface reduced the incidence of deep abdominal complications (bleeding, hematoma, infection with or without purulent discharge through drains, or bile leakage). The authors found that while deep abdominal complications were significantly associated with major hepatic resections, omentoplasty did not reduce their incidence (77). Abdominal Drainage The use of routine drainage after liver resection and its role in preventing complications remains controversial. A prospective randomized trial involving 186 patients compared closed suction drainage with open drainage after elective hepatectomy. The trial showed that the incidence of infected subphrenic collections, postoperative ascites, and pleural effusion was significantly lower in the closed suction drainage group. However, both groups showed similar rates of subphrenic hematoma and biloma formation (78). In contrast, another trial prospectively randomized 120 patients undergoing elective hepatectomy to closed suction drainage or no drainage (79). This showed no difference in overall complication rate between the two groups. However, 18% of patients in the no drainage group subsequently required a percutaneous drain, compared to 8% in the drained group, but this was not statistically significant. The authors concluded that routine drainage was unnecessary after elective hepatectomy and adopted a selective drainage policy. A trial from Hong Kong, which randomized 104 patients with chronic liver disease to closed suction drainage or no drainage, showed that there was significantly higher morbidity in the drainage group (73%) compared to the no drainage group (38%) (80). Further, specifically there was a higher incidence of wound complications in the drainage group and a trend towards more septic complications. In conclusion, elective closed suction drainage in patients with chronic liver disease is not recommended. For all other patients, there is no evidence that routine abdominal drainage prevents postoperative abdominal septic complications. However, for patients at high risk of bile leakage (as outlined earlier in this chapter), routine drainage is recommended.

respiratory complications and pain relief Incidence Respiratory complications such as pleural effusion and bronchopneumonia are common after hepatectomy. In the Hong Kong series, 7% of patients developed a postoperative pneumonia and 5% of patients had a pleural effusion requiring

MANAGING COMPLICATIONS OF HEPATECTOMY aspiration (8). In the Sloan-Kettering series of 1803 resections, the corresponding incidence was 3% pneumonia and 8.5% symptomatic pleural effusion; 2.5% of patients had basal atelectasis, with a further 2.5% developing respiratory failure requiring support. In addition, 1% of patients suffered a pulmonary embolus postoperatively (6). Prevention and Management As with any abdominal operation, a patient’s risk for respiratory complications should be assessed preoperatively. Smokers should be encouraged to stop. Patients with chronic lung disease should have aggressive preoperative physiotherapy. Good postoperative pain relief to facilitate early mobilization, deep breathing, and coughing is paramount. Epidural analgesia is one of the best methods for provision of postoperative pain relief in patients recovering from major upper abdominal operations (81,82). However, the procedure itself is associated with complications such as hypotension, bradycardia, immediate or delayed respiratory depression, urinary retention, dural puncture and hematoma, and/or infection within the spinal cord. Furthermore, patients undergoing hepatectomy are at risk of a prolonged prothrombin time postoperatively and this may affect the timing of removal of the epidural catheter (83). A retrospective review of 367 patients who underwent elective hepatectomy showed that patients who had epidural analgesia had a significantly lower mean arterial blood pressure in the theater recovery area and were more likely to have a blood transfusion during their hospital course (84). Thus in our unit, for the past five years, we have moved away from epidural anesthesia to using a continuous intermuscular bupivacaine infusion combined with patientcontrolled analgesia (85). This is a safe, simple, and efficacious method of providing postoperative pain relief in patients after liver resection and is associated with a low incidence of pulmonary complications (85). To prevent the small but potentially fatal risk of thromboembolic complications, all our patients wear graduated compression stockings. Pneumatic foot pumps are worn in the operating theatre and continued until the patient is fully mobile. Lowdose subcutaneous low-molecular-weight heparin is given daily postoperatively, once the prothrombin time has returned to within three seconds of normal. When respiratory complications do occur, they should be managed aggressively and proactively to minimize the risk of sepsis precipitating hepatic insufficiency.

cardiac complications In our own series, the Sloan-Kettering and the Hong-Kong series, the most common cardiac complication of hepatectomy is arrhythmia, with an incidence of 2% to 5% (6,8). Myocardial infarction and heart failure will also occur in about 1% of patients. At-risk patients should be identified preoperatively and undergo a cardiac assessment with exercise or pharmacological stress echocardiography and coronary angiography. Cardiac function should be optimized preoperatively with medical therapy, coronary stenting, and coronary artery bypass grafting as required. We have also used a perioperative intra-aortic balloon pump (86).

Patients who develop cardiac complications following hepatectomy should be managed in conjunction with the local cardiologists. If required, aspirin, clopidogrel, and formal anticoagulation with heparin can be given within days of a hepatectomy, although it is advisable to avoid the administration of a large loading dose of warfarin, to minimize the risk of early secondary hemorrhage.

renal failure Definition and Incidence Renal failure is defined as the need for renal replacement therapy. Studies have shown that 3% to 7% of patients require renal replacement therapy after liver resection (21,87). In our own case series, the incidence is 0.9% (unpublished data). Etiology of Renal Failure After Hepatic Resection There are three main factors which may contribute to the development of renal failure following liver resection. Elderly patients and those with conditions such as hypertension, atherosclerosis, or chronic kidney disease are at risk (88). These patients have a reduced capacity for neurohumoral autoregulation of glomerular blood flow during surgery and thus an increased risk of acute tubular necrosis (ATN) (88). Perioperative use of NSAIDs may also impair normal autoregulation of glomerular perfusion through inhibition of arteriolar dilatory prostaglandins (88) and should be avoided in patients with preoperative renal impairment. The second factor relates to the “hit” of surgery. Two key factors in the pathogenesis of ATN are hypovolemia and renal damage by inflammatory mediators (87). Both these events are predictable in every hepatic resection that employs low CVP anesthesia and portal inflow occlusion. Obstruction of the portal blood flow with the Pringle maneuver causes splanchnic venous congestion and, in combination with warm ischemic liver injury, results in a flush of anerobic metabolites and cytokines into the systemic circulation on release of the hepatic inflow clamp (23). Low CVP anesthesia relies on patients being maintained in a hypovolemic state until liver resection has been completed (20,21). This is in contrast to most other major surgical procedures, where patients are given significant volumes of crystalloid and colloid in the perioperative period. Moreover, vasodilators are often used to further reduce the CVP, leading to distributive changes in blood flow (20). Certainly, low CVP anesthesia with or without hepatic inflow occlusion can produce major circulatory changes, potentially resulting in ATN and subsequent renal impairment or failure (87). Another factor, which contributes to the etiology of renal failure following liver resection is a low perfusion state either secondary to cardiac dysfunction or distributive circulatory changes, such as sepsis or hepatorenal failure (87,88). Postoperative renal dysfunction is often multifactorial. Consequences of Postoperative Renal Failure The potential consequences of acute kidney injury include increased risk of mortality and may contribute to the development of chronic kidney disease (89).

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Hepatectomy in Patients with Preoperative Renal Impairment Patients with preoperative renal impairment, as defined by a raised preoperative serum creatinine, are at increased risk of both renal and non-renal complications (6). These patients require careful monitoring in the early postoperative period in order to optimize fluid balance and cardiac output and in some instances may require hemofiltration.

wound complications The incidence of wound infection was 5.2% in the SloanKettering series, with a further 10 patients (0.5%) having a wound dehiscence (6). The Hong Kong series of 1222 liver resections reports double these complication rates—with 115 patients (9.4%) developing a wound infection and 16 patients (1.3%) suffering wound dehiscence (8). An explanation of the higher incidence of wound complications in the Hong Kong series may be their higher percentage of cirrhotic patients (33% vs. 9%). A study from Japan of 626 liver resections, with a 7.7% incidence of incisional hernias, examined the risk factors for this (90). Risk factors included the type of incision, with a reversed T incision having a significantly higher incidence of an incisional hernia (21.7%) compared to midline (6.3%), J-shaped (4.7%), or a right transverse incision with long midline extension (5.4%). Furthermore, postoperative ascites, body mass index, repeat hepatectomy, and steroid use were also significant risk factors. The incidence of reported incisional hernia was 0.2% in our own series, with the two known patients who developed incisional hernias undergoing repair of these at the time of repeat liver resection. We believe this low incidence is related to the method of closure of the J-shaped wound, with a tension-free, 2-layer closure, using a 6:1 suture (looped 0-nylon) to wound–length ratio, as opposed to the traditional 4:1 ratio (85).

conclusions The safety of elective liver surgery has improved dramatically in the past 30 years, despite ever-widening indications for hepatectomy. However, complications still happen and prevention is the key to minimizing their incidence. When complications do occur, they should be aggressively managed, in a high-dependency environment, by a multidisciplinary team. International consensus regarding definitions of complications and a severity classification is still required.

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55. Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Transection of the esophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646–9. 56. Schneider PD. Preoperative assessment of liver function. Surg Clin N Am 2004; 84: 355–73. 57. 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: 602–11. 58. Vauthey JN, Chaoui A, Do KA, et al. Standardised measurement of the future liver remnant prior to extended resection: methodology and clinical associations. Surgery 2000; 127: 512–9. 59. 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; 31:1643–51. 60. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007; 94: 274–86. 61. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24: 2065–72. 62. Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future prospects. Br J Surg 2001; 88: 165–75. 63. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 2003; 237: 208–17. 64. Kokudo N, Makuuchi M. Current role of portal vein embolization/ hepatic artery chemoembolization. Surg Clin N Am 2004; 84: 643–57. 65. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg 2008; 247: 49–57. 66. Abdalla EK, Adam R, Bilchik AJ, et al. Improving resectability of hepatic colorectal metastases; expert consensus statement. Ann Surg Oncol 2006; 13: 1271–80. 67. Ogata S, Kianmanesh R, Belghiti J. Doppler assessment after right hepatectomy confirms the need to fix the remnant left liver in the anatomical position. Br J Surg 2005; 92: 592–5. 68. Scatton O, Plasse M, Dondero F, et al. Impact of localised congestion related to venous deprivation after hepatectomy. Surgery 2008; 143:483–9. 69. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006; 55 Suppl 6: 1–12. 70. Mirouze D, Zipser RD, Reynolds TB. Effect of inhibitors of prostaglandin synthesis on induced diuresis in cirrhosis. Hepatology 1983; 3:50–5. 71. Planas R, Arroyo V, Rimola A, et al. Acetylsalicylic acid suppresses the renal haemodynamic effect and reduces the diuretic action of furosemide in cirrhosis with ascites. Gastroenterology 1983; 84: 247–52. 72. Van de Kerkhove MP, de Jong KP, Rijken AM, et al. MARS treatment in post hepatectomy liver failure. Liver Int 2003; 23 Suppl 3: 44–51. 73. Liu JP, Gluud LL, Als-Nielsen D, et al. Artificial and bioartificial support systems for liver failure. Cochrane Database of Systematic Reviews 2004; Issue 1. Art No.: CD003628. DOI: 10.1002/14651858.CD003628. 74. Yanaga K, Kanematsu T, Takenaka K, et al. Intraperitoneal septic complications after hepatectomy. Ann Surg 1986; 203: 148–52. 75. Togo S, Matsuo K, Tanaka K, et al. Perioperative infection control and its effectiveness in hepatectomy patients. J Gastroent Hep 2007; 22: 1942–8. 76. Wu CC, Yeh DC, Lin MC, et al. Prospective randomised trial of systemic antibiotics in patients undergoing liver resection. Br J Surg 1998; 85: 489–93. 77. Paquet JC, Dziri C, Hay JM, et al. Prevention of deep abdominal complications with omentoplasty on the raw surface after hepatic resection. The French Association for Surgical Research. Am J Surg 2000; 179: 103–9. 78. Uetsuji S, Kwon AH, Komada H, et al. Clinical evaluation of closed suction drainage following hepatectomy. Surgery Today 1997; 27: 298–301. 79. Fong Y, Brennan MF, Brown K, et al. Drainage is unnecessary after elective hepatic resection. Am J Surg 1996; 171: 158–62. 80. Liu CL, Fan ST, Lo CM, et al. Abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases. Ann Surg 2004; 239: 194–201. 81. Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. Br Med J 2000; 321: 1493. 82. Lui S, Carpenter RL, Neal JM. Epidural anaesthesia and analgesia. Their role in postoperative outcome. Anaesthesiology 1995; 82: 1474–506.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 83. Matot I, Scheinin O, Eid A, et al. Epidural anesthesia and analgesia in liver resection. Anesth Analg 2002; 95:1179–81. 84. Page A, Rostad B, Staley CA, et al. Epidural analgesia in hepatic resection. J Am Coll Surg 2008; 206: 1184–92. 85. Basu S, Taamijmarane A, Bulters D, et al. An alternative method of wound pain control following hepatic resection: a preliminary study. HPB 2004; 6: 186–9. 86. Oliver JC, Welsh FKS, Bell J, et al. Elective intra-aortic balloon counterpulsation during a high-risk liver resection. Anaesth 2008; 63: 1365–8.

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87. Saner F. Kidney failure following liver resection. Transplant Proc 2008; 40: 1221–4. 88. Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med 2007; 357: 797–805. 89. Mehta RL, Kellum JA, Shah SV, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11: R31. 90. Togo S, Nagano Y, Masumoto C, et al. Outcome of and risk factors for incisional hernia after partial hepatectomy. J Gastrointest Surg 2008; 12: 1115–20.

8

Pancreatic resection Thilo Hackert, Moritz Wente, and Markus W. Büchler

background Pancreatic cancer remains—with an overall long-term survival rate of less than 1%—one of the most difficult cancers to treat. It is the fourth leading cause of cancer-related mortality in the Western world and is responsible for around 30,000 deaths per year in the United States and 65,000 per year in Europe (1,2). In only 10% to 20% of pancreatic cancer patients potentially curative surgery is possible, and even in these patients, the median survival is only 10 to 18 months with 5-year survival rates of approximately 20% to 25% (3,4). Nonetheless, surgery remains the only treatment option with the chance of cure. Pancreatic surgery has significantly changed during the past few years. Irrespectively, pancreas resections remain an intervention of particular significance, often technically challenging and with high logistic demands for preoperative diagnostics and perioperative management. Recently, the value of centralization of pancreatic surgery in “high volume institutions” has been demonstrated. The current mortality rates following pancreatic resections are well below 5% in specialized surgical centers (5,6).

standard resections Whipple Resection Partial Pancreaticoduodenectomy (Whipple resection) with or without distal stomach resection is the surgical option for tumors of the pancreatic head, which account for the majority of pancreatic cancers (Fig. 8.1). Pylorus-preserving pancreaticoduodenectomy has been proven to be equal to the classical pancreaticoduodenectomy in terms of tumor recurrence or long-term survival, and should therefore be considered the standard procedure for tumors of the pancreatic head (7). Key steps of the surgical procedure are the postpyloric division of the duodenum, which is usually carried out by use of a stapling device and—meanwhile common in many centers—the supracolic division of the ascending duodenum as soon as this portion is reached during resection. This modification facilitates the resection procedure and allows manual control of the pancreatic head without switching positions between the supra- and infracolic department. Division of the pancreas is done sharply above the superior mesenteric vein after this has been tunneled to make sure that the vein is not injured during resection and that the dissection can be done without vein replacement (see below). After removing the specimen, tumor-free resection margins should be confirmed intraoperatively by frozen sections of the cut end of the bile duct and the cut end of the pancreatic remnant. Bleeding control along the pancreatic dissection margin is achieves by carefully stitching single bleeding sites with monofilament and nonabsorbable sutures. The pancreatic duct must be seen and protected during this procedure. During pancreaticoduodenectomy, a standardized lymphadenectomy needs to be carried out. This includes the complete

dissection of the hepatoduodenal ligament, the lymph nodes along the common hepatic artery, portal vein, and the cranial portion of superior mesenteric vein as well as dissection of the right-sided lymph nodes of the celiac trunk and along the right side of the superior mesenteric artery (Fig. 8.2). Today, we have good evidence that there is no benefit for a more extended approach of lymphadenectomy. Meta-analysis from four randomized controlled clinical trials has shown no survival benefit after extended lymph node dissection but has demonstrated a significant increase in surgical morbidity (8). Completion of the dissection can then be done from the infracolic aspect by removing the first jejunal loop (20–25 cm) to ensure tensionless mobility of the next loop that is used for the following reconstruction and is transposed into the right upper quadrant transmesocolically. One of the most important operative steps to prevent severe postoperative complications is the pancreaticojejunostomy. We prefer to perform this anastomosis end-to-side in a twolayer fashion stitching the pancreatic duct separately (Fig. 8.3). Using this technique, insufficiency rates of less than 3.5% can be achieved (9,10). Bile duct reconstruction should be standardized as well to avoid leakage or postoperative bile collections. Although this complication is less frequent than pancreatic fistula, it may cause severe and long-lasting complications. An approach that can be performed even in technically challenging situations with small and deep ducts is the single-stitch distant suture of the posterior wall by a one-layer technique completed by single stitches of the anterior wall. Finally, an end-to-side duodenojejunostomy completes the reconstruction. Recent studies have shown that an antecolic reconstruction is much more favorable in terms of delayed gastric emptying (1,12). Drain placement seems to be another essential step at the end of the operation as there has been growing evidence that pancreatic leakage can be recognized and severe complications caused by intra-abdominal pancreatic fluid collections can be prevented by adequate drain positions. As there may be need for a long-lasting maintenance of intra-abdominal drains in case of fistulas, soft silicon drains should favorably be used. Drain removal—which can usually be done 48 hours postoperatively—should be preceded by analysis of pancreatic enzyme levels in the drain fluid. Amylase levels of more than 5000 iU/ml seem to represent a cutoff value for the recognition of pancreatic fistulas and should therefore be respected carefully (13–17). Distal Pancreatectomy Distal pancreatectomy is performed for tumors in the body or tail of the pancreas and includes—depending on the dignity of the underlying tumor—total splenectomy. From the surgical point of view, tumors above or on the left side of the superior

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Figure 8.1 Partial pancreaticoduodenectomy. Classical Whipple resection (left) and pylorus-preserving modification (right).

Figure 8.2 Intraoperative situs after partial pancreaticoduodenectomy. Pancreatic remnant with probe introduced, dissected portal vein and hepatic artery. A jejunal loop is prepared for the pancreaticojejunostomy.

mesenteric vein are suitably located for this procedure. Dissection of the pancreas is performed above the vein after tunneling and lifting up the body of the gland. The dissection itself can be done sharply or by using a stapling device, preferably with a thickness-adopted adjustment of the stapler. To date, there are no high-power studies to support either procedure. In case of sharp dissection, we prefer a V-shaped transection line. As in other resections, tumor-free resection margins should be examined by intraoperative frozen section. The pancreatic duct is separately closed by a monofilament Z-shaped nonabsorbable suture and the transection line can afterward be closed by single stitches covering the complete margin by pancreatic capsular tissue. There is no need or evidence for any further covering of the resection margin by sealants or patches (18). This procedure implies a certain limitation concerning the extent of distal resection toward the head of the

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pancreas. The larger the tissue area of the transected parenchyma gets, the more difficult it gets to close the parenchyma, which is associated with increased fistula rates. Therefore, the right margin of the superior mesenteric vein represents the limit to which a safe surgical closure of the pancreatic remnant can be performed. In case of transection by a stapling device, this limitation is technically implied by the length of the stapler line. No additional sutures are necessary after stapler dissection. Despite all approaches, fistula development after distal pancreatectomy remains an unsolved problem. Fistula rates range from 12% to 40% (8,19). To address this clinical problem, remnant closure by sutures after sharp dissection is currently compared to stapler dissection in a randomized controlled study (DISPACT trial) in a multicenter approach including 21 European centers and 360 patients by February 2009 (20). A spleen-preserving distal pancreatectomy can be performed in benign lesions or intraductal papillary mucinous neoplasias (IPMNs), if the splenic vessels are not involved in the tumor or cystic process. However, there are no clear advantages in preserving the spleen in adult patients (21). Possible advantages could be infection prophylaxis, less operative blood loss, fistula rates as well as fewer thromboembolic complications (22,23). By contrast, the risk of splenic infarction and portal hypertension has to be regarded whenever the spleen is preserved. From the currently available literature— mainly retrospective studies—none of these parameters is clearly proven, further studies have to address this topic in the future. By contrast, there is growing evidence that distal pancreatectomy can be performed with good results laparoscopically. This approach is usually performed using 5 trocars and stapler dissection of the pancreas. It is routinely performed in several centers with results comparable to the open approach in terms of operative morbidity and outcome (23). The possible advantages of laparoscopic operations, with faster patient recovery, less pain medication, and better cosmetic results are currently evaluated in larger series. Total Pancreatectomy The concept of total pancreatectomy has to be divided into the rescue procedure in not conservatively managed postoperative

PANCREATIC RESECTION

Figure 8.3 Pancreatico-jejunostomy. Preparation of duct sutures (upper left), position of the jejunal loop (upper right), anterior wall sutures (lower left), and completed anastomosis (lower right).

complications caused by the pancreatic remnant after head resections and the primarily performed total removal of the gland with or without the spleen (24). Completion pancreatectomy may be necessary in case of severe complication like insufficiency of the pancreaticojejunostomy with septic or bleeding complications. In this situation, an early completion operation can be life-saving for the patient and is technically similar to a distal pancreatectomy after disconnection of the pancreas anastomosis (25,26). Primary total pancreatectomy can be required in patients with a nonaltered pancreatic remnant due to the soft tissue texture, e.g., in distal bile dust cancer or duodenal tumors without congestion of the pancreatic duct, which can make the pancreatic anastomosis a dangerous reconstruction. The surgeon has to evaluate the cost–benefit relation carefully; in doubtful situations a risky anastomosis should rather be avoided. From the oncological point of view, extensive main-duct IPMNs, IPMNs with progression to carcinoma, familial or multifocal pancreatic cancer are indications for a primary total pancreatectomy. Furthermore, this procedure may be necessary if a tumor-free resection margin and R0 situation cannot be achieved otherwise (24–29). The resection can be performed as a two-part procedure with an

initial head resection similar to a Whipple procedure followed by the distal resection, which facilitates the surgical preparation, or with a removal of the gland as a complete specimen, if a pancreatic transection implies the risk of tumor cell spilling. Whenever possible, a pylorus-preserving reconstruction should be preferred. Duodenum-Preserving Pancreatic Head Resection The best technique for the surgical treatment of pancreatic head lesions in chronic pancreatitis is still under debate. Partial pancreatoduodenectomy with or without preservation of the pylorus have served for many years as the primary surgical procedure. However, these resections are unsatisfactory in terms of late morbidity with an incidence of up to 48% of postoperative diabetes mellitus (30). Today, duodenumpreserving pancreatic head resection duodenum-preserving pancreatic head resection (DPPHR), which was introduced by Beger in 1972 (31), has undergone several modifications and is considered the standard procedure for nonmalignant head lesions in chronic calcified pancreatitis (32). Whenever possible, depending on the extent of the calcified and fibrotic lesions, the Berne modification as the most tissue-sparing

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS approach should be performed (Fig. 8.4). The surgical procedure starts with an extensive Kocher maneuver of the pancreatic head to palpate the head of the pancreas and achieve bleeding control by compression during the resection phase. The anterior aspect of the head should be prepared under dissection of the right gastroepiploic vessels and ligation of the gastroduodenal artery to minimize blood loss during excision of the head. It is not necessary to tunnel the pancreas above the mesenteric vein, especially as this is often difficult due to the chronic inflammatory adherence of the parenchyma. The resection margin should be defined by circular sutures around the altered tissue area. Afterward, the head is sharply excised manually to control bleeding and perforation of the posterior parenchyma layer. All fibrotic and calcified tissue should be removed and the pancreatic duct has to be opened and inspected to extract stones and ensure free drainage into the resection cavity. Special attention has to be paid to the bile duct. In case of preoperative cholestasis and/or preceding stents, the bile duct needs to be opened by a T-shaped incision and the orifice should be fixed in the

Figure 8.4 Pylorus-preserving pancreatic head resection (Berne modification). Note the incision and fixation of the bile duct in the resection cavity.

resection cavity to avoid postoperative recurrence of bile duct stenosis (33). Hemostasis in the resection cavity is achieved by selective single stitches with nonabsorbable sutures. The operation is completed by an anastomosis with a Roux-Y-transected jejunal loop in a side-to-side fashion by a two-layer running suture (Fig. 8.5). As in all other resections, drainage placement is important to monitor postoperative secretion and recognize possible fistula development soon. the DPPHR procedure is widely accepted nowadays and has proven to be equally efficient as the Whipple procedure in terms of long-term pain relief, overall morbidity and mortality combined with significantly less intraoperative blood replacement, shorter hospital stay, more postoperative weight gain, less exocrine insufficiency, better occupational rehabilitation, and quality of life in randomized controlled trials and a recent meta-analysis (32–37). Segmental Resection Segmental resections of the pancreas can be performed in benign lesions located in the body of the gland (38). Surgical technique includes a careful mobilization of the pancreatic segment under clipping of vessels followed by sharp dissection of the defined segment. Afterward, reconstruction was done by two-layer sutured anastomosis toward the tail of the pancreas similar to the Whipple anastomosis and V-shaped closure of the dissected margin toward the pancreatic head comparable to the left resection technique. In case of extended resections toward the head leading to a large resection margin, this can additionally be sealed with a seromuscular patch using the jejunal loop that has been anastomosed onto the pancreatic tail before. No fibrin glue or other sealants are required. At present, fistula rates between 8% and 63% are reported, which shows the heterogeneity of the present studies (38–41). However, a surgical mortality of 2% shows that segmental resections can be performed safely and offers a useful tissue-sparing tool in selected patients. Enucleation Especially benign tumors, cystic lesions or IPMNs do not necessarily require extensive pancreatic resections to

Figure 8.5 Pylorus-preserving pancreatic head resection (Berne modification). Resection cavity with first layer of the posterior wall of the pancreaticojejunostomy (left), completed anastomosis (right).

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PANCREATIC RESECTION achieve surgical cure. Limited resections represent a tissuesparing treatment option to minimize the risk of exocrine or endocrine pancreatic insufficiency postoperatively (42) and to reduce surgical morbidity and mortality by reduced operative trauma. One of the most important aspects to perform an enucleation successfully is the accurate localization of the tumor or cystic lesion. Besides preoperative localization by CT or MRI scan, the most important tool for tumor location is the experience of the surgeon performing the exploration (43–46). Mobilization of the pancreas is essential when tumors or cystic lesions have to be located to enable a careful digital examination of the suspected lesion. This should be supplemented by intraoperative ultrasound to exclude multifocal tumorous lesions especially in endocrine tumors or IPMNs. In addition, a possible relation to the pancreatic duct can only be clarified by ultrasound examination, if there is any doubt about it intraoperatively (47). A tumor size of 2.5 cm in diameter can be regarded as the limit for a safely performed enucleation. Tumors measuring more than 2.5 cm in size show malignant histological changes significantly more frequently, making a local surgical approach impossible. Besides, tissue trauma and wound surface following an enucleation reach a critical size for development of fistulas or other complications including bleeding or postoperative pancreatitis (47). Enucleation itself is performed by careful dissection along the tumor under clip ligation or stitching of vessels supplying the lesion (Fig. 8.6). There is no evidence for

Figure 8.6 Tumor enucleation in the body of the pancreas.

any sealant or glue application after completing of the enucleation. Drain placement is essential as currently fistula rates of approximately 20% are reported (48), most of them, however, clinically uncomplicated.

exceptional indications Vessel Resections A common problem in pancreatic head resections is tumor adherence to the superior mesenteric or portal vein. Today, portal vein resection has become an established procedure and can be carried out with morbidity rates of that are comparable to standard Whipple procedures (49–56). Portal vein resection can be performed as a tangential resection with a direct suture or a patch reconstruction. In cases where a segmental resection is required due to a more extensive tumor adherence, either a direct anastomosis or the interposition of an autologous venous graft such as the saphenous vein or an allograft, e.g., a gore-tex tube. In case of a primary anastomosis, it is essential to mobilize the mesenteric root completely, which implies the complete mobilization of the right hemicolon. After this preparation, a tension-free reconstruction of defects up to 3 cm length is usually possible. The anastomosis is performed as a running suture of the posterior and anterior vessel wall with two 5-0 or 6-0 nonabsorbable sutures. When defects cannot be reconstructed by the patient’s vein alone, a size-adopted graft should be inserted in a similar end-to-end manner (52). Kinking of any venous anastomosis must be avoided to prevent intra- and postoperative vein or graft thrombosis with consecutive failure of the bowel circulation. In certain situations, it may be helpful not only to minimize the time of intraoperative occlusion of the mesenteric/portal vein but also to clamp the superior mesenteric artery for this period to avoid venous congestion and swelling of the small bowel and the right hemicolon (Fig. 8.7). Arterial resection is a rather uncommon surgical procedure during pancreatic cancer resection. If the superior mesenteric artery is involved in the tumor process, this is a general exclusion criterion for resection and has only been reported in few patients (56). By contrast, tumor adherence or infiltration along the celiac axis must not be considered as generally irresectable (43,53). In selected patients, the celiac trunk might be resected down to its aortic orifice in Whipple as well as in left resection or total pancreatectomies (54–56). As long as the proper hepatic artery can be preserved, a reconstruction is possible. The left gastric and splenic artery can usually be cut without reconstruction, a consecutive

Figure 8.7 Examples of portal vein resections. Direct end-to-end anastomosis (left) and graft implantation (right).

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS splenectomy may be necessary in some patients. Restoration of the hepatic perfusion must be ensured by re-anastomosing the proper or common hepatic artery. This reconstruction can be done with an interposition of any arterial vessel of the celiac axis or a venous interposition graft. However, the arterial perfusion of the liver should be controlled by regular duplex examinations and restored aggressively in case of a vessel occlusion. Arterial hepatic perfusion failure may otherwise cause acute problems postoperatively in terms of liver ischemia, necrosis, and infection and is a risk factor for bile duct-associated complications in the long-term follow-up (54,55). Yet, it needs to be mentioned that there are no larger patient series on arterial resections in pancreatic surgery. Therefore, this procedure can be carried out safely in experienced hands but is not based on high-quality scientific data and outcome studies so far. Multivisceral Resections There are several studies (57–60) on the outcome after multivisceral resection for pancreatic cancer. In general, resection of adjacent organs, most commonly the stomach or left hemicolon in left resections and the right hemicolon in Whipple procedures as well as either adrenal gland or kidney in both types of resection can be performed safely to achieve a R0 situation. Technically, an en bloc resection should be performed without preparation along or injuring the tumor surface. This may result in “typical” resections such as right or left colectomies as well as individual segmental- or wedge-type resections. Multivisceral approaches can also be combined with vessel resections of the portal vein or the celiac axis. From the limited number of available studies, this approach is associated with an increased intraoperative blood loss and overall surgical morbidity as well as ICU and hospital stay (58,60). However, there seems to be a survival advantage in these patients and overall mortality is not increased compared to standard resections (59,60). Due to the limited number of patients reported so far, it is not possible to give valid data on long-term

oncological outcome, making multivisceral resections an individually tailored approach that requires careful patient selection and surgical experience. Recurrence Resections Localized recurrence in pancreatic cancer may be an indication for relaparotomy and resection in selected patients. Although a large number of recurrences are located close to the arterial vessels, and therefore not resectable, recent studies support the concept of surgical exploration and resection whenever possible (61–63). This approach can be combined with intraoperative radiotherapy and radiation of the tumor bed to reduce the risk of another recurrence at the site of resection (Fig. 8.8). In case of local irresectability, intraoperative radiation can be performed with a palliative intention in terms of tumor reduction and pain control. An extended resection of the recurrent tumor with arterial vessels does not seem to be justified as the chance for a radical tumor removal is poor and patients do not seem to benefit from R1 or R2 resections. The available studies report successful resection rates of approximately 50% with acceptable surgical morbidity and suggest a survival benefit for those patients, especially in situations with a long time interval (>9–12 months) between the initial tumor diagnosis and the recurrence manifestation (63). As these are observational studies, there is no proven evidence for this approach today and larger controlled trials are required to evaluate long-term oncological value. Metastasis Resections Resection for metastatic pancreatic cancer is clearly restricted to exceptional indication and has only been reported anecdotally so far (64,65). Most commonly, the indication for metastasis resection arises in young patients with the accidental finding of a synchronous single liver lesion intraoperatively, which can be removed without increasing operative morbidity (64). Apart from this individual indication, metastasis resection can be performed in long-term survivors with

Figure 8.8 Pancreatic cancer recurrence resection. Intraoperative finding of the recurrence located in the interaortocaval space (left), situs after resection (right) prior to intraoperative radiation.

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PANCREATIC RESECTION localized metastastic disease, indicating favorable tumor biology and justifying the aggressive operative approach. This has to be embedded in a global oncological concept, must be decided highly individually and cannot be regarded as a standard procedure (65).

conclusion Pancreatic surgery has undergone a remarkable development during the last decades. Appropriate surgical approaches have been established and can be used in differential indications today. In pancreatic cancer, standard resections include the classical Whipple operation and the pylorus-preserving modification, which should be preferred whenever possible as well as a distal or total pancreatectomy in extended tumors of the gland. All of these procedures can be carried out safely with surgical mortality rates well below 5% in specialized centers due to a high grade of standardization and experience. Modern tissue-sparing procedures such as the duodenum-preserving pancreatic head resection in chronic pancreatitis or tumor enucleations offer limited approaches for circumscribed nonmalignant pancreatic pathologies. Furthermore, extended resections for the treatment of pancreatic malignancies— including multivisceral and recurrence resections—are technically feasible although the oncological outcome of these procedures has to be further evaluated and pancreatic cancer treatment must always be embedded in an interdisciplinary concept of surgery and adjuvant therapy to ensure best possible outcome.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 36. Klempa I, Spatny M, Menzel J, et al. Pancreatic function and quality of life after resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized comparative study after duodenum preserving resection of the head of the pancreas versus Whipple’s operation. Chirurg 1995; 66: 350–9. 37. Izbicki JR, Bloechle C, Knoefel WT, et al. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized trial. Ann Surg 1995; 221: 350–8. 38. Müller MW, Friess H, Kleeff J, et al. Middle segmental pancreatic resection: An option to treat benign pancreatic body lesions. Ann Surg 2006; 244: 909–18; discussion 918–20. 39. Bassi C. Middle segment pancreatectomy: A useful tool in the management of pancreatic neoplasms. J Gastrointest Surg 2007; 11: 726–9. 40. Adham M, Giunippero A, Hervieu V, Courbière M, Partensky C. Central pancreatectomy: Single-center experience of 50 cases. Arch Surg 2008; 143: 175–180; discussion 180–1. 41. Christein JD, Smoot RL, Farnell MB. Central pancreatectomy: A technique for the resection of pancreatic neck lesions. Arch Surg 2006; 141: 293–9. 42. Fang WL, Su CH, Shyr YM, et al. Functional and morphological changes in pancreatic remnant after pancreaticoduodenectomy. Pancreas 2007; 35: 361–5. 43. Chung JC, Choi SH, Jo SH, et al. Localization and surgical treatment of the pancreatic insulinomas. ANZ J Surg 2006; 76: 1051–5. 44. Ritzel RA, Isermann B, Schilling T, et al. Diagnosis and localization of insulinoma after negative laparotomy by hyperinsulinemic, hypoglycaemic clamp and intra-arterial calcium stimulation. Rev Diabet Stud 2004; 1: 42–6. 45. Kisker O, Bastian D, Bartsch D, Nies C, Rothmund M. Localization, malignant potential, and surgical management of gastrinomas. World J Surg 1998; 22: 651–7; discussion 657–8. 46. Schmitz-Winnenthal FH, Z’graggen K, Volk C, Schmied BM, Büchler MW. Intraductal papillary mucinous tumors of the pancreas. Curr Gastroenterol Rep 2003; 5: 133–40. 47. Lee CJ, Scheiman J, Anderson MA, et al. Risk of malignancy in resected cystic tumors of the pancreas < or =3 cm in size: Is it safe to observe asymptomatic patients? A multi-institutional report. J Gastrointest Surg 2008; 12: 234–42. 48. Crippa S, Bassi C, Salvia R, et al. Enucleation of pancreatic neoplasms. Br J Surg 2007; 94: 1254–9. 49. Fuhrman GM, Leach SD, Staley CA, et al. Rationale for en bloc vein resection in the treatment of pancreatic adenocarcinoma adherent to the superior mesenteric-portal vein confluence. Pancreatic Tumor Study Group. Ann Surg 1996; 223(2): 154–62. 50. Hartel M, Niedergethmann M, Farag-Soliman M, et al. Benefit of venous resection for ductal adenocarcinoma of the pancreatic head. Eur J Surg 2002; 168(12): 707–12.

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51. Harrison LE, Klimstra DS, Brennan MF. Isolated portal vein involvement in pancreatic adenocarcinoma. A contraindication for resection? Ann Surg 1996; 224(3): 342–7; discussion 347–9. 52. Weitz J, Kienle P, Schmidt J, Friess H, Büchler MW. Portal vein resection for advanced pancreatic head cancer. J Am Coll Surg 2007; 204(4): 712–6. Epub 2007 Feb 26. 53. Hartel M, Wente MN, Di Sebastiano P, Friess H, Büchler MW. The role of extended resection in pancreatic adenocarcinoma: is there good evidence-based justification? Pancreatology 2004; 4(6): 561–6. Epub 2004 Nov 15. 54. Martin RC 2nd, Scoggins CR, Egnatashvili V, et al. Arterial and venous resection for pancreatic adenocarcinoma: operative and long-term outcomes. Arch Surg 2009; 144(2): 154–9. 55. Nakao A, Takeda S, Inoue S, et al. Indications and techniques of extended resection for pancreatic cancer.World J Surg 2006; 30(6): 976–82; discussion 983–4. 56. Yekebas EF, Bogoevski D, Cataldegirmen G, et al. En bloc vascular resection for locally advanced pancreatic malignancies infiltrating major blood vessels: Perioperative outcome and long-term survival in 136 patients. Ann Surg 2008; 247(2): 300–9. 57. Sasson AR, Hoffman JP, Ross EA, et al. En bloc resection for locally advanced cancer of the pancreas: is it worthwhile? J Gastrointest Surg 2002; 6(2): 147–57; discussion 157–8. 58. Shoup M, Conlon KC, Klimstra D, Brennan MF. Is extended resection for adenocarcinoma of the body or tail of the pancreas justified? J Gastrointest Surg 2003; 7(8): 946–52; discussion 952. 59. Imamura M, Doi R. Treatment of locally advanced pancreatic cancer: Should we resect when resectable? Pancreas 2004; 28(3): 293–5. 60. Kleeff J, Diener MK, Z’graggen K, et al. Distal pancreatectomy: risk factors for surgical failure in 302 consecutive cases. Ann Surg 2007; 245(4): 573–82. 61. Meyers MO, Meszoely IM, Hoffman JP, et al. Is reporting of recurrence data important in pancreatic cancer? Ann Surg Oncol 2004; 11(3): 304–9. 62. Shibata K, Matsumoto T, Yada K, et al. Factors predicting recurrence after resection of pancreatic ductal carcinoma. Pancreas 2005; 31(1): 69–73. 63. Kleeff J, Reiser C, Hinz U, et al. Surgery for recurrent pancreatic ductal adenocarcinoma. Ann Surg 2007; 245(4): 566–72. 64. Shrikhande SV, Kleeff J, Reiser C, et al. Pancreatic resection for M1 pancreatic ductal adenocarcinoma. Ann Surg Oncol 2007; 14(1): 118–27. Epub 2006 Oct 25. 65. Gleisner AL, Assumpcao L, Cameron JL, et al. Is resection of periampullary or pancreatic adenocarcinoma with synchronous hepatic metastasis justified? Cancer 2007; 110(11): 2484–92.

9

Surgical complications of pancreatectomy Steven C. Katz and Murray F. Brennan

Pancreatic resection and the associated complications remain challenging problems for patients and surgeons. Since the earliest reports describing the technique of pancreaticoduodenectomy (PD) by Kausch and Whipple, significant reductions in operative mortality and morbidity have been achieved (1,2). Postoperative mortality rates have been reduced from greater than 25% in the 1960s to less than 5% in specialized centers (3). The lower risk of death following pancreatic resection is due to advances in operative technique, improvements in perioperative care, percutaneous and endoscopic management of complications, and refinements in patient selection (4). Unfortunately, morbidity rates for PD continue to exceed 30% to 40% in large series (5–9). We discuss the prevalence, nature, predisposing factors, and management for major surgical complications that occur following pancreatic resection. While there are many nonsurgical complications that occur following pancreatic resection, these are not addressed. Right, left, central, and total pancreatectomies are discussed separately where appropriate. The most common individual complications are considered, followed by factors affecting morbidity rates. Throughout, we outline operative strategies and postoperative interventions that impact the risk and severity of surgical complications following pancreatectomy.

specific complications Pancreatic Anastomotic Leak and Pancreatic Fistula Pancreatic leak occurs in 7% to 29% of patients following pancreatic resection (Tables 9.1 and 9.2) (5,7,10–14). The wide range in incidence is due in part to variability in defining the manifestations of pancreatic leaks and several classification systems have been proposed (9,15,16). Given similarity in management and clinical manifestations, pancreatic leak, fistula, fluid collection, and abscess will be considered together (12). Parenchymal consistency and the extent of operation are associated with pancreatic leak following right or left pancreatectomy (Table 9.3) (17). Small pancreatic duct diameter is a predictor of leak following PD (7,18). Management of fluid collections resulting from a pancreatic leak may involve operative drains, placement of postoperative drains, or reoperation (Fig. 9.1). Vin et al. reported that prolonged drainage was predicted by volume collected during the first 48 hours, fluid amylase >1000, or distal pancreatectomy (12). The magnitude of the pancreatic leak may also depend on whether the source is the main duct or parenchyma (19). Those patients who do develop pancreatic leaks are more likely to suffer from other complications or death, and this risk is exacerbated by superimposed infection (12). Numerous strategies have been attempted to minimize the chances of pancreatic leakage and these are discussed below.

Delayed Gastric Emptying The incidence of delayed gastric emptying (DGE) following PD ranges from 4% to 29% (5,11,13) and is associated with other intraabdominal complications (Table 9.1). While DGE is not associated with an increased risk of death, it does prolong hospitalization time (5,20). Parameters used to define DGE include the volume of nasogastric tube output, the length of time before tolerance of oral feeding, and results of scintigraphic studies. At our institution, DGE is defined as failure to achieve oral intake sufficient to maintain adequate hydration by postoperative day 10 (9). DGE is thought to be due to numerous factors, including management of the pylorus, extent of retroperitoneal dissection, intraabdominal fluid collections, and decreased motilin activity (21). Early reports indicated that pylorus-preserving pancreaticoduodenectomy (PPPD) increased the risk of DGE (22,23) but subsequent studies have failed to confirm this (Table 9.4) (24,25). Radical resection or extended retroperitoneal dissection may also be associated with DGE (26). It is unclear if more extensive dissection has a direct effect or if higher rates of pancreatic leak, sepsis, or hemorrhage predispose to DGE (25). Expeditious management of fluid collections, infection, or bleeding may limit gastric dysmotility. An additional contributing factor to DGE may be reduced levels of circulating motilin following PD (27). In a randomized control trial (RCT) including 118 patients undergoing PD, erythromycin, the motilin analogue, reduced the DGE rate from 30% to 19% compared to placebo (21). By contrast, routine nasogastric decompression or withholding of oral feeding has not been shown to affect the rate of DGE. Based upon data from RCTs involving patients subjected to gastrectomy, routine nasogastric tube placement following pancreatic surgery is unnecessary (28,29). Furthermore, early oral feeding should be considered following major abdominal procedures (30,31). Postpancreatectomy Hemorrhage Postpancreatectomy hemorrhage (PPH) occurs in 2% to 9% of cases and the consequences may be severe (8,32–37). The initial evidence of hemorrhage may be the “sentinel bleed,” which is present in 30% to 100% of patients prior to massive PPH (38–41). Risk of PPH is related to inadequate intraoperative hemostasis, bile leak, pancreatic leak, intraabdominal infection, and sepsis (39,40,42–44). The presence of jaundice at the time of pancreatic resection may increase the risk of PPH, but this is not lessened by preoperative biliary drainage (37). The implications and management of PPH vary depending on the time of onset and source (4). Postoperative bleeding within the first 24 hours is most often due to a technical failure and requires reoperation if severe (35). The most appropriate course of action for PPH occurring beyond the immediate postoperative period will

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 9.1 Complications Following Pancreaticoduodenectomy Author Balladur (42) Bottger (10) Gouma (11) Balcom (5) Muscari (7) Winter (13) Vin (12) House (49) Baker (47)

N

Pancreatic Fistula or Leak

Delayed Gastric Emptying

Hemorrhage

Bile Leak

Overall Complications

223 228 300 489 300 1423 680 356 440

13% 8% 7% 13% 17% 9% 18% 15% 16%

NR NR 29% 12% NR 15% NR 4% 7%

9% NR 5% NR 6% NR NR NR 2%

NR <1% 2% 2% <1% 2% NR NR 2%

41% 26% 48% 39% 39% 38% NR 38% 36%

Death 9% 6.1% 10.1% 11% 2% 2.0%* 1.7% 1.6%

*Includes pancreaticoduodenectomy, central pancreatectomy, and distal pancreatectomy.

Table 9.2 Complications Following Distal Pancreatectomy Author Bottger (10) Balcom (5) Pannegeon (103) Siergaza (104) Ridolfini (105) Kleeff (50) Ferrone (14) Vin (12)

N

Fistula or Leak

Hemorrhage

Overall Complications

72 190 175 132 64 302 462 220

13% 13% 23% 14% 22% 12% 29% 13%

NR NR 2% 4% 3% 3% NR NR

27% 26% 42% 57% 37% 35% NR NR

Death 1.7% 1.5% 0 5.0% 1.5% 2.0% 0.8% 2.0%*

*Includes pancreaticoduodenectomy, central pancreatectomy, and distal pancreatectomy.

Table 9.3 Predictors of Pancreatic Leak or Fistula Following Pancreaticoduodenectomy Small duct diameter (7,10) Friable parenchyma (7,10) Extended resection (7) Placement of intraoperative drains (59) Blood loss (10) Obesity (49) Following Distal Pancreatectomy Multivisceral resection (14,104,105) Proximal (body) transaction (103) Friable parenchyma (105) Malnutrition (104) Obesity (14)

depend on its location. Extraluminal PPH may arise from the gastroduodenal artery (GDA), splenic artery, or tributaries of the superior mesenteric vessels. Intraperitoneal hemorrhage is often associated with a pancreatic leak and options include reoperation or angioembolization. When reoperation is selected, completion pancreatectomy and suture ligation of the bleeding vessel have been advocated (45). Operative intervention more than 1 week following pancreatic resection may be particularly challenging due to adhesions and tissue friability (46). Arterial embolization is valuable under these circumstances, with a success rate of approximately 80% (Fig. 9.2) (41). We advocate distal ligation of the GDA to

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ensure the technical feasibility of angioembolization as it may not be possible when the bleeding point is in close proximity to the common hepatic or superior mesenteric artery. Intraluminal PPH should be initially addressed endoscopically and may originate from anastomoses, mucosal ulceration, or the cut pancreatic surface. When bleeding is found to originate from the cut pancreatic surface, hemostasis may be achieved during reoperation through a jejunotomy or gastrotomy (32). In summary, PPH may occur in up to 9% of patients. The timing and location of the bleeding in patients suffering from PPH are important factors in predicting outcome and determining appropriate management. The overall mortality of PPH is as high as 16% and delayed PPH is associated with a 47% chance of death (41,43). Appreciation of the clinical factors associated with PPH, including sentinel bleeding, sepsis, and pancreatic leak, facilitates prompt recognition. Bile Leak The incidence of choledochoenteric leak following PD is notably lower than pancreatic leak or fistula (Table 9.1). The larger size of the bile duct and more reliable tissue integrity may account for the relative infrequency of biliary leak when compared to pancreatic leak. Similar to pancreatic leak, bile leak is associated with both sterile and infected intraabdominal fluid collections (47). The vast majority of biliary leaks or fistulae can be managed by percutaneous, transhepatic, or transabdominal drainage (48).

SURGICAL COMPLICATIONS OF PANCREATECTOMY Table 9.4 Pylorus Preservation DGE %

Morbidity %

Mortality %

LOS (days)

OR TIME (minutes)

EBL

Author

N

PD

PPPD

PD

PPPD

PD

PPPD

PD

PPPD

PD

PPPD

PD

PPPD

Van Berge Henegouwen (25)

200

34

37

48

44

6

1

20

18*

1580

1247*

360

288*

Lin (23)

31

6

38

50

56

0

6

–

–

687

451

237

215

Jimenez (106)

62

12

33

45

44

0

3

12

15*

723

707

–

–

114

45

32

72

57*

5

3

24

25

2096

1453*

476

404*

Seiler (24)

*p < 0.05, DGE = delayed gastric emptying, PD = standard pancreaticoduodenectomy, PPPD = pylorus-preserving pancreaticoduodenectomy, LOS = length of stay, EBL = estimated blood loss.

Figure 9.1 The patient presented with fever and abdominal pain 2 weeks after a pancreaticoduodenectomy. A CT scan revealed a fluid collection in the RUQ (long arrow), which was managed with CT-guided percutaneous drainage (catheter indicated by short arrow). The amylase level in the aspirated fluid was consistent with a pancreatic leak (11,320 U/L).

Death Long-term survival following pancreatic resection is a function of the underlying disease, while perioperative mortality is related to the occurrence of complications, in addition to patient, institutional, and technical factors. Fortunately, the perioperative mortality rate following pancreatic resection has been reported to be less than 2% in the most recent large series (12–14,47,49,50). Pancreatic leak (11) and PPH (40,51,52) are the complications most frequently associated with perioperative mortality. As noted above, the improved mortality rates following pancreatic resection are due in large part to better management of complications. The vast majority of complications can be managed percutaneously, thereby reducing their severity and the risk of death (47).

factors affecting complication rates following pancreatectomy Pancreatic Duct Management Following Resection Pancreatic leaks prolong hospitalization, and are associated with other complications including DGE, intraabdominal abscess, and cholangitis (3,53). Numerous strategies for management of the pancreatic duct following PD have been advocated, including pancreaticojejunostomy (PJ), pancreaticogastrostomy (PG), and duct ligation (DL). In addition, several technical modifications to distal pancreatectomy (DP) have been tested to reduce the leak rate.

Figure 9.2 Following a pancreaticoduodenectomy and hemodynamic instability, metallic coils were placed in the gastroduodenal artery stump (long arrow) to treat a suspected pseudoaneurysm. The catheter is positioned within the common hepatic artery (short arrow).

Investigators at Johns Hopkins compared PG and PJ in 145 patients who underwent PD and found that the two methods were associated with similar leak rates (53). Several

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS variations of PJ have been reported including invagination, end-to-side anastomosis, and side-to-side anastomosis. When compared to end-to-side (duct to mucosa) PJ, end-to end (invaginating) PJ was associated with a trend toward a higher pancreatic fistula rate (15% vs. 4%, p > 0.05). (54) Pancreatic duct ligation following PD as opposed to PG or PJ posed a greater risk of adverse outcomes (55). Marcus et al. also reported that duct ligation following PD was an independent risk factor for pancreatic leakage (18). Whether PG or PJ is employed, ensuring robust perfusion to the cut pancreatic surface prior to anastomosis is essential (56). Various techniques have been applied to both right and left pancreatic resections. Suc et al. (57) conducted an RCT with 182 patients undergoing DP or PD and determined that the use of fibrin glue did not affect the overall complication rate or incidence of pancreatic fistula. Thaker et al. reported that the use of absorbable mesh with a stapler reduced the leak rate significantly among 40 patients undergoing DP compared to the 40 control cases (58). Ferrone et al. did not confirm the efficacy of reinforcing pancreatic transection margins (14). Peritoneal Drainage The only randomized trial addressing the value of routine intraperitoneal drainage following pancreatic resection did not show a benefit (59). Patients who underwent pancreatic resection at the Memorial Sloan-Kettering Cancer Center were randomized to placement of closed suction drains (n = 88) or to no drain placement (n = 91). Those patients who had drains placed were significantly more likely to develop intraperitoneal sepsis, fluid collections, or fistulae (22% vs. 9%, p < 0.02). Thus, placement of drains following pancreatic resection should be considered on a selective basis. Octreotide The pathogenesis of pancreatic leaks has been thought to involve the enzymatic activity of the exocrine secretions. Thus, investigators have tested the ability of octreotide, a synthetic somatostatin analogue, to reduce the risk of postpancreatectomy complications (Table 9.5) (60). The majority of trials demonstrated that octreotide was associated with a significant reduction in perioperative morbidity (61–64). Two trials showed a significant reduction in the incidence of pancreatic fistula in patients receiving octreotide (62,63). The overall frequency of pancreatic fistula was particularly low in two of the trials in which octreotide and placebo were similar (65,66).

The trials differ with respect to the proportion of patients undergoing right or left pancreatic resection, frequencies of various diagnoses, the dose of octreotide, and the definitions of pancreatic leak. Given the discrepant results among available trials, the routine use of octreotide for the prevention of pancreatic fistulas cannot be recommended. Individuals at high risk for pancreatic leak (61), such as those with ampullary cancer or soft, friable glands may benefit from exocrine inhibition. The cost of the drug must be balanced against its impact on length of stay and potential avoidance of additional procedures. Pylorus-Preserving Pancreaticoduodenectomy In a RCT comparing classic PD and pylorus-preserving PD (PPPD), the incidence of pancreatic fistula was not significantly different but PPPD was associated with more instances of DGE (23). This study was limited by small sample size and the difference in incidence of DGE between the two groups was not statistically significant. A subsequent RCT demonstrated that cumulative morbidity was significantly more frequent following classic PD when compared to PPPD (72% vs. 57%, p = 0.05) (24). Other trials failed to show significant differences in the rates of DGE or overall surgical complications when comparing classic PD to PPPD (Table 9.4). The decision to perform a PPPD or classic PD is a matter of surgeon preference as the two procedures do not result in markedly different perioperative outcomes. Extended Lymphadenectomy and Resection of Contiguous Structures Several investigators have studied the impact of extended retroperitoneal lymphadenectomy in patients with adenocarcinoma of the pancreas. In a multicenter prospective randomized trial involving 81 patients, extended lymphadenectomy did not significantly affect operative time, blood loss, morbidity, or mortality when compared to the standard dissection (67). The number of lymph nodes removed was similar among the two groups and the extent of resection did not correlate with locoregional control. Yeo et al. reported that radical PD increased operative times (68), as well as the rates of pancreatic fistula, delayed gastric emptying, and overall morbidity (26). Radical or extended PD does not appear to confer an oncologic benefit in patients with adenocarcinoma and may be associated with higher morbidity rates.

Table 9.5 Prophylactic Octreotide Pancreatic Fistula % Author Buchler (61) Pederzoli (64) Montorsi (63) Friess (62) Lowy (65) Yeo (66)

Mortality %

N

Placebo

Octreotide

Placebo

Octreotide

Placebo

Octreotide

246 252 218 247 110 211

38 19 20 22 6 11

18^ 9 9* 10* 12 9

55 29 36 30 25 34

32* 16* 22* 16* 30 40

5.8 3.8 5.6 0.8 0 0

3.2 1.6 8.1 1.6 2 1

*p < 0.05 versus the control group, ^statistical significance not indicated.

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Morbidity %

SURGICAL COMPLICATIONS OF PANCREATECTOMY Among the 10% to 20% of patients with adenocarcinoma of the pancreas who are potentially curable, resection of contiguous structures, including the portal vein or spleen, may be necessary in up to 39% (69). While those undergoing resection of contiguous structures may experience higher degrees of intraoperative blood loss and longer hospital stays, perioperative and long-term outcomes are not significantly different (70). When portal vein involvement is the only factor precluding a potentially curative pancreatectomy, resection of the vessel with appropriate reconstruction may be performed without a significant change in operative mortality (71). In a separate study, splenectomy did not lead to increased perioperative morbidity but was associated with decreased survival in patients with pancreatic adenocarcinoma (72). Whether these findings are the result of direct immunologic effects of splenectomy or reflections of more aggressive tumor biology remains uncertain. Total and Central Pancreatectomy The incidence of multifocal pancreas adenocarcinoma is sufficiently low to render total pancreatectomy (TP) unnecessary in the vast majority of cases (73,74). The perioperative (75) and long-term outcomes (76) following TP for adenocarcinoma are even less favorable than those obtained following partial pancreatectomy. The lack of an incremental benefit of TP, along with the endocrine and exocrine sequelae, has limited the use of TP (77). However, increased recognition of intraductal papillary mucinous neoplasms (IPMNs) has led to increased interest in TP (78). Quality of life following TP may not be significantly different from patients with diabetes mellitus not undergoing pancreatic resection (79). Intermittent hypoglycemia is the most common endocrine complication, but fewer than 3% die following TP due to metabolic derangements (80,81). Although islet cell transplantation may delay or prevent the diabetic complications of total pancreatectomy, the role of the procedure is not fully defined (82). As the use of cross-sectional imaging has increased, the frequency of cystic and neuroendocrine lesions of the pancreas is growing. Given that cystic and neuroendocrine pancreatic tumors are often noninvasive, parenchyma-sparing pancreatic resections, such as central pancreatectomy (CP), may be appropriate (83). CP may pose a lower risk of diabetes mellitus than extended DP (84,85) and the rate of exocrine insufficiency is reported to be between 0% and 20% (84–87). The range of pancreatic fistula formation following CP is 14–62% (83–88), which is somewhat higher than what has been associated with right or left pancreatic resection. However, in a recent series, the overall rate of major complications was similar following CP when compared to extended DP (84). Laparoscopic Pancreatectomy Since initially reported (89), laparoscopic distal pancreatectomy is being performed with increasing frequency due to growing interest among patients and physicians. There are no RCTs from which to draw definitive conclusions about complications. Two series including a total of 286 laparoscopic left pancreatectomies indicate a pancreatic fistula rate of 16% to 17% (90,91). The oncologic equivalence of laparoscopic

pancreatic resection to conventional approaches remains to be proven. One advantage of laparoscopic pancreatectomy appears to be a decreased length of stay (90). Laparoscopic right and central pancreatectomies are not widely performed and the literature is limited to case reports and small series. In properly selected patients, laparoscopic pancreatectomy may offer shortterm benefits when performed by experienced surgeons. Institutional Factors Hospital or surgeon volume and practice paradigms influence outcome and cost following pancreatic resection. Short-term mortality rates following PD are lower in high-volume compared to low-volume centers (92,93). Improved outcomes in high-volume centers are more likely a reflection of systematic factors rather than an independent effect of more experienced surgeons (93). Utilization of clinical pathways following pancreatic resection has been demonstrated to lower overall cost and decrease the average length of stay by 3 to 6 days (94,95). Clinical pathways have not been associated with significant reductions in morbidity or mortality in patients undergoing pancreatic resection (96). Patient Factors Numerous patient-related factors have been purported to increase the risks of complications and death following pancreatic resection. As noted elsewhere in this chapter, large duct diameter and firm pancreatic parenchymal texture may be associated with a lower risk of pancreatic leak (Table 9.3). Other patient variables that have been reported to increase morbidity rates include coagulopathy, severe jaundice, acute renal failure, obesity, and protein-calorie malnutrition (97–99). Age has not been shown to be an independent risk factor for morbidity and mortality following pancreatectomy (10). The impact of morbid obesity on the risk for postpancreatectomy complications deserves special attention given the scope of this problem in the U.S. population. House et al. determined that retrorenal visceral fat thickness was an independent predictor of overall morbidity, wound infection, and pancreatic fistula (49). Whether jaundice increases the risks of pancreatic resection and the impact of preoperative biliary drainage on perioperative outcomes remain an area of considerable controversy. Povoski et al. (100) demonstrated that in patients undergoing PD, preoperative biliary drainage was an independent predictor of postoperative infection, overall complications, and death. In contrast, Pisters et al. (101) reviewed their experience with preoperative biliary decompression in patients subjected to PD and determined that drainage did not increase the overall morbidity or mortality rates, but did increase the rate of wound infections. A recent meta-analysis of RCTs and comparative cohort studies concluded that there is no benefit to routine preoperative biliary drainage (102). Routine preoperative biliary drainage in jaundiced patients with pancreatic head tumors does not appear to be warranted, but may be appropriate in properly selected patients. Biliary decompression should be considered to address acute cholangitis, intractable pruritis, or to facilitate participation in studies investigating neoadjuvant therapy.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 9.6 Recommendations for Prevention or Management of Pancreatectomy Complications

Radical pancreatectomy or extended retroperitoneal lymphadenectomy may be associated with a higher rate of certain complications and does not confer a significant benefit in oncologic outcome. Restoration of pancreaticoenteric continuity as opposed to ductal ligation is associated with significantly lower rates of pancreatic fistula and endocrine insufficiency. Pancreaticojejunostomy and pancreatogastrostomy following PD have similar complication rates. Pylorus preservation and PD with distal gastrectomy lead to similar perioperative outcomes. Utilization of absorbable mesh when transecting the distal pancreas with a stapling device has not been definitively shown to decrease the risk of pancreatic leak. Routine use of octreotide following pancreatic resection is not indicated but may be useful in selected, high-risk patients. Routine preoperative biliary drainage prior to pancreaticoduodenectomy is not indicated and should be performed in selected patients based upon the presence of symptoms, infection, or severe hyperbilirubinemia.

Evidence Category

Recommendation Strength Category

Ib

A

Ib

A

Ib

A

Ib

A

III

C

Ib

A

Ia

A

Recommended grading of categories of evidence: Ia, evidence from meta-analysis of randomised controlled trials; Ib, evidence from at least one randomised controlled trial; IIa, evidence from at least one controlled study without randomisation; IIb, evidence from at least one other type of quasi-experimental study; III, evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies and case-control studies; IV, evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Recommended strengths of management recommendation: A, directly based on category I evidence; B, directly based on category II evidence or extrapolated recommendation from category I evidence; C, directly based on category III evidence or extrapolated recommendation from category I or II evidence; D, directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence.

summary While the mortality rates following pancreatic resection have improved dramatically, the incidence of complications remains high. Based upon the available literature, several recommendations have been proposed ( Table 9.6). Refinements in our abilities to detect and manage complications following pancreatectomy account, in large part, for improved perioperative mortality statistics. Further progress in enhancing the safety of pancreatic resection will depend upon the development of more effective measures to prevent and treat postpancreatectomy complications. Better understanding of the biology of the diseases we subject to pancreatic resection will allow for more precise patient selection and improve both perioperative and long-term outcomes.

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85. Adham M, Giunippero A, Hervieu V, et al. Central pancreatectomy: single-center experience of 50 cases. Arch Surg 2008; 143(2): 175–80; discussion 180–1. 86. Iacono C, Bortolasi L, Serio G. Is there a place for central pancreatectomy in pancreatic surgery? J Gastrointest Surg 1998; 2(6): 509–16; discussion 516–7. 87. Rotman N, Sastre B, Fagniez PL. Medial pancreatectomy for tumors of the neck of the pancreas. Surgery 1993; 113(5): 532–5. 88. Celis J, Berrospi F, Ruiz E, et al. Central pancreatectomy for tumors of the neck and body of the pancreas. J Surg Oncol 2001; 77(2): 132–5. 89. Gagner M, Pomp A, Herrera MF. Early experience with laparoscopic resections of islet cell tumors. Surgery 1996; 120(6): 1051–4. 90. Kooby DA, Gillespie T, Bentrem D, et al. Left-sided pancreatectomy: a multicenter comparison of laparoscopic and open approaches. Ann Surg 2008; 248(3): 438–46. 91. Mabrut JY, Fernandez-Cruz L, Azagra JS, et al. Laparoscopic pancreatic resection: results of a multicenter European study of 127 patients. Surgery 2005; 137(6): 597–605. 92. Birkmeyer JD, Finlayson SR, Tosteson AN, et al. Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy. Surgery 1999; 125(3): 250–6. 93. Lieberman MD, Kilburn H, Lindsey M, Brennan MF. Relation of perioperative deaths to hospital volume among patients undergoing pancreatic resection for malignancy. Ann Surg 1995; 222(5): 638–45. 94. Kennedy EP, Rosato EL, Sauter PK, et al. Initiation of a critical pathway for pancreaticoduodenectomy at an academic institution—the first step in multidisciplinary team building. J Am Coll Surg 2007; 204(5): 917– 23; discussion 923–4. 95. Porter GA, Pisters PW, Mansyur C, et al. Cost and utilization impact of a clinical pathway for patients undergoing pancreaticoduodenectomy. Ann Surg Oncol 2000; 7(7): 484–9. 96. Vanounou T, Pratt W, Fischer JE, et al. Deviation-based cost modeling: a novel model to evaluate the clinical and economic impact of clinical pathways. J Am Coll Surg 2007; 204(4): 570–9. 97. Gilsdorf RB, Spanos P. Factors influencing morbidity and mortality in pancreaticoduodenectomy. Ann Surg 1973; 177(3): 332–7. 98. Warren KW, Cattell RB, Blackburn JP, Nora PF. A long-term appraisal of pancreaticoduodenal resection for peri-ampullary carcinoma. Ann Surg 1962; 155: 653–62. 99. Winter JM, Cameron JL, Yeo CJ, et al. Biochemical markers predict morbidity and mortality after pancreaticoduodenectomy. J Am Coll Surg 2007; 204(5): 1029–36; discussion 1037–8. 100. Povoski SP, Karpeh MS, Jr., Conlon KC, et al. Association of preoperative biliary drainage with postoperative outcome following pancreaticoduodenectomy. Ann Surg 1999; 230(2): 131–42. 101. Pisters PW, Hudec WA, Hess KR, et al. Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients. Ann Surg 2001; 234(1): 47–55. 102. Sewnath ME, Karsten TM, Prins MH, et al. A meta-analysis on the efficacy of preoperative biliary drainage for tumors causing obstructive jaundice. Ann Surg 2002; 236(1): 17–27. 103. Pannegeon V, Pessaux P, Sauvanet A, et al. Pancreatic fistula after distal pancreatectomy: predictive risk factors and value of conservative treatment. Arch Surg 2006; 141(11): 1071–6; discussion 1076. 104. Sierzega M, Niekowal B, Kulig J, Popiela T. Nutritional status affects the rate of pancreatic fistula after distal pancreatectomy: a multivariate analysis of 132 patients. J Am Coll Surg 2007; 205(1): 52–9. 105. Ridolfini MP, Alfieri S, Gourgiotis S, et al. Risk factors associated with pancreatic fistula after distal pancreatectomy, which technique of pancreatic stump closure is more beneficial? World J Gastroenterol 2007; 13(38): 5096–100. 106. Jimenez RE, Fernandez-del Castillo C, Rattner DW, et al. Outcome of pancreaticoduodenectomy with pylorus preservation or with antrectomy in the treatment of chronic pancreatitis. Ann Surg 2000; 231(3): 293–300.

10

Laparoscopy in HPB surgery Nicholas O’Rourke and Richard Bryant

introduction Laparoscopy offers great advantages to the patient with HPB disease. Although described in the early part of the 20th century, crude instrumentation limited its use. Progress seemed slow until the 1960s saw widespread uptake in the gynecologic community, with the Hopkins rod lens system greatly improving the optics. Sporadic reports of laparoscopic staging for HPB cancer soon followed, but it was not until the handheld camera development in the 1980s that the minimal access explosion began. Now surgeons could view the image on a monitor, and use two hands to operate instruments, while an assistant held the camera. Even the gall bladder could be removed using tiny incisions. The next 10 years saw almost every abdominal operation attempted, such that the interest now is not in what can be done, but in what should be done, and how best to do it.

laparoscopic cholecystectomy Cholecystectomy was the first general surgical procedure to be widely performed laparoscopically. Following the first reports in 1985 and 1988 (1), the technique was rapidly popularized (2–5). Despite a possible increase in the incidence of severe bile duct injuries, the benefits of the laparoscopic approach have subsequently been confirmed by meta-analysis (6), demonstrating shorter hospital stay and faster convalescence with no difference in operating time or complications. There are various techniques in common usage, with the surgeon standing either on the patient’s right or left or between the legs, with the choice of technique depending on local teaching and personal preference. There are, however, fundamental principles to safely performing a laparoscopic cholecystectomy. Correct identification of the anatomy is fundamental. Most bile duct injuries are due to misperception rather than technical errors (7). It is important to understand the normal variations in biliary anatomy and how pathological changes may alter the relationships between the structures. The 30º telescope permits better visualization of Calot’s triangle. Hartmann’s pouch is retracted laterally and inferiorly so that the angle between the cystic and common hepatic ducts is increased rather than closed. Calot’s triangle is dissected high, just beneath the edge of the gall bladder, on both its anterior and posterior surfaces, to clearly identify the cystic duct and cystic artery as the only structures passing to the gall bladder (the “critical view” (8)). Dissection is never carried below the plane of Rouvière’s sulcus (9). Routine intraoperative cholangiography is recommended. This has been shown to decrease the risk and severity of biliary injury (10). It is essential that the full complement of upper duct anatomy is visualized to be certain that the common bile duct or an aberrant right hepatic duct is not being excised. It

also enables the identification of choledocholithiasis, which in most cases can then be successfully managed during the same laparoscopic procedure (11). In the setting of acute cholecystitis, early laparoscopic cholecystectomy is preferred (12,13). The problem with a policy of delayed laparoscopic cholecystectomy is that a significant proportion of patients require an emergency cholecystectomy for recurrent or nonresolving acute cholecystitis in the difficult intermediate period with a higher rate of conversion. However, if symptoms have been present for more than a week or there is a mass present without generalized peritonism then it may be more prudent to manage the patient conservatively with a view to a delayed cholecystectomy. For mild gall stone pancreatitis, laparoscopic cholecystectomy with intraoperative cholangiogram should be performed during the same admission (14). A policy of interval cholecystectomy incurs a real risk of recurrent pancreatitis (15–21). Laparoscopic cholecystectomy has traditionally been performed with an overnight stay, but appropriately selected patients can be safely managed as a day case (22).

laparoscopic common bile duct exploration Most common duct stones can be managed laparoscopically (11,23–36). This allows treatment in one operation, rather than endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy done as a separate procedure, either before or after laparoscopic cholecystectomy. Obviously, operative cholangiography, with fluoroscopy, and accurate interpretation is mandatory. Techniques used, in order of increasing complexity, are as follows: ● ● ● ● ●

Transcystic flushing Transcystic stone extraction Choledochotomy Transampullary stenting Choledochoduodenostomy

Flushing Small filling defects in the bile duct may be air bubbles, and only the dynamic image of fluoroscopy may allow visible distortion or coalescence of these bubbles. Small stones low in the bile duct may be flushed or pushed into the duodenum using the cholangiogram catheter, with intravenous glucagon occasionally helping by relaxing the sphincter. Transcystic Stone Extraction Formal duct exploration is performed, where possible (in about two-thirds of cases), via a transcystic approach. We prefer to use a purpose-built Nathanson CBD exploration catheter (Cook). This allows manipulation of a basket under contrast-assisted fluoroscopy. The cystic duct is dissected lower, close to the common bile duct. Balloon dilatation of the

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS cystic duct may occasionally be required. The stone to be extracted must not be larger than this diameter. If so, the stone may become stuck in the junction and require fragmentation or, worse, incision to remove. Choledochotomy as a primary procedure may be preferred for large or numerous stones. When inserting the Nathanson transcystic catheter, one must be careful that the basket is 1 to 2 cm inside the flexible tip of the catheter, to avoid turning the device into a spear, which can perforate the posterior aspect of the common duct. Under fluoroscopic guidance, the wire basket is deployed in the distal common bile duct, without traversing the ampulla. Gentle “jiggling” of the basket entraps the stone, which can then be retrieved by withdrawing the open basket. The stone can “flip” out of the duct and land anywhere in the right abdomen, often too quickly to be seen (Figs. 10.1 and 10.2). The characteristics of the basket employed are important. A fourwire steel basket will spring open in the bile duct such that with “jiggling” the stone is able to enter between the wires to then be trapped in the apex as the open basket is withdrawn. A softer nitonol basket will not tend to spring open in the same fashion and it is therefore often difficult to ensnare the stone under fluoroscopic guidance. An alternative transcystic approach is with a flexible choledochoscope. A 3-mm scope is normally required, as a 5-mm scope will only rarely pass trans-cystically. A grasper in the epigastric port provides traction to the right. A long 5-mm trocar in the right subcostal position is positioned against the cystic duct incision to prevent bowing of the choledochoscope within the abdomen. The choledochoscope is advanced into the common bile duct and the stone retrieved under direct vision. In these circumstances, a nitonol basket with a parachute arrangement at the apex is usually more effective as the stone entrapment is performed under direct vision. Clearance of the common bile duct can be confirmed by transcystic flexible choledochoscopy; however it is often difficult transcystically to introduce the choledochoscope to the common hepatic duct to confirm that there are no calculi above the cystic duct junction.

If the transcystic approach fails, then a decision must be made between postoperative ERCP versus laparoscopic choledochotomy. A randomized controlled trial between these two options, after failure of transycstic CBDE, did not demonstrate any differences (27), and therefore the choice depends on individual patient factors and local expertise. If the common bile duct is narrow (<7 mm) then a choledochotomy should be avoided due to the risk of stricturing. Postoperative ERCP can be facilitated by the passage of an antegrade biliary stent (37).

Figure 10.1 Laparoscopic transcystic cholangiography demonstrating calculus in the distal common bile duct.

Figure 10.2 The calculus from Figure 10.1 after transcystic extraction utilizing the Nathanson basket. Inset: completion cholangiography.

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Choledochotomy In certain circumstances, a transcystic approach is unlikely to be successful, and if the CBD is of sufficient diameter, then it is reasonable to proceed straight to a laparoscopic choledochotomy. These circumstances include large stones (>10mm), multiple stones (>3) or stones above the cystic duct confluence. To perform laparoscopic choledochotomy, the anterior surface of the common bile duct is dissected just sufficiently to confidently identify the anatomy. A 1.5-cm vertical incision is made in the common bile duct below the cystic duct confluence. Filling of the duct system with saline via the transcystic catheter distends the collapsed duct and helps prevent injury to the posterior duct wall when the anterior wall is incised. Another method is to gently lift up the anterior wall with a suitable small atraumatic grasper (such as a “dolphin-nose”) introduced via the right subcostal port. This will create a small transverse ridge of the anterior duct wall, which can then be cut using scissors introduced via the epigastric port, thus creating a vertical incision that can then be extended with the scissors. A similar effect can also be created using stay sutures. Initial flushing via the choledochotomy with the suckeraspirator and massaging of the duct may remove the stones. A choledochoscope can be introduced, this time from the epigastric port. A 3 or 5 mm flexible scope may be employed, or even a rigid ureteroscope if the orientation is suitable. (On the rare occasions that a rigid ureteroscope is required, it can

LAPAROSCOPY IN HPB SURGERY sometimes be introduced transcystically via the epigastric port if the orientation is suitable.) With the choledochoscope, the stones can be removed under direct vision, and the flexible choledochoscope can be maneuvered into both the upper ducts and lower CBD to confirm clearance of all calculi. On rare occasions, hydraulic lithotripsy may be required to break up impacted stones (27). Where there is confidence about stone clearance and biliary drainage, choledochotomy can be simply closed by suturing (25). If there is any doubt about biliary drainage or duct clearance, then choledochotomy should be closed after passage of an antegrade biliary stent, or a T-tube inserted. Choledochoduodenostomy For the elderly patient with a suspected benign stricture, and a reasonable stone load, laparoscopic choledochoduodenostomy is a good option (23). As in open surgery, a common duct diameter of greater than 10 mm is preferable. A continuous absorbable suture is used, and the operation mimics the open procedure with anastamosis of the choledochotomy to a longitudinal opening in the duodenum.

pancreatic pseudocyst Pancreatic pseudocysts can be managed endoscopically with gastrotomy and stenting (perhaps the only current valid indication for NOTES [Natural Orifice Transabdominal Endoscopic Surgery]). Pancreatic pseudocysts can also be drained internally via a laparoscopic approach (38–46). Most commonly the pseudocyst is located in the lesser sac and the appropriate procedure is a cyst-gastrostomy. An anterior gastrotomy is made. The cyst can be seen bulging forward, adherent to the posterior stomach wall, which is incised with diathermy or the harmonic scalpel to enter the cyst. Cyst fluid will come flowing out under pressure at this point, and is important to have an instrument ready to pass into the cyst so that the point of communication is not lost. The cyst fluid is aspirated with the sucker and the cyst emptied. A linear stapler is then introduced into the small cyst-gastrotomy to create a wide cystgastrostomy, and the residual unstapled edges are sutured together. The pseudocyst can be entered with the laparoscope and inspected, and any debris removed. The anterior gastrotomy is then closed with sutures or a stapling device. In some cases, the position of the pseudocyst will require a side-to-side cyst-gastrostomy or Roux-en-Y cyst-enterostomy. Published reports suggest that laparoscopic cyst-gastrostomy has a higher initial success rate and lower recurrence rate than endoscopic cyst-gastrostomy (42,47). As the cyst-gastrostomy created via the endoscopic approach is only small, any large debris is unable to exit the cyst. However, endoscopic approaches can be improved with using balloon dilatation and multiple stents to maintain better drainage, endoscopic ultrasound to guide the procedure and avoid vessels (48,49), and with the development of stapling instrumentation for natural orifice surgery (50).

imaging studies, but be found to have locally advanced disease or small liver or peritoneal metastases (imaging-occult metastases) that render the disease inoperable (Fig. 10.3). Staging laparoscopy can identify these patients and therefore spare the patient a laparotomy. Staging laparoscopy in its simplest form involves visual inspection of the peritoneal and liver surfaces, but may also include laparoscopic ultrasound, trial dissection, or peritoneal washing for cytology. Staging laparoscopy is preferable to a nontherapeutic laparotomy to identify unresectability. The hospital stay is shorter (51,52), and the patient is able to start chemotherapy sooner (53). The risks of a staging laparoscopy are low, with morbidity reported at 0% to 4% and mortality 0% to 0.15% (54). Port-site recurrences are uncommon, between 0% and 2% (54), and usually occur in patients with extensive peritoneal carcinomatosis. Staging laparoscopy may be performed as a prelude to resection in the same procedure or as a separate procedure prior to planned resection—there can be significant scheduling issues depending on the institution if an aborted procedure means allocated theater time is unable to be utilized. The yield of staging laparoscopy depends on many factors. The type and stage of the malignancy affects the likely presence of imaging-occult metastases, as does the quality and type of the imaging performed. The extent of the staging procedure is also important—whether laparoscopic ultrasound, peritoneal washings or trial dissection is included. It is also obviously influenced by what findings are considered to contraindicate resection; for example, localized peritoneal disease or porta hepatis nodes for colorectal liver metastases, or involvement of the portal vein requiring vein resection and grafting in pancreas cancer may not be considered contraindications to resection. The value of a positive staging laparoscopy also depends on whether any required palliative procedures, such as biliary or gastric bypass in carcinoma of the head of the pancreas, can be performed laparoscopically. In adenocarcinoma of the pancreas, after high-quality CT scanning, staging laparoscopy has been shown to identify

laparoscopic staging A proportion of patients with hepatobiliary and pancreatic malignancies will appear to be resectable on noninvasive

Figure 10.3 Peritoneal metastases at staging laparoscopy and carcinoma of the head of the pancreas.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS unresectability in 15% to 51% of patients, and spare 10% to 31% of patients an unnecessary laparotomy (51,55–61). Laparoscopic ultrasound has been shown to add information in 12% to 14% of patients (62–64). Patients with tumors larger than 3 cm are more likely to have unsuspected metastases at exploration (65), as are patients with a Ca 19.9 level greater than 150 kU/L (66,67). Positive peritoneal lavage has been found in 3% to 51% of patients (57,68–76), and is more likely in locally advanced or metastatic tumors (77), larger tumors, and tumors of the body or tail (70,78). Positive peritoneal cytology, which has the same prognosis as metastatic disease (79), is the only marker of unresectability in 1% to 14% of patients (57,69,70,76). Tumors of the body and tail of the pancreas are twice as likely as pancreatic head lesions to have imaging-occult metastases (57,69). Imaging-occult metastases are uncommon in nonpancreatic periampullary tumors (60,80,81) and routine laparoscopy in these patients is probably not indicated. Patients who on imaging have locally advanced, unresectable pancreatic cancer should also be considered for staging laparoscopy, as those without metastatic disease can be considered for chemoradiotherapy regimens aimed at local control or even downstaging followed by resection, regimens which would incur unnecessary treatmentrelated morbidity for those with metastatic disease (69,77,82). In colorectal liver metastases, laparoscopy will identify unresectable disease in 10% to 38% of patients, with a sensitivity of 39% to 75% (83–90). Laparoscopy is more likely to be positive in patients with a higher clinical risk score (83,86,91). In noncolorectal, nonneuroendocrine liver metastases, laparoscopy has been reported to identify unresectable disease in 25% of patients, with a sensitivity of 66% (92). Staging laparoscopy is useful for patients with primary biliary malignancies. For patients with suspected resectable gall bladder carcinoma on imaging, the yield for detecting unresectable disease is 56% to 62% (93,94), though the yield is less for intrahepatic cholangiocarcinoma (93) at 36% and hilar cholangiocarcinoma (93–95) at 25%. The yield for hilar cholangiocarcinomas is higher for T2 or T3 lesions than for T1 lesions (94) (36% vs. 9%). In hepatocellular carcinoma that is considered suitable for curative resection, peritoneal dissemination is uncommon, and standard laparoscopy is unlikely to add much information. Laparoscopy with laparoscopic ultrasound, however, can identify the extent of the primary tumor, additional imagingoccult tumors, portal or hepatic venous tumor thrombus or an inadequate hepatic remnant, with a yield for unresectability of 10% to 36% and a sensitivity of 63% to 96% (96–100). The results obtained will depend on the type and quality of preoperative imaging and the level of experience with laparoscopic ultrasound.

laparoscopic palliative bypass In patients with inoperable periampullary tumors, there is often biliary and/or gastric obstruction that requires relief. The traditional teaching in open surgery was to perform both a biliary and gastric bypass whether or not the patient was symptomatic. If at laparoscopy the tumor is found to be unresectable, in the absence of actual or impending biliary or

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gastric outlet obstruction, it is not necessary to perform a palliative biliary or gastric bypass (101). In many instances, the endoscopic approach is effective to relieve obstruction. Duodenal stenting is safer and provides a better quality of life than laparoscopic gastrojejunostomy in the short term (102), although laparoscopic gastrojejunostomy may provide a more durable result for patients with a longer life expectancy (103). ERCP with placement of a plastic biliary stent has a lower morbidity than traditional open surgical bypass, although plastic biliary stents have a tendency to occlude, resulting in recurrent biliary obstruction requiring a repeat procedure (104). Metallic stents, however, have a much higher patency rate in the longer term, and can serve many patients for the remainder of their survival (104–106). In some cases, however, stenting fails for technical reasons or due to inability to access the ampulla. In these cases, a laparoscopic bypass is a useful option (107–116), with the potential for lower morbidity and shorter hospital stay than an open surgical procedure (113,115). A laparoscopic biliary bypass is most easily performed as a stapled or sutured side-to-side cholecystojejunostomy. The main limitation of this approach is that the confluence of the cystic and common hepatic ducts must be well above the tumor to prevent recurrent biliary obstruction (117). This can be confirmed at the procedure by cholangiography via the fundus of the Gall bladder—a Verres needle with large syringe attached is used to empty the gall bladder of bile, which is then filled with contrast to confirm that the cystic duct confluence is more than 1 cm above the level of the tumor. If this is not the case, an hepaticojejunostomy is constructed. A gastrojejunostomy is typically fashioned in an antecolic, isoperistaltic stapled side-to-side manner.

laparoscopic pancreatectomy Distal pancreatectomy is well suited to a laparoscopic approach. The usual indication is a solid or cystic tumor of the tail of the pancreas that is not clearly benign on preoperative imaging. The procedure may involve en-bloc resection of the spleen and splenic vessels; preservation of the spleen with preservation of the splenic vessels; or preservation of the spleen without preservation of the splenic vessels with the spleen supplied from the short gastric and gastroepiploic vessels (the Warshaw technique (118)). For lesions close to the spleen, when splenectomy is necessary, the approach can be similar to laparoscopic splenectomy, with the patient left side up, and the spleen and distal pancreas mobilized from lateral to medial. After division of the short gastric vessels and the gastrocolic omentum, the pancreas can be divided en bloc with the splenic vessels using a linear stapler. For a medial to lateral approach, the pancreatic neck is divided, either with a stapling device or with the harmonic scalpel with subsequent suture closure of the pancreatic stump. Where the splenic vessels are being resected, the splenic vein is divided with a stapling device and the splenic artery divided with a stapling device or locking clips. If the splenic vessels are to be preserved, then the tail of the pancreas is dissected carefully from them with control of the small vessels with clips and/or the harmonic scalpel or

LAPAROSCOPY IN HPB SURGERY electrosurgical sealing device. Otherwise the dissection continues in the relatively avascular plane behind the splenic vein. At this point, if the spleen is to be preserved with the Warshaw technique, then the splenic hilum is divided with a stapling device taking care to preserve the short gastric vessels, and the gastroepiploic arcade. Otherwise if the spleen is to be resected, the dissection continues in this plane behind the splenic vein to complete the mobilization of the spleen and complete the resection. The specimen is retrieved in a bag and a closed suction drain is placed. Laparoscopic distal pancreatectomy has been shown to be a safe procedure, with a shorter hospital stay and overall morbidity that is less than the open procedure (119–124). The main complication is a pancreatic fistula occurring in about 15% of patients, though this occurs at no greater rate than with an open resection (120,124). The application of fibrin glue to the stump (125) and the use of staple line mesh reinforcement (126) have both shown some benefit in small studies in reducing this rate, and in open surgery the placement of a transampullary stent (127) has shown some benefit, as has identification and direct suture of the main pancreatic duct (128), although the optimal management of the pancreatic stump is still to be determined. Preservation of the spleen by the Warshaw technique can be complicated by infarction of the lower pole of the spleen (129,130). Laparoscopic central pancreatectomy has been reported in the literature (131) and successfully been performed twice by one of the authors. The indication of a central tumor where diabetes is a risk postoperatively is not common. Laparoscopic enucleation of insulinomas has been reported in small series but is associated with a significant rate of pancreatic fistula (129,132,133). Intraoperative ultrasound is essential to ensure that the main pancreatic duct is not close to the resection line. Laparoscopic pancreaticoduodenectomy has been reported in small numbers (134–137). The procedure is feasible but prolonged and difficult, and the potential role for this procedure remains to be determined.

laparoscopic liver resection The laparoscopic approach to liver resections presents certain technical challenges. It is a heavy solid organ that can be cumbersome to mobilize and manipulate, parenchymal transection requires the identification and control of large vessels with the potential for significant bleeding, and the paucity of external anatomical markers can make the maintenance of surgical orientation to ensure a satisfactory oncologic clearance difficult. Laparoscopic liver resection was initially reported in 1995 by Rau (138), Cuesta (139), and Hashizume (140). Anatomic resections in the form of left lateral sectionectomy were reported in 1996 by Azagra (141) and Kaneko (142), formal hemihepatectomies were reported in 1998 by Huscher (143), and Cherqui (144) reported the first significant series of 30 patients in 2000. The largest series were recently reported by Koffron (145) and Buell (146). Dr. Joe Buell organized the first international consensus meeting on laparoscopic liver resection, held in Louisville,

Kentucky in November 2008. Agreed definitions of laparoscopic liver surgery include the following: ●

●

●

●

Pure laparoscopic: where the liver resection is completed laparoscopically and the specimen removed via a remote incision; Hand assisted: where the surgeon operates with his nondominant hand inside the abdomen, placed via an airtight device, through which the specimen is removed; Hybrid liver resection (145): where the liver is mobilized laparoscopically and most of the resection is done through a smaller than usual right upper quadrant incision; Conversion: where the surgeon changes to an open operation from one of the above. One can also convert from pure laparoscopic to hand assist or hybrid.

The most suitable cases for a laparoscopic approach are solitary small (<5 cm) lesions located in the peripheral segments (2–6) of the liver. Larger lesions are acceptable if they are pedunculated or located in the left lateral section. Multiple lesions may be suitable if they can be resected with a single anatomic hepatectomy with a clear margin, but not where multiple complicated or bilobar procedures are required. Hemihepatectomies can be considered for a laparoscopic approach where the plane of transection and major structures (pedicles, hepatic veins and inferior vena cava) are well clear of any lesions. Lesions located in segments 7 and 8 are difficult to approach laparoscopically for a tumorectomy as the costal margin limits the approach angles of the instruments, and there is a real risk of compromising the deep margin for fear of causing difficultto-control bleeding—they should only be considered for a laparoscopic tumorectomy if they are particularly small and superficial, otherwise they need to be considered for an open procedure or a laparoscopic right hemihepatectomy. The procedures are usually performed in the supine position, often with the surgeon standing between the legs. The left lateral decubitus position is useful for lesions in segments 6 and 7, which enables better exposure of the right posterior section of the liver. Hand ports may be used. These are most useful in right sided resections where mobilization is difficult, either in nonanatomical resections with a posterior tumor in the right lobe, or right hemihepatectomies with a bulky right lobe. Good quality laparoscopic equipment is vital. A good 10-mm laparoscopic right angle is also a very important tool. An initial laparoscopy is performed, and laparoscopic ultrasound is used to identify the lesions and their relationships to the appropriate anatomy (Fig. 10.4). A tape can be placed around the hepatic pedicle in readiness for a Pringle maneuver if required; this is usually reserved for situations where bleeding is encountered rather than used routinely, and uses an intermittent protocol (as the time of transection tends to be longer than in open surgery). The gall bladder is resected where indicated, but after division of the cystic duct and artery, it may be left attached to the liver until later in the procedure to help maneuver the liver, such that the gall bladder and round ligament become the two “handles of the liver.” It is a

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Figure 10.4 Laparoscopic ultrasound used to mark out resection line for a tumor in segment 6.

useful point to divide the round ligament flush with the anterior abdominal wall such that there is not dangling tissue irritatingly obstructing the view and dirtying the camera through the whole procedure. There are many methods of parenchymal transection: harmonic scalpel (Ethicon), Ligasure device (Covidien), Gyrus (Gyrus ACMI), CUSA (Integra), TissueLink (Salient Surgical Technologies), stapling devices, water jet, and metal clips. Each have their advantages and disadvantages, and used appropriately each can have their place. Personal preference and experience as well as local teaching and availability determine the choice. The various energy-delivery devices will not control the large venous structures; these must be identified intraparenchymally and controlled with clips or stapling devices. It is also prudent to individually control the large pedicular branches. Stapling devices can be used en-masse across portions of the parenchyma to control the larger structures within, but a degree of finesse is lost and unexpected bleeding can be encountered. The combination of the harmonic scalpel for the superficial 2 cm of dissection with the CUSA for the deeper dissection is a good technique (147). A good alternative is the Ligasure device, which when used with a modified technique (closing while activating, using the cutting blade sparingly, with gentle saline irrigation to prevent charring) can be used to dissect out the larger intraparenchymal structures (148). Left lateral sectionectomy begins with mobilization of the falciform ligament, left coronary ligament, and lesser omentum to mobilize the left lobe. The parenchyma is divided so as to expose the upper surface of the segments 2 and 3 pedicles intrahepatically. The pedicles are then divided with a stapler. The parenchymal transection is then completed to expose the left hepatic vein intrahepatically, which is divided with a stapler. An alternative to this technique is mass stapling of the left lateral section (149,150). Left lateral sectionectomy is particularly suitable to a laparoscopic approach and arguments have been made that the laparoscopic approach should be used routinely for this resection (149,151).

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Figure 10.5 Laparoscopic dissection of the right portal vein. The right hepatic artery has been divided. The cystic duct has been divided and is used to retract the bile duct. The right portal vein has been looped. The left portal vein is clearly demonstrated and the right portal vein can be seen dividing into its anterior and posterior branches.

For a left hepatectomy, the left liver is mobilized as above. The left hepatic artery and left portal vein are dissected extrahepatically, demonstrating the line of demarcation. The parenchymal transection is then begun, opening the liver to allow a good exposure of the left pedicle and sufficient space to introduce a stapling device to divide the left bile duct. The parenchymal transection is then continued, exposing the left hepatic vein intrahepatically, which is divided with a stapling device to complete the transection. A right hepatectomy can be performed either with an anterior or a traditional approach. An anterior approach begins with an extrahepatic dissection and division of the right hepatic artery and right portal vein (Fig. 10.5). The parenchymal transection is then begun, opening the liver to allow an intrahepatic division of the right bile duct. The parenchymal transection is then completed down to the anterior surface of the inferior vena cava. The minor hepatic veins are then divided between clips, followed by the right hepatic vein and hepatocaval ligament with stapling devices. The final step is mobilization of the liver and division of the right coronary ligament. In the traditional approach, there is the same extrahepatic division of the right hepatic artery and right portal vein, with full mobilization of the liver and division of the hepatocaval ligament and right hepatic vein before transection of the parenchyma (Fig. 10.6). Laparoscopic right hepatectomy is a difficult procedure that requires expertise in both laparoscopic and hepatic surgery. The specimen is removed intact in a bag, either through the hand port incision, a previous appendicectomy scar, or a Pfannenstiel incision. After this period of desufflation, the extraction incision is closed to allow re-establishment of the pneumoperitoneum to confirm hemostasis, as bleeding may have been tamponaded by the pressure of the pneumoperitoneum. In any type of laparoscopic liver resection, significant

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references

Figure 10.6 Mobilization of the right liver from the inferior vena cava.

bleeding can be encountered, and the surgeon must have the requisite laparoscopic skills to be able to control this situation. Good skills in laparoscopic suturing are essential. Conversion to laparotomy may certainly be required, but immediate conversion is not always the best response. Venous bleeding is often partly tamponaded by the pneumoperitoneum. The bleeding source is identified and controlled with a grasper, and hemostasis is achieved with suturing or a clip as appropriate. If initial maneuvers are not successful then conversion is required without persisting for too long or worsening the bleeding. These are potentially dangerous situations that require both skill and judgment. Assessment of laparoscopic liver resection has been based on series (144,147–149,151–173) and retrospective comparative studies (145,174–185). These reports from expert centers demonstrate that laparoscopic liver resection can be performed safely, and that despite a longer operating time there is the potential for reduced hospital stay and reduced bleeding. Despite initial concerns, CO2 embolus occurs uncommonly. The oncologic results in nonrandomized studies have been good (145,158,174–177,180), but care must be taken in interpreting these series, as those patients undergoing laparoscopic resection have been selected with smaller and fewer tumors that would normally also infer a better prognosis. There is a potential benefit in cirrhotic patients, with a lower incidence of ascites postoperatively (147,176), as well as fewer adhesions that facilitate subsequent transplantation (186).

conclusion Laparoscopic approaches for the simplest of HPB procedures, cholecystectomy, have literally exploded around the world. More complex operations have been reported in small series, but have not been taken up with the same enthusiasm. As technology improves, and the skill set of surgeons increases, it seems inevitable to us that more and more will be done. As long as basic oncologic principles are adhered to, and the surgical maxim of conversion if concerned is followed, patients will continue to benefit from this exciting surgery.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 116. Shimi S, Banting S, Cuschieri A. Laparoscopy in the management of pancreatic cancer: endoscopic cholecystojejunostomy for advanced disease. Br J Surg 1992; 79(4): 317–9. 117. Tarnasky PR, England RE, Lail LM, Pappas TN, Cotton PB. Cystic duct patency in malignant obstructive jaundice. An ERCP-based study relevant to the role of laparoscopic cholecystojejunostomy. Ann Surg 1995; 221(3): 265–71. 118. Warshaw AL. Conservation of the spleen with distal pancreatectomy. Arch Surg 1988; 123(5): 550–3. 119. Eom B, Jang J, Lee S, et al. Clinical outcomes compared between laparoscopic and open distal pancreatectomy. Surg Endosc [Internet] 2007 November 20 [cited 2009 January 3]. Available from: http://www.ncbi. nlm.nih.gov/pubmed/18027035 120. Kooby DA, Gillespie T, Bentrem D, et al. Left-sided pancreatectomy: a multicenter comparison of laparoscopic and open approaches. Ann Surg 2008; 248(3): 438–46. 121. Matsumoto T, Shibata K, Ohta M, et al. Laparoscopic distal pancreatectomy and open distal pancreatectomy: a nonrandomized comparative study. Surg Laparosc Endosc Percutaneous Techn 2008; 18(4): 340–3. 122. Nakamura Y, Uchida E, Aimoto T, et al. Clinical outcome of laparoscopic distal pancreatectomy. J Hepat Biliary Pancreatic Surg [Internet]. 2008 December 16 [cited 2009 January 3]. Available from: http://www. ncbi.nlm.nih.gov/pubmed/19083146 123. Tang CN, Tsui KK, Ha JPY, Wong DCT, Li MKW. Laparoscopic distal pancreatectomy: a comparative study. Hepat Gastroenterol 2007; 54(73): 265–71. 124. Velanovich V. Case-control comparison of laparoscopic versus open distal pancreatectomy. J Gastrointest Surg 2006; 10(1): 95–8. 125. Velanovich V. The use of tissue sealant to prevent fistula formation after laparoscopic distal pancreatectomy. Surg Endosc 2007; 21(7): 1222. 126. Thaker RI, Matthews BD, Linehan DC, et al. Absorbable mesh reinforcement of a stapled pancreatic transection line reduces the leak rate with distal pancreatectomy. J Gastrointest Surg 2007; 11(1): 59–65. 127. Fischer CP, Bass B, Fahy B, Aloia T. Transampullary pancreatic duct stenting decreases pancreatic fistula rate following left pancreatectomy. Hepat Gastroenterol 2008; 55(81): 244–8. 128. Bilimoria MM, Cormier JN, Mun Y, et al. Pancreatic leak after left pancreatectomy is reduced following main pancreatic duct ligation. Br J Surg 2003; 90(2): 190–6. 129. Fernández-Cruz L, Martínez I, Cesar-Borges G, et al. Laparoscopic surgery in patients with sporadic and multiple insulinomas associated with multiple endocrine neoplasia type 1. J Gastrointest Surg 2005; 9(3): 381–8. 130. Taylor C, O’Rourke N, Nathanson L, et al. Laparoscopic distal pancreatectomy: the Brisbane experience of forty-six cases. HPB 2008; 10(1): 38–42. 131. Sa Cunha A, Rault A, Beau C, Collet D, Masson B. Laparoscopic central pancreatectomy: single institution experience of 6 patients. Surgery 2007; 142(3): 405–9. 132. Sweet MP, Izumisato Y, Way LW, et al. Laparoscopic enucleation of insulinomas. Arch Surg 2007; 142(12): 1202–4; discussion 1205. 133. Toniato A, Meduri F, Foletto M, Avogaro A, Pelizzo M. Laparoscopic treatment of benign insulinomas localized in the body and tail of the pancreas: a single-center experience. World J Surg 2006; 30(10): 1916–9; discussion 1920–1. 134. Cuschieri SA, Jakimowicz JJ. Laparoscopic pancreatic resections. Semin Laparosc Surg 1998; 5(3): 168–79. 135. Dulucq JL, Wintringer P, Stabilini C, et al. Are major laparoscopic pancreatic resections worthwhile? A prospective study of 32 patients in a single institution. Surg Endosc 2005; 19(8): 1028–34. 136. Mabrut J, Fernandez-Cruz L, Azagra JS, et al. Laparoscopic pancreatic resection: results of a multicenter European study of 127 patients. Surgery 2005; 137(6): 597–605. 137. Sa Cunha A, Rault A, Beau C, et al. A single-institution prospective study of laparoscopic pancreatic resection. Arch Surg 2008; 143(3): 289–95; discussion 295. 138. Rau HG, Meyer G, Cohnert TU, et al. Laparoscopic liver resection with the water-jet dissector. Surg Endosc 1995; 9(9): 1009–12. 139. Cuesta MA, Meijer S, Paul MA, de Brauw LM. Limited laparoscopic liver resection of benign tumors guided by laparoscopic ultrasonography: report of two cases. Surg Laparosc Endosc 1995; 5(5): 396–401.

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LAPAROSCOPY IN HPB SURGERY 168. O’Rourke N, Fielding G. Laparoscopic right hepatectomy: surgical technique. J Gastrointest Surg 2004; 8(2): 213–6. 169. Poultsides G, Brown M, Orlando R. Hand-assisted laparoscopic management of liver tumors. Surg Endosc 2007; 21(8): 1275–9. 170. Shimada M, Hashizume M, Maehara S, et al. Laparoscopic hepatectomy for hepatocellular carcinoma. Surg Endosc 2001; 15(6): 541–4. 171. Soubrane O, Cherqui D, Scatton O, et al. Laparoscopic left lateral sectionectomy in living donors: safety and reproducibility of the technique in a single center. Ann Surg 2006; 244(5): 815–20. 172. Tang CN, Tsui KK, Ha JPY, Yang GPY, Li MKW. A single-centre experience of 40 laparoscopic liver resections. Hong Kong Med J 2006; 12(6): 419–25. 173. Vibert E, Perniceni T, Levard H, et al. Laparoscopic liver resection. Br J Surg 2006; 93(1): 67–72. 174. Belli G, Fantini C, D’Agostino A, et al. Laparoscopic versus open liver resection for hepatocellular carcinoma in patients with histologically proven cirrhosis: short- and middle-term results. Surg Endosc 2007; 21(11): 2004–11. 175. Kaneko H, Takagi S, Otsuka Y, et al. Laparoscopic liver resection of hepatocellular carcinoma. Am J Surg 2005; 189(2): 190–4. 176. Laurent A, Cherqui D, Lesurtel M, et al. Laparoscopic liver resection for subcapsular hepatocellular carcinoma complicating chronic liver disease. Arch Surg 2003; 138(7): 763–9; discussion 769. 177. Lee KF, Cheung YS, Chong CN, et al. Laparoscopic versus open hepatectomy for liver tumours: a case control study. Hong Kong Med J 2007; 13(6): 442–8.

178. Abu Hilal M, McPhail MJW, Zeidan B, et al. Laparoscopic versus open left lateral hepatic sectionectomy: A comparative study. Eur J Surg Oncol 2008; 34(12): 1285–8. 179. Cai X, Wang Y, Yu H, Liang X, Peng S. Laparoscopic hepatectomy for hepatolithiasis: a feasibility and safety study in 29 patients. Surg Endosc 2007; 21(7): 1074–8. 180. Cai XJ, Yang J, Yu H, et al. Clinical study of laparoscopic versus open hepatectomy for malignant liver tumors. Surg Endosc 2008; 22(11): 2350–6. 181. Farges O, Jagot P, Kirstetter P, Marty J, Belghiti J. Prospective assessment of the safety and benefit of laparoscopic liver resections. J Hepat Biliary Pancreatic Surg 2002; 9(2): 242–8. 182. Lesurtel M, Cherqui D, Laurent A, Tayar C, Fagniez PL. Laparoscopic versus open left lateral hepatic lobectomy: a case-control study. J Am Coll Surg 2003; 196(2): 236–42. 183. Mala T, Edwin B, Gladhaug I, et al. A comparative study of the shortterm outcome following open and laparoscopic liver resection of colorectal metastases. Surg Endosc 2002; 16(7): 1059–63. 184. Morino M, Morra I, Rosso E, Miglietta C, Garrone C. Laparoscopic vs open hepatic resection: a comparative study. Surg Endosc 2003; 17(12): 1914–8. 185. Troisi R, Montalti R, Smeets P, et al. The value of laparoscopic liver surgery for solid benign hepatic tumors. Surg Endosc 2008; 22(1): 38–44. 186. Laurent A, Tayar C, Andréoletti M, et al. Laparoscopic liver resection facilitates salvage liver transplantation for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 2009; 16(3): 310–14.

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11

Cross-sectional imaging for HPB disorders (MRI and CT) Lawrence H. Schwartz

overview The maturation of surgery of the liver, biliary tract, and pancreas as field unto itself has happened concomitantly with, and partly as a result of, advances in cross-sectional imaging. Rather than relying on expected anatomy based on textbooks, surgeons can now plan operations based on the precise anatomical details of each individual patient. The ability to predict anatomical variations, which are present in nearly one-half of the patients, has taken the element of surprise out of the operating room and can help reduce operative morbidity (1). In this chapter, we briefly discuss the application of computed tomography (CT) and magnetic resonance imaging (MRI) to the surgical management of disease of the liver, biliary tract, and pancreas. We begin by reviewing the relevant cross-sectional anatomy of the organs being studied. Next, we discuss the various techniques used to obtain high-quality CT and MRI images of the liver, biliary tract, and pancreas. Finally, we review the cross-sectional imaging characteristics of important pathological entities commonly encountered by surgeons caring for patients with diseases of the liver, biliary tract, and pancreas.

cross-sectional anatomy The effective use of cross-sectional imaging in the diagnosis and treatment of disorders of the liver, biliary tract, and pancreas mandates a strong understanding of anatomy. Developing this understanding of the complex three-dimensional structures and being able to extrapolate from two-dimensional representations requires a structured approach. A more detailed description of relevant anatomy can be reviewed in the previous chapters and elsewhere, therefore we will here focus on the interpretation of cross-sectional anatomy and its relation to in situ anatomy (2). Liver and Biliary Tract Segmental liver anatomy is the basis for modern liver surgery; therefore, we provide a framework with which to define this anatomy for each patient based upon cross-sectional imaging. Cantlie’s plane, also known as the main portal fissure, is an imaginary plane drawn from the gallbladder fossa toward the inferior vena cava (IVC) that divides the anatomical right and left lobes of the liver. The course of the middle hepatic vein (MHV) is fairly constant and lies in this otherwise potentially avascular plane; therefore, it can be used to delineate the two lobes on cross-sectional imaging (3). The right hepatic vein (RHV) defines the plane separating the anterior (segments 5 and 8) and posterior sectors (segments 6 and 7) of the right lobe. While the plane of the left hepatic vein (LHV) separates the anterior and posterior sectors of the left lobe, its anatomy is highly variable, making it a less useful landmark.

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In contrast to hepatic veins, which course between liver segments, portal veins and their accompanying artery and bileduct branches define the center of each segment. The main portal vein (PV) typically branches extrahepatically into the left and right portal veins (LPV and RPV, respectively); the RPV divides into the anterior and posterior sectoral branches, while the LPV enters the umbilical fissure and provides branches to the left lobe. While this describes standard anatomy, approximately one-third of patients have variant portal venous anatomy (Table 11.1) (4). In standard arterial anatomy the common hepatic artery arises from the celiac axis and divides into the gastroduodenal artery and the proper hepatic artery. The proper hepatic artery then gives rise to the right and left hepatic arteries. However, nearly one-half of patients have variations in their hepatic arterial system. A list of arterial variants demonstrated in a recent study is shown in Table 11.2 (1). Pancreas The pancreas is divided into the head, uncinate process, neck, body, and tail. These divisions are based upon external landmarks such as the superior mesenteric vein (SMV), which lies under the neck of the gland and defines the separation between the head and the body. The pancreas has a long course through the retroperitoneum and is intimately associated with multiple organs including the transverse colon, stomach, duodenum, and spleen. Additionally, it has a close relationship with the portal venous system that, in part, defines the resectability of pancreatic masses. The pancreas has a rich arterial supply that comes from multiple branches of the celiac and superior mesenteric arteries. As in hepatic surgery, preoperative determination of variations in peripancreatic vascular anatomy can greatly aid in operative planning.

technique Liver and Biliary Tract CT is commonly used as the primary modality to detect, characterize, and follow hepatic or biliary pathology. Modern multislice helical CT scanners allow for the rapid acquisition of large volumes of data in a single patient breath-hold, thereby allowing for the construction of high-resolution axial, coronal, sagittal, and three-dimensional images. Noncontrast CT allows us to make determinations about the character of the liver parenchyma based on changes in density. This is useful for detecting global hepatic abnormalities; however, it does not allow for the precise delineation of hepatic vascular structures nor the detection and characterization of subtle hepatic masses. CT examination of the liver, therefore, relies on iodinated contrast enhancement. Accurate CT imaging requires achieving maximal differences in attenuation between tissues, therefore understanding the contrast enhancement

CROSS-SECTIONAL IMAGING FOR HPB DISORDERS (MRI AND CT) characteristics of the liver and each type of liver tumor is essential. The liver receives approximately 20% of its blood from the hepatic artery and the remaining 80% from the portal vein. Since intravenously injected contrast reaches the liver via the hepatic artery before it does via the portal vein, and takes some time to reach a state of equilibrium, a triphasic CT scan based on hepatic arterial, portal venous, and equilibrium phases is favored for examination of the liver. Although CT remains the most commonly used modality for obtaining cross-sectional images of the liver because of its lower cost and its greater ease of interpretation by clinicians, the indications for liver MRI continue to grow. As compared with triphasic liver CT, liver MRI has the advantages of not

Table 11.1 Anatomic Variations in Portal Vein Anatomy in 200 Patients Patients Type

Portal vein variant

No.

%

1 2 3(Z)

Standard anatomy Trifurcation Right posterior portal vein as first branch of main portal vein Segment VII branch as separate branch of right portal vein Segment VI branch as separate branch of right portal vein Other

130 18 26

65 9 13

2

1

12

6

12

6

4 5

exposing patients to ionizing radiation, a greater measure of safety in patients with renal insufficiency, and an improved ability to characterize certain types of lesions. However, MRI is costly, more time intensive for patients, and contraindicated in patients with certain metal implants. In many centers, magnetic resonance cholangiopancreatography (MRCP) has nearly replaced diagnostic percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP), thus reserving the latter studies for situations in which there is therapeutic intent or in which there is a need for tissue diagnosis. Using heavily T2-weighted sequences, MRCP represents stationary water with high signal intensity (5). As MRCP does not require the administration or biliary excretion of contrast, it works well even in the setting of hepatic dysfunction or obstructive jaundice. Pancreas As for liver and biliary tract imaging, contrast-enhanced CT remains the primary modality used in the setting of pancreatic disease; however, MRI again has some advantages. While CT has higher spatial resolution, MRI may have a better ability to characterize lesions based on tissue composition. Optimal CT imaging of the pancreas relies on the ability of multidetector CT scanners to rapidly capture large volumes of information during specific time periods after IV contrast administration. Thin slices and the ability to reformat images in multiple axes are helpful in preoperative preparation. Furthermore, water is administered as an oral contrast agent to improve differentiation among bowel, pancreas parenchyma,

Table 11.2 Frequency of Different Arterial Variants Seen at CT Angiography in 371 Patients Type of finding Classic celiac arterial anatomy Replaced RHA off SMA Replaced LHA off LGA Artery to segments 2 and 3 off LGA Artery to segments 4A and 4B off RHA Trifurcation of CHA into GDA, RHA, and LHA RHA off celiac axis Accessory LHA off LGA LGA directly oft abdominal aorta CHA off SMA CHA directly off the aorta RHA off GDA Accessory RHA Common trunk of celiac axis and SMA Medial and lateral branches separate off CHA LHA off CHA GDA off RHA SMA gives rise to GDA LHA off celiac axis RHA off aorta Segment 4 branch off GDA Extrahepatic branching of RHA into anterior and posterior with artery to segment 4 off anterior division of RHA

No. of findings (o = 394|) 188 54 30 19 17 15 13 13 11 6 6 5 3 2 2 2 2 2 1 1 1 1

% of patients (n = 371) 51 15 8 5 5 4 4 4 3 2 2 1 1 <1 <1 <1 <1 <1 <1 <1 <1 <1

Note: Twenty patients had two variants seen at CT and one patient had four variants. Abbreviations: LHA, left hepatic artery; RHA, right hepatic artery; LGA, left gastric artery; SMA, superior mesenteric artery; CHA, common hepatic artery; GDA, gastroduodenal artery. Source: Reprinted with permission from Ref. 4.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS and blood vessels. Importantly, modern CT scans may have even greater ability than endoscopic ultrasound to determine the involvement of major vascular structures by periampullary pancreatic cancers (6). MRI is of particular use in patients with contrast allergies or renal insufficiency, although optimal imaging with MRI still requires the administration of gadolinium as a contrast agent. As for biliary pathology, MRCP is often useful in assessing biliary and pancreatic ductal obstruction due to pancreatic masses. In clinical practice, these techniques are often supplemented by ERCP and endoscopic ultrasound.

cross-sectional imaging characteristics of liver and biliary tract lesions Cysts Nonparasitic simple hepatic cysts are fluid-filled thin-walled benign lesions that have no malignant potential, and are found in 1% to 5% of the population. Although treatment of large hepatic cysts may be undertaken to relieve compressive symptoms, most cysts require no treatment at all. Hepatic cysts are recognized on CT imaging by their spherical or near-spherical shape, water-attenuation fluid contents, and barely visible wall that lacks contrast enhancement. By MRI, simple cysts are homogeneous and have low-T1 and high-T2 signal intensity. Multiple hepatic cysts may also be present in the setting of polycystic kidney disease. Distinguishing simple cysts from cystadenoma, which is a very rare tumor, is important in that the latter lesion has the potential to compress the bile ducts, bleed, or develop into a cystadenocarcinoma. On crosssectional imaging, cystadenomas may demonstrate internal septations and a thick wall that enhances with contrast administration (Fig. 11.1). Echinococcal or hydatid cysts are common in certain parts of the world that are endemic for this echinococcus granulosis, which is a parasitic disease transmitted from dogs. Hydatid cysts are recognized as being well-circumscribed cystic lesions that often contain multiple smaller cysts known as daughter cysts. As the primary treatment for hydatid disease consists of administering the anthelmintic agent albendazole, recognition of this entity based on imaging characteristics is essential.

(A)

Hepatic Hemangioma Hepatic hemangiomata are common vascular lesions of the liver that receive their blood supply from the hepatic artery. Hemangiomata rarely cause symptoms; however, giant ones can be associated with abdominal pain or other compressive symptoms (7). Hemangiomata are diagnosed based on their nodular, clump-like pattern of early arterial enhancement on CT (Fig. 11.2). Although small ones are fairly homogeneous in appearance, large hemangiomata may have a heterogeneous appearance due to areas of thrombosis. MRI is the most accurate imaging modality for diagnosing hepatic hemangiomata. On T2-weighted imaging, they are hyperintense and have a lobulated appearance. Administration of gadolinium again shows early peripheral nodular enhancement. Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is a common benign liver tumor made up of all elements of the hepatic parenchyma. FNH are completely benign and rarely, if ever, lead to symptoms. However, the fibrolamellar variant of hepatocellular carcinoma may be mistaken for FNH based on similar imaging characteristics (8). Therefore, accurate identification of FNH is of paramount importance. On pathological examination, FNH typically have a central scar that may be demonstrated on cross-sectional imaging. Contrast-enhanced CT show rapid homogeneous enhancement during the arterial phase with reduced attenuation during the portal venous phase (Fig. 11.3). MRI imaging of FNH reveals isointensity or slight T1 hypointensity or T2 hyperintensity, with a central scar that has even less T1 intensity or more T2 intensity (9). Contrast administration shows early enhancement with delayed enhancement of the central scar. Hepatocellular Adenoma Hepatocellular adenomas are benign proliferations of hepatocytes with a dramatically increased prevalence in patients with a history of oral contraceptive use. Although they are benign lesions, resection of hepatocellular adenomas is recommended because of their propensity for hemorrhage and, albeit rare, risk of malignant transformation. Adenomas are recognized

(B)

Figure 11.1 Biliary cystadenoma. (A) T2- and (B) postcontrast T1-weighted images of a biliary cystadenoma hanging off the inferior portion of the right lobe of the liver. Arrows indicate solid enhancing component of mass distinguishing this from a simple cyst.

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CROSS-SECTIONAL IMAGING FOR HPB DISORDERS (MRI AND CT)

(A)

(B)

Figure 11.2 Hemangioma. (A) T1-weighted postcontrast imaging reveals a nodular peripheral enhancement (black arrow) pattern in the early arterial phase that is characteristic of hemangiomas. (B) T2-weighted imaging reveals a hyperintense, lobulated lesion.

(A)

(B)

(C)

(D)

Figure 11.3 Focal Nodular Hyperplasia (A) T1-weighted precontrast image is isointense to hepatic parenchyma (B) T2-weighted image is also isointense to hepatic parenchyma except the central scar (arrow), which is bright (C) T1-weighted postcontrast image in the arterial phase demonstrates homogenous, hyperintense enhancement with the central scar enhancing on (D) delayed postcontrast images.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS on CT as hypervascular, heterogeneous lesions during arterial phase that become isodense or hypodense during the portal venous phase. MRI also shows hepatocellular adenomas to be heterogeneous, with T1 hyperintensity due to the presence of fat or hemorrhage and typically show arterial phase enhancement as with CT. Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) ranks among the most common causes of cancer-related mortality worldwide; however, its incidence is markedly variable based on geography and prevalence of hepatitis B and C virus infection (10). As it occurs most commonly in the setting of cirrhosis, its radiological diagnosis can be challenging. This is due to the presence of fibrosis and regenerative nodules that can be difficult to distinguish from dysplastic nodules or HCC. Contrastenhanced CT helps provide some distinction, as small dysplastic nodules or HCC that can be mistaken for regenerative nodules typically enhance during the arterial phase and have contrast washout in the delayed venous phase (11). Larger HCC are more heterogeneous in their appearance and may not demonstrate contrast enhancement. MRI adds sensitivity to the diagnosis by showing differences in signal intensity between areas of carcinoma and cirrhotic liver (12). Although HCC are typically hypointense on T1-weighted images, welldifferentiated HCC may be hyperintense. T2-weighted images typically show HCC as hypointense lesions, however, this is variable as well. HCC usually enhance with gadolinium administration (Fig. 11.4). Fibrolamellar Carcinoma Fibrolamellar carcinoma (FLC) is a rare malignant tumor of the liver that typically arises in the absence of cirrhosis in relatively young patients (13). FLC is thought to be a variant of HCC, and is therefore also referred to as fibrolamellar HCC. On CT, FLC are usually large, hypoattenuating tumors with heterogeneous contrast enhancement and a nonenhancing central scar. The central fibrous scar usually show low signal intensity on both T1-weighted and T2-weighted images. Accurate diagnosis is essential since FLC may mimic FNH on cross-sectional imaging due to the presence of a fibrous central scar on both. Cholangiocarcinoma Adenocarcinoma that develops from epithelial cells lining the intrahepatic and extrahepatic bile ducts is termed cholangiocarcinoma. Hilar cholangiocarcinomas (Klatskin tumors), which arise at the confluence of the right and left hepatic ducts, are the most common type and typically present with jaundice (14). CT or MRI of patients with hilar cholangiocarcinoma shows intrahepatic biliary ductal dilatation, often in association with unilobar parenchymal atrophy, bile duct crowding, and portal vein impingement. An associated mass lesion may or may not be present, while a more prognostically favorable papillary variant may show a nodular mass within the biliary system (15). Extrahepatic cholangiocarcinoma, which arises in the common hepatic or common bile ducts, also presents with jaundice. Cross-sectional imaging demonstrates both

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intrahepatic and extrahepatic biliary ductal dilatation. Again, a mass lesion is rarely present, although papillary lesions are possible in this location as well. More commonly, the distal bile duct will show an area of focal thickening that enhances with contrast administration. Peripheral (intrahepatic) cholangiocarcinoma has an appearance on cross-sectional imaging that is more similar to that of more commonly encountered liver tumors. Biliary ductal dilatation is only focal in association with a low attenuation mass that shows peripheral enhancement (Fig. 11.5). Gallbladder Carcinoma Gallbladder carcinoma is a highly aggressive tumor that is notable for its highly variable incidence. Early gallbladder carcinoma may have few findings on cross-sectional imaging. CT of early lesions may demonstrate focal gallbladder-wall thickening or a polypoid mass within the lumen of the gallbladder. More advanced tumors may show a hypoattenuating mass in or replacing the gallbladder, which may be associated with hepatic involvement or biliary ductal dilatation. T2-weighted MRI images show heterogeneous signal intensity with irregular contrast enhancement (16) (Fig. 11.6). Metastatic Cancer to the Liver The most common indication for liver resection in the western world is metastatic disease, especially from colorectal cancer. Liver metastases from colorectal cancer, as well as those from other GI malignancies, are typically characterized by low attenuation relative to normal liver parenchyma; however, there is high variability in their appearance. Colorectal liver metastases are most readily appreciated on portal venous phase CT (Fig. 11.6), and have variable levels of rim enhancement. By contrast, neuroendocrine (Fig. 11.7) and other hypervascular metastases tend to show early arterial enhancement (17). MRI may help to characterize liver metastases, which are typically of low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.

cross-sectional imaging characteristics of pancreatic lesions Cysts The widespread use of high-quality abdominal cross-sectional imaging for a variety of indications has lead to an increased recognition of cystic lesions of the pancreas. Cystic pancreatic lesions may be non-neoplastic, as in the case of pseudocysts, or can be neoplasms that are completely benign, premalignant, or frankly cancerous. Given the broad differential diagnosis of pancreatic cysts, determining their histological origin, while challenging, is of paramount importance in deciding on management, especially for tumors greater than 3 cm in diameter (18,19). Pseudocysts, which are common sequelae of acute pancreatitis, are the most common cystic lesions of the pancreas. As such, differentiating pseudocysts from cystic neoplasms of the pancreas prior to treatment is desirable. Since a clinical history of prior episodes of acute pancreatitis is not perfectly correlated with the diagnosis of pseudocyst, radiological

CROSS-SECTIONAL IMAGING FOR HPB DISORDERS (MRI AND CT)

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Figure 11.4 Hepatocellular carcinoma. (A) Arterial phase CT image demonstrating a dominate right-lobe mass. (B) Note the change in enhancement on the portal venous phase of imaging.

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Figure 11.5 Gallbladder carcinoma. T2-weighted MRI (A) axial and (B) coronal images demonstrate a solid mass in the gallbladder with hyperintense surrounding liver parenchyma consistent with local extension of the tumor into the liver parenchyma.

differentiation is necessary. The presence on MRI of dependent debris within a cystic pancreatic lesion has been found to be highly suggestive of the diagnosis of pseudocyst (20). Serous cystadenoma (SCA) are the most common benign neoplasm of the pancreas and are typically asymptomatic findings, however a proportion of patients do present with symptoms due to mass effect (21). SCA are comprised of multiple smaller cysts and may have a variable appearance based on the size of the cysts that comprise them. In fact, microcystic tumors may have an appearance on CT more consistent with that of a solid tumor. MRI and ultrasound may be helpful in defining the cystic nature of such tumors. Since asymptomatic SCA do not require treatment, differentiating them from other malignant or premalignant lesions is critical. In the event that imaging characteristics are nondiagnostic, biopsy or resection may be indicated. Intraductal papillary mucinous neoplasms (IPMN) are premalignant tumors arising from the main pancreatic duct or its

Figure 11.6 Colorectal cancer metastasis. Irregular hypodense central lesion on contrast-enhanced CT represents a colorectal liver metastasis.

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Figure 11.7 Neuroendocrine metastases. (A) Innumerable hypodense neuroendocrine metastatic nodules with variable levels of rim-enhancement on portal venous phase contrast-enhanced CT. (B) Coronal slice demonstrates direct extension of tumor into the portal vein (arrow).

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Figure 11.8 Intraductal papillary mucinous neoplasm (IPMN). (A) T1-weighted postcontrast imaging reveals a low-intensity multilocular lesion in the head and uncinate process of the pancreas suspicious for a side-branch IPMN. (B) T2-weighted images demonstrate high signal intensity.

branches. IPMN contain epithelium ranging from benign adenoma to invasive adenocarcinoma. IPMN are differentiated based on whether they arise from side-branches or from the main pancreatic duct, with the latter having a higher potential for progressing to invasive malignancy. Cross-sectional imaging reveals a cystic region within or adjacent to the pancreatic parenchyma that may demonstrate continuity with the pancreatic ductal system. Factors that influence the decision to perform pancreatectomy for IPMN include size, growth, and the presence of fibrous septations or solid components. Mucinous cystic neoplasms (MCN) are less common lesions, typically seen in women, which are characterized by ovarian-type stroma. MCN are also felt to be premalignant lesions, therefore their resection is recommended. MCN have imaging characteristics similar to those of IPMN, with the absence of a definable connection to the main pancreatic ductal system (Fig. 11.8). Pancreatic Neuroendocrine Tumors Pancreatic neuroendocrine tumors (PNET), also known as islet cell tumors, are rare malignant neoplasms that have a relatively slow growth rate. While most PNET are nonfunctional, they

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may secrete hormones that lead to clinical symptoms, especially in the setting of metastatic disease to the pancreas. PNET are typically hypervascular lesions that show early arterial phase enhancement on CT, but may be isodense on portal venous phase. Small functional tumors may prove difficult to identify on cross-sectional imaging studies, therefore accurate timing of imaging to the arterial phase of enhancement is important. Similarly, MRI imaging of PNET usually demonstrate high signal intensity on T2-weighted images and low intensity on T1-weighted images with significant contrast enhancement (22) (Fig. 11.9). Solid Pseudopapillary Tumor Solid pseudopapillary tumor (SPT) of the pancreas is a rare, indolent tumor that most commonly affects women in the first three decades of life. Although it has metastatic potential, malignant behavior is uncommon, therefore resection is considered curative. CT imaging is varied and may demonstrate a large lesion with internal hemorrhage or cystic degeneration. While vascular encasement, pancreatic ductal dilatation, and hepatic metastases are seen only in the carcinomatous variant

CROSS-SECTIONAL IMAGING FOR HPB DISORDERS (MRI AND CT)

Figure 11.9 Neuroendocrine pancreatic tumor. A well-preserved fat plane is seen separating this large hypervascular neuroendocrine tumor in the head of the pancreas from the superior mesenteric/portal vein. Areas of hypoattenuation towards the middle of the tumor are suggestive of central ischemia.

of this tumor, more typical findings based on size, capsule thickness, internal composition, and calcification pattern do not help to differentiate benign and malignant lesions (23). Acinar Cell Carcinoma Although acinar cells comprise the bulk of pancreatic tissue, acinar cell carcinomas (ACC) are very uncommon. ACC are typically well-circumscribed tumors that may be lobulated and may be heterogeneous or homogeneous in appearance on cross-sectional imaging (24). ACC range from being completely solid to mostly cystic with at least some solid components and central necrotic areas may be seen. Biliary or pancreatic ductal dilatation is occasionally seen. Contrast-enhanced CT shows homogeneous enhancement of solid components, but less than that of the surrounding pancreas. T2-weighted MRI images may show hyperintense signal in relation to pancreatic parenchyma. Pancreatic Adenocarcinoma Pancreatic adenocarcinoma, commonly referred to as pancreatic cancer, is the most common malignant neoplasm of the pancreas. It is a highly aggressive malignancy that carries with it an extremely high mortality rate, having an incidence that nearly equals its mortality rate. Because of the biologically aggressive nature of pancreatic cancer, the majority of patients present with metastatic or unresectable disease. Contrast-enhanced CT usually shows a hypoattenuating poorly defined mass with dilatation of the pancreatic duct distally and, in the case of tumors of the pancreatic head, biliary ductal dilatation as well. Biliary and/or pancreatic ductal dilatation may also be seen in the absence of an identifiable mass, and dilatation of both of these ductal systems—the double duct sign—is a classic sign of adenocarcinoma of the head of the pancreas. The double duct sign is not, however, pathognomonic for pancreatic cancer and may be associated with benign processes (25). MRI has the advantage of being usable in patients with diminished renal function and can be combined with MRCP to provide detail about the biliary and pancreatic ductal systems in a noninvasive fashion (Fig. 11.10). The primary determinants of the resectability of pancreatic lesions inevitably relate to vascular involvement, since the

Figure 11.10 Pancreatic adenocarcinoma. Contrast-enhanced CT reveals a hypointense solid-appearing mass in the tail of the pancreas. This appearance on cross-sectional imaging is characteristic of pancreatic adenocarcinoma.

pancreas is intimately associated with the portal venous system and in close proximity to the celiac artery and superior mesenteric artery (SMA). High-quality cross-sectional imaging clearly defines these relationships and predicts the likelihood of successful resection. Metastatic Cancer to the Pancreas In contrast to the liver, the pancreas is a rare site of metastatic disease. Although multiple types of cancer have been reported to metastasize to the pancreas, renal cell carcinoma, nonsmall cell lung carcinoma, and lymphoma are the most common sources of isolated pancreatic metastases. Renal cell carcinoma metastases to the pancreas are typically well-circumscribed, arterial-enhancing lesions, while other histologies tend to be more diffuse and variable in enhancement patterns.

conclusions CT and MRI have become essential components in the diagnosis, perioperative management, and follow-up of hepatic, biliary, and pancreatic pathology. Therefore, the ability to appropriately order and interpret these studies, in consultation with radiologists, is a prerequisite to the surgical management of patients with such diseases.

references 1. Winston CB, Lee NA, Jarnagin WR, et al. CT angiography for delineation of celiac and superior mesenteric artery variants in patients undergoing hepatobiliary and pancreatic surgery. AJR Am J Roentgenol 2007; 189(1): W13–19. 2. Blumgart LH. Surgery of the Liver, Biliary Tract, and Pancreas, 4th edn. Philadelphia, PA: Saunders Elsevier, 2007. 3. Kamel IR, Lawler LP, Fishman EK. Variations in anatomy of the middle hepatic vein and their impact on formal right hepatectomy. Abdom Imaging 2003; 28(5): 668–74. 4. Covey AM, Brody LA, Getrajdman GI, Sofocleous CT, Brown KT. Incidence, patterns, and clinical relevance of variant portal vein anatomy. AJR Am J Roentgenol Oct 2004; 183(4): 1055–64.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 5. Adam A, Dixon AK, Allison DJ, Grainger RG. Grainger & Allison’s Diagnostic Radiology: a Textbook of Medical Imaging 5th edn. Edinburgh: Churchill Livingstone, 2008. 6. Mansfield SD, Scott J, Oppong K, et al. Comparison of multislice computed tomography and endoscopic ultrasonography with operative and histological findings in suspected pancreatic and periampullary malignancy. Br J Surg 2008; 95(12): 1512–20. 7. Yoon SS, Charny CK, Fong Y, et al. Diagnosis, management, and outcomes of 115 patients with hepatic hemangioma. J Am Coll Surg 2003; 197(3): 392–402. 8. Blachar A, Federle MP, Ferris JV, et al. Radiologists’ performance in the diagnosis of liver tumors with central scars by using specific CT criteria. Radiology 2002; 223(2): 532–9. 9. Hussain SM, Terkivatan T, Zondervan PE, et al. Focal nodular hyperplasia: findings at state-of-the-art MR imaging, US, CT, and pathologic analysis. Radiographics 2004; 24(1): 3–17, discussion 18–19. 10. Pang RW, Joh JW, Johnson PJ, Monden M, Pawlik TM, Poon RT. Biology of hepatocellular carcinoma. Ann Surg Oncol 2008; 15(4): 962–71. 11. Takayama T, Makuuchi M, Kojiro M, et al. Early hepatocellular carcinoma: pathology, imaging, and therapy. Ann Surg Oncol 2008; 15(4): 972–8. 12. Coakley FV, Schwartz LH. Imaging of hepatocellular carcinoma: a practical approach. Semin Oncol 2001; 28(5): 460–73. 13. Stipa F, Yoon SS, Liau KH, et al. Outcome of patients with fibrolamellar hepatocellular carcinoma. Cancer 15 2006; 106(6): 1331–8. 14. Akoad M, Jenkins R. Proximal biliary malignancy. Surg Clin North Am 2008; 88(6): 1409–28, x–xi. 15. Jarnagin WR, Bowne W, Klimstra DS, et al. Papillary phenotype confers improved survival after resection of hilar cholangiocarcinoma. Ann Surg 2005; 241(5): 703–12, discussion 712–14.

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16. Schwartz LH, Black J, Fong Y, et al. Gallbladder carcinoma: findings at MR imaging with MR cholangiopancreatography. J Comput Assist Tomogr 2002; 26(3): 405–10. 17. Tamm EP, Kim EE, Ng CS. Imaging of neuroendocrine tumors. Hematol Oncol Clin North Am 2007; 21(3): 409–32, vii. 18. Allen PJ, Brennan MF. The management of cystic lesions of the pancreas. Adv Surg 2007; 41: 211–28. 19. Allen PJ, D’Angelica M, Gonen M, et al. A selective approach to the resection of cystic lesions of the pancreas: results from 539 consecutive patients. Ann Surg 2006; 244(4): 572–82. 20. Macari M, Finn ME, Bennett GL, et al. Differentiating pancreatic cystic neoplasms from pancreatic pseudocysts at MR imaging: value of perceived internal debris. Radiology 2009; 251(1): 77–84. 21. Tseng JF, Warshaw AL, Sahani DV, et al. Serous cystadenoma of the pancreas: tumor growth rates and recommendations for treatment. Ann Surg 2005; 242(3): 413–19, discussion 419–21. 22. Rha SE, Jung SE, Lee KH, et al. CT and MR imaging findings of endocrine tumor of the pancreas according to WHO classification. Eur J Radiol 2007; 62(3): 371–7. 23. Lee JH, Yu JS, Kim H, et al. Solid pseudopapillary carcinoma of the pancreas: differentiation from benign solid pseudopapillary tumour using CT and MRI. Clin Radiol 2008; 63(9): 1006–14. 24. Tatli S, Mortele KJ, Levy AD, et al. CT and MRI features of pure acinar cell carcinoma of the pancreas in adults. AJR Am J Roentgenol 2005; 184(2): 511–19. 25. Plumley TF, Rohrmann CA, Freeny PC, Silverstein FE, Ball TJ. Double duct sign: reassessed significance in ERCP. AJR Am J Roentgenol 1982; 138(1): 31–5.

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Liver metastases: detection and imaging Valérie Vilgrain, Ludovic Trinquart, and Bernard Van Beers

The liver is the second most frequent site of metastases, after lymph nodes, providing a very suitable environment for the growth of metastases because of its rich blood supply from the systemic and splanchnic system. The overall extent of liver involvement in cancer patients is unknown but liver metastases have been found in 30% to 70% of patients who die because of cancer, depending on their primary tumor (1). Liver metastases frequently arise from colorectal cancer (CRC), with 15% to 20% of patients presenting with synchronous liver metastases and another 15% developing metachronous metastases to the liver within five years (2,3). But unlike many other types of cancers, the presence of distant metastases from CRC does not necessarily preclude curative treatment. In fact, CRC metastases are confined to the liver in 25% of patients (4). This confinement of metastatic disease to the liver has allowed progress in the treatment of these patients—via hepatic resection, regional chemotherapy, and thermoablative treatments, and the benefits of such approaches are demonstrated by the fact that survival of up to 25% of patients 10 year after resection of these metastases is possible. Isolated liver metastases also often arise from gastric and pancreatic cancers—because of the portal venous drainage to the liver—and less frequently from breast or lung cancers. But most non-CRC liver metastases are associated with distant metastatic spread to other organs and so require a more systemic therapeutic approach. However, metastases confined to the liver may also be seen in ocular melanoma, breast cancer, neuroendocrine tumors, renal cell cancers, and some sarcomas (5–7). In this context, the goal of imaging for liver metastases is twofold: first to establish an early and accurate diagnosis of liver metastases, second to stage preoperatively those patients with liver metastases confined to the liver, especially when the primary tumor is CRC. The diagnostic value of ultrasound (US), contrast-enhanced US, multidetector computed tomography (CT), and magnetic resonance (MR) imaging with nonspecific gadolinium chelates and liver-specific contrast agent is discussed. Pitfalls and limitations of imaging are shown. Lastly, the role of imaging in assessing number, localization, and size of metastases to determine resectability is emphasized.

The role of Doppler techniques is often limited because flow signals in liver metastases are usually too low to be detected except in markedly hypervascular liver metastases. Because there are no specific features of metastases at conventional US, the differentiation of a single metastasis from other lesions is usually not possible but on the other hand, US is helpful to characterize benign lesions such as hepatic cysts and hemangiomas in oncological patients. While in many European countries, US was the recommended imaging follow-up method, CT or MRI is nowadays preferred in oncological patients.

The principle of this technique is to increase the lesion-to-liver contrast, using intravascular microbubble contrast agents, which allows enhanced detection of smaller liver metastases not seen on conventional US. Most contrast agents used nowadays provide strong and persistent signal enhancement due to harmonic resonance at low mechanical index, where minimal or no bubble destruction occurs. Examination includes a continuous evaluation of the lesion enhancement during the arterial (15–30 seconds delay), portal venous (30–60 seconds delay), and delayed (2–3 minutes delay) phases. Most liver metastases are hypovascular and exhibit no or minimal enhancement on the arterial phase. Interestingly, whatever the lesion enhancement is on the arterial phase, metastases show nonenhancing defects on the delayed phase, which seem to be the most useful determinant for both lesion detection and characterization (Fig. 12.1). This strong washout sign is caused by the biokinetics of the US contrast agents that are purely vascular effects; conversely to nonspecific CT and MR contrast agents that spread into the interstitium. Indeed, the use of contrast agents improves the sensitivity of US in detecting individual lesions by about 20% in comparison to baseline, independent of the type of contrast agent used (9). Contrast-enhanced US imaging is technically successful in most patients except those with severe obesity and marked steatosis in whom penetration of contrast-specific imaging is limited.

imaging techniques

computed tomography

Ultrasound Liver metastases are generally multiple, spherical, and have well-defined margins. Most lesions are hypoechoic. The most common hyperechoic metastases are observed in patients with CRC or neuroendocrine tumors. Large lesions often have more central hypoechogenicity related to areas of necrosis. A hypoechoic halo is seen surrounding the lesions in 40% of cases (8). More rarely, liver metastases may appear as diffuse infiltration.

Computed tomography (CT) is the most commonly used imaging modality for both detection and characterization of liver metastases. Multidetector helical CT is now the standard technique. It reduces the scan time, with high coverage and high-quality 3D reconstructions. The examination comprises of an unenhanced scan and, after intravenous administration of nonionic iodine contrast medium, two acquisitions at the late arterial phase and the portal venous phase. During the latter, the liver parenchyma enhances

contrast-enhanced ultrasound

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(C) Figure 12.1 (A–C) Portal-phase CT shows a small liver tumor that is not characteristic of liver metastasis. This lesion is homogeneous and hyperechoic on ultrasound (B). Portal-phase contrast-enhanced ultrasound demonstrates washout, which is highly suggestive of liver malignancy (C).

the arterial phase. A key finding is the presence of a halo (11), which has been shown as a quite sensitive and specific finding for liver metastases. However, unenhanced, arterial-phase and delayed-phase imaging (which is optional) are helpful for differentiating benign lesions such as cyst, hemangioma, or hepatocellular tumors from metastases.

magnetic resonance imaging

Figure 12.2 Portal-phase CT demonstrating multiple heterogeneous lesions suggestive of liver metastases.

and it increases the lesion conspicuity of hypovascular tumors (10) (Fig. 12.2). Most liver metastases are hypoattenuating and hypovascular on unenhanced scans, meaning that they are better seen on the portal venous phase than on

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The routine magnetic resonance (MR) imaging protocol includes nonenhanced T1- and T2-weighted pulse sequences and postcontrast sequences. On T1-weighted images, most liver metastases are hypointense, but isointense lesions are seen in approximately 10% of patients (12). Hyperintense liver metastases are very uncommon but may be seen in melanoma. On T2-weighted images, liver metastases are most commonly moderately hyperintense, whereas the remnants are isointense or markedly hyperintense (12). The areas of marked hyperintensity correspond to cystic changes or necrosis (12). It seems that the signal intensity on T2-weighted images is not related to metastases from a specific primary neoplasm. Contrast agents can improve diagnostic accuracy. Two groups of MR contrast agents may be used: nonspecific gadolinium chelates whose biokinetics are similar to iodine contrast agents, and liver-specific contrast agents, either for

LIVER METASTASES: DETECTION AND IMAGING

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Figure 12.3 (A–D) MR imaging of a colorectal metastasis. The tumor is hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note the peripheral halo on portal-phase T1-weighted imaging and the delayed enhancement due to fibrous stroma (C and D).

reticuloendothelial system (ferumoxides) or hepatobiliary captation (Mn-DPDP or specific hepatobiliary gadolinium chelates). Briefly, the nonspecific gadolinium chelates are used for lesion characterization, while the others have been proposed for preoperative staging. The principle of the latter is to increase the lesion-to-liver contrast by decreasing markedly the signal of the liver on T2 sequences (ferumoxides) or increasing it on T1-weighted sequences (13). Some authors have also proposed double-contrast MR combining specific and nonspecific contrast agents. Similarly to CT, nonspecific gadolinium MR imaging should include baseline precontrast images and sequential acquisitions at arterial, portal, and equilibrium phases. In a large series of 516 liver metastases from various tumors in 165 consecutive patients, most liver metastases were hypovascular (64% of all patients and 91% of patients with colon cancer) ( 12 ). A hypervascular pattern of enhancement was identified in 36% of patients. During the arterial phase, peripheral ring enhancement was seen in 72% of patients. On the portal venous and delayed phase, incomplete central progression of lesion enhancement was found in two-thirds of patients ( 12 ) ( Fig. 12.3 ). Peripheral washout in metastases on delayed-phase images was identified in one-third

of patients with hypervascular metastases and almost never in hypovascular metastases ( 12 ) ( Fig. 12.4 ). After administration of liver-specific contrast agents, liver metastases that lack functioning hepatocytes or Kupffer cells do not enhance postcontrast, resulting in improved lesion conspicuity ( 14 ). Diffusion-weighted MR imaging is quite interesting in liver metastases. Nasu et al. (15) have shown increased detection of metastatic lesions with a combination of diffusion-weighted imaging and precontrast T1- and T2-weighted imaging when compared with liver-specific contrast MR imaging. Parikh et al. have shown that diffusion-weighted sequences were as accurate as T2-sequences for characterization of focal liver lesions including metastases (16) (Fig. 12.5).

positron emission tomography Conversely to the other imaging modalities, which give more morphologic than functional information, positron emission tomography (PET) imaging is essentially functional imaging and provides a physiological survey for hypermetabolic tumors. PET scanning after administration of [18F] 2-fluoro-2-deoxyglucose (FDG) is based upon higher glycolytic activity of many tumors compared to normal tissue. [18F]FDG is transported into cells and phosphorylated by

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS the enzyme hexokinase to [18F]FDG-6-phosphate, which cannot proceed down the glycolytic pathway and is therefore accumulated in malignant tissue. This technique has improved markedly over the past decade, and many centers routinely incorporate PET imaging results in the staging of patients with liver metastases, especially when consideration is being given for liver resection. Most studies have focused on the diagnostic yield of fluorodeoxyglucose (FDG)-PET in patients with liver metastases from colon and rectal cancer. The two main limitations of PET are the lack of anatomical landmarks and poor spatial

resolution. Development of PET/CT has overcome these drawbacks; unfortunately, most PET/CT examinations are performed with unenhanced CT images. Recently, some authors have investigated the role of IV iodinated contrast material in the evaluation of liver metastases at [18F]FDG PET/CT (17). They have shown that more liver metastases were detected on PET/contrast-enhanced CT compared with PET/unenhanced CT (83% and 67%, respectively). Similarly, liver metastases were more accurately characterized at PET/ contrast-enhanced CT compared with PET/unenhanced CT (73% and 57%, respectively).

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Figure 12.4 (A–D) MR imaging of endocrine metastases. The tumors are strongly hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note the strong hypervascularity on arterial-phase T1-weighted imaging and the washout on portal-phase imaging (C and D).

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Figure 12.5 MR imaging of liver metastases. Multiple tumors are seen on T2-weighted imaging (A). Conspicuity of small tumors is more evident on diffusionweighted imaging (B).

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perfusion imaging Liver metastases induce changes in liver perfusion and have been shown to increase arterial blood flow and the arterial– portal flow ratio (hepatic perfusion index) compared to normal liver. Interestingly, animal studies have demonstrated that those changes may be detected at an early stage when liver metastases are occult on other imaging modalities (18). Hepatic perfusion index can be obtained using various techniques: nuclear medicine, US, CT, or MR imaging. Early results in patients were promising but lack of standardization in utilization, lack of consensus regarding the imaging modality, and the presence of multiple mathematical models have meant that perfusion has not been adopted in routine practice.

other imaging findings Hypervascular Metastases Liver metastases from colon carcinoma, other gastrointestinal carcinoma, and pulmonary carcinoma are considered hypovascular, and those from thyroid carcinoma, neuroendocrine tumor, and renal cell carcinoma are hypervascular (12) (Fig. 12.5). Breast carcinoma metastases can be either hypovascular or hypervascular. Furthermore, in Danet’s series, patients with metastases that exhibit the nonclassical type of enhancement according to the primary tumor were not uncommon. For example, 9% of patients with colon carcinoma had hypervascular metastases (12). This observation emphasizes the role of imaging in characterizing liver lesions in cancer patients, and the importance of multiple complementary examinations. Cystic Metastases Liver metastases may have a cystic appearance with strong hyperintensity on heavily T2-weighted MR images. However, these tumors usually have other findings that are not seen in typical hepatic cysts such as internal septations, thick walls, and wall enhancement. Most cystic liver metastases arise from cystadenocarcinoma, neuroendocrine tumor, and sarcoma. Calcified Metastases Up to 11% of patients with colon carcinoma have calcified liver metastases at presentation. Patients may also develop

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calcification during response to chemotherapy (19) (Fig. 12.6). Whether liver metastatic calcification carries a prognostic significance in CRC is still questionable. Intrabiliary Metastases Intrinsic bile duct involvement by metastases may occur either by growing from within or invading the lumen of the bile ducts. The most common intrabiliary metastases arise from colorectal carcinoma. Most patients present with various degree of biliary obstruction including jaundice (20). The presence of macroscopic intrabiliary extension seems to be a good indicator in patients with CRC showing less aggressive features (21). Pitfalls and Limitations The two most difficult situations in oncological patients are the changes in the liver such as steatosis that can create pseudolesions or hide true metastases, and the characterization of small lesions. Steatosis is not always homogeneous and may have either focal fatty sparing, or more rarely focal fatty deposit. Furthermore, fatty livers are often observed in cancer patients who have received chemotherapy. Clearly, in this context, MR is superior to CT by combining fat-suppressed T1 sequences and in- and opposed-phase T1-weighted imaging that can diagnose both focal and diffuse changes, and help to differentiate focal fat from metastases (Fig. 12.7). Another issue is the characterization of small liver lesions in cancer patients. Those lesions (smaller than 1 or 2 cm) are often deemed “too small to characterize,” and due to the high prevalence of benign lesions in the liver, are more frequently benign than malignant. Schwartz et al. reported in a series of 2978 cancer patients that metastases represented only 11.6% of patients with small liver lesions (22). Other authors have shown that the positive predictive value for malignancy increased notably using a cut-off of 20 mm compared to 10 mm (23). Yet, for an individual patient, we cannot rely only on lesion size for characterization. While CT is an excellent imaging modality for detection, it is not as good as US, contrast-enhanced US, and MR imaging when characterizing small liver lesions (24,25).

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Figure 12.6 (A and B) Liver metastases before and after chemotherapy. Note the significant decrease in size of the tumors. Furthermore, the tumors present diffuse calcifications after chemotherapy.

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(C)

Figure 12.7 (A–C) Liver metastases developed on a fatty liver. The tumor located in the posterior part of the segment 4 is barely visible on portal-phase CT (A) and is better seen on pre- and postcontrast T1-weighted imaging (B and C).

detection of liver metastases: which imaging modality? Many different noninvasive imaging modalities are available for the preoperative detection of liver metastases: US and contrast-enhanced US, multidetector CT, MR imaging, and PET using FDG. Comparison of these imaging techniques is challenging and results have evolved over time due to technological improvements. Multidetector CT has notably increased the performance of CT in decreasing slice thickness and optimizing lesion enhancement on multiphasic studies after intravenous contrast. The use of liver-specific contrast agents in MR imaging has given new horizons for this imaging modality. Diffusion-weighted MR has markedly improved the detection of liver metastases. The use of US contrast agents has completely changed the role of US in oncology. Integrated PET/CT scanners combining metabolic and anatomical information has also resulted in an increased interest in PET studies, and it is likely that the role of IV iodinated contrast material in PET/CT scanners will be quite significant. Consequently, many studies have assessed and compared the diagnostic value of these imaging techniques, resulting in an extensive body of literature and the absence of any consensus on the diagnostic algorithm (26). Two systematic reviews (27,28) and one narrative review (29) have analyzed the available evidence (Tables 12.1 and 12.2). The first systematic review was published by Kinkel et al. in 2002, and aimed at comparing current noninvasive imaging methods such as US, CT, MR imaging, and FDG PET for the detection of hepatic metastases from colorectal, gastric, and esophageal cancers (28). Papers published between December 1985 and December 2000 were studied. Among the 54 studies included, 9 assessed US (686 patients, 74% with CRC), 25 assessed CT (1747 patients, 78% with CRC), 11 addressed MRI (401 patients, 100% with CRC), and 9 reported on PET (423 patients, 100% with CRC). In a “per-patient” meta-analysis, the authors concluded that [18F]FDG PET was the most sensitive examination (Level of evidence II): the combined per-patient sensitivity of [18F]FDG PET (0.90, 95% CI 0.82– 0.96) being significantly superior to that of US (0.66, 95% CI 0.54–0.77), CT (0.70, 95% CI 0.63–0.77), and MRI (0.71, 95%

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Table 12.1 Levels of Evidence for Studies of Diagnostic Test Accuracy Ia: Systematic review (with homogeneity)* of level-1 studies Ib: Level 1 studies II: Level 2 studies or systematic reviews of level-2 studies III: Level 3 studies or systematic reviews of level-3 studies IV: Expert committee reports or opinions Level 1 studies are studies that use a blind comparison of the test withw a validated reference standard (gold standard) In a sample of patients that reflects the population to whom the test would apply Level 2 studies are studies that have only one of the following: Narrow population (the sample does not reflect the population to whom the test would apply) Use a poor reference standard (defined as that where the “test” is included in the “reference” or where the “testing” affects the “reference”) The comparison between the test and reference is not blind Case–control studies Level 3 studies are studies that have at least two or three of the features listed above *Homogeneity means there are no or minor variations in the directions and degrees of results between individual studies that are included in the systematic review.

Table 12.2 Grading of Recommendations on Diagnostic Tests Grade A: Studies with level of evidence Ia or Ib Grade B: Studies with level of evidence II Grade C: Studies with level of evidence III Grade D: Studies with level of evidence IV

CI 0.61–0.80). Moreover, in the 35 studies with specificity higher than 85%, [18F]FDG PET was still the most sensitive technique, the combined sensitivity being 55% for US, 72% for CT, 76% for MR imaging, and 90% for FDG PET. The second systematic review was published by Bipat et al. in 2005 and aimed at evaluating CT, MR imaging, and [18F]

LIVER METASTASES: DETECTION AND IMAGING FDG PET for the detection of colorectal liver metastases on a per-patient and per-lesion bases, reviewing articles from 1990 to 2003 (27). Among the 61 selected studies, 28 assessed nonhelical CT, 15 assessed helical CT, 5 concerned 1.0T MRI, 12 concerned 1.5T MRI, and 21 addressed [18F]FDG PET. On a “per-patient” basis, the combined sensitivity of PET (0.95, 95% CI 0.93–0.96) was significantly superior to that of nonhelical CT (0.60, 95% CI 0.58–0.65), helical CT (0.65, 95% CI 0.30–0.89), and 1.5T MRI (0.76, 95% CI 0.56–0.89) (Level of evidence II). On a “per–lesion” basis, nonhelical CT sensitivity (0.52, 95% CI 0.52–0.53) was significantly lower than that of helical CT (0.64, 95% CI 0.54–0.72), 1.0T MRI (0.66, 95% CI 0.66–0.66), 1.5T MRI (0.64, 95% CI 0.58–0.71), and PET (0.76, 95% CI 0.61–0.86). In other words, there was no evidence that the “per-lesion” sensitivities of PET, helical CT, and MRI differed significantly. For lesions of 1 cm or larger, SPIO-enhanced MR imaging was the most accurate modality. Therefore, considerable debate continues about which imaging modality offers the best noninvasive examination of the liver, and so some comments concerning the existing evidence need to be addressed. First, the diagnostic value of imaging techniques can be computed per patient (detection of at least one lesion per patient) or per lesion (detection of all lesions per patient). But, in cancer patients, the per-patient analysis is not adequate because the main question is not: “Does the patient have liver metastases?” But rather, “How many metastases are in the liver, and where?” As previously seen in the results of the prior metaanalyses, the per-lesion comparison of imaging modalities is still open. The second point worth considering is the frequent use of a suboptimal diagnostic reference standard. The most reliable reference standard is the combination of direct visualization and bimanual palpation of the liver, intraoperative US, and histopathological examination of resected liver tissue of each lesion found in the liver, so allowing for a lesion-by-lesion analysis. But only a minority of studies used this reference standard, resulting in underdetection of lesions and overestimation of sensitivity. Studies that analyzed the detection of liver metastases without this surgical reference standard (that is using imaging follow-up or a combination of other imaging modalities) are of limited value because sensitivity of the methodology will appear higher than the true one. It should be noted that even with this extensive pre- and intraoperative workup, lesions may be missed and in two series approximately 15% of patients were found to have “new” tumors on follow-up CT scans performed four to six months after hepatic resection (30,31). Third, the imaging modalities analyzed in the two metaanalyses extended for a long period of time from 1985 or 1990 to 2000 and their results are difficult to compare with up-to-date imaging. Research on hepatic contrast agents has advanced in two directions: first the development of US contrast agent, especially the more stable second generation of contrast media, has prompted a revival of interest in contrast-enhanced US; second tissue-specific MR contrast agents have been developed to target the main cell

populations of the liver. These advances, as well as those of multidetector-row CT (32 or 64 slice systems) or PET/CT, were not integrated in the two available systematic reviews but were discussed in the Rappeport and Loft narrative review (29). Considering the available comparisons of modern MR imaging, multidetector-row CT and PET in the same group of patients with surgical reference standards, Rappeport and Loft questioned the conclusions of the two prior systematic reviews. The authors concluded that “state-of the-art anatomical imaging, e.g., liver-specific MR imaging and multidetector CT, must be considered more sensitive than PET in the detection of individual liver metastases” (Level of evidence II) (29). They also stated that “a preoperative PET/CT-study for detection of possible extra-hepatic tumor contraindicating liver surgery is also recommended.” Moreover, recent articles have pointed out the limitation of FDG-PET in detecting small liver metastases, with a significant superiority of CT and MR imaging (32–34). This is a key result because most lesions larger than 1 cm are depicted on all imaging techniques, but the detection of subcentimeter metastases remains disappointing and therefore the comparison of imaging modalities should focus on these small lesions. Consequently, the question seems to be which is the better imaging modality between CT and MR? And should we use nonspecific MR contrast or liver-specific contrast agents? We have to take into consideration the following: ●

●

Multidetector-row CT scanning is often the first choice for a “screening” liver examination at many institutions. This technique also enables rapid scanning of the chest and abdomen and allows evaluation of extrahepatic disease. MRI enhanced with SPIO is probably a more sensitive method than multidetector-row CT for detecting liver metastases (35,36), but to our knowledge, no study has evaluated the added value of MR imaging after multidetector-row CT examination and the consequences in treatment planning.

Based on the existing evidence, it is difficult to provide highstrength management recommendations. Our policy at our institution is to perform systematically a multidetector CT in patients with liver metastases. PET/CT is indicated for the detection of extrahepatic tumor before liver surgery. MR imaging is not routinely performed and is reserved for characterization of small liver lesions, in fatty livers, and in difficult cases after multidetector CT. For lesion characterization, we use nonspecific contrast MR agents, while for tumor detection and preoperative staging, we use liver-specific contrast agents. In both cases, our protocol includes diffusion-weighted MR sequences. Intraoperative US is routinely performed in our institution and intraoperative contrast-enhanced US is under investigation.

preoperative staging Due to their biological properties, most liver metastases that are resected are secondary to CRC. Selected isolated liver metastases from breast cancer, sarcoma, renal cell cancer

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS and Wilms’ tumors, melanoma, other GI cancers, and, most frequently, endocrine tumors, may benefit from liver resection (5). Assessment of the number and location of liver metastases is a major issue of preoperative staging and has been described previously. Yet, imaging has to answer other questions relevant to technical success and R0 resection: ●

●

●

●

Does the future liver remnant have sufficient volume for the perioperative and postoperative course? This question is easily addressed by CT or MR volumetric measurement. Does the future liver remnant have satisfactory vascular inflow, venous outflow, and biliary drainage? Again CT or MR imaging is adequate to answer this question. Is there any contraindication to performing an R0 resection? This point is more difficult as classical contraindications such as bilobar metastases are overcome in most specialized centers either by twostep resection with preoperative portal embolization to increase the remaining normal liver parenchyma or downsizing with chemotherapy, or combination of resection and thermal ablation (37). However, it is crucial to evaluate the relationship between the liver tumors and important anatomical landmarks such as the inferior vena cava (IVC), hepatic venous confluence, and the main portal pedicles. Did the liver metastases respond to preoperative chemotherapy? Preoperative chemotherapy is currently performed in resectable patients as it has been shown to reduce the risk of events of progression-free survival in eligible and resected patients (38). In these patients, the role of imaging is to evaluate the tumor response according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Association with targeted therapy may render more complex this assessment.

references 1. Pickren J, Tsukada Y, Lane W. Analysis of autopsy data. In: Weiss L, Gilbert H, eds. Liver Metastasis. Boston, MA: Hall, 1982: 2–18. 2. Kune GA, Kune S, Field B, et al. Survival in patients with large-bowel cancer. A population-based investigation from the Melbourne Colorectal Cancer Study. Dis Colon Rectum 1990; 33: 938–46. 3. Manfredi S, Lepage C, Hatem C, et al. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006; 244: 254–9. 4. Ballantyne GH, Quin J. Surgical treatment of liver metastases in patients with colorectal cancer. Cancer 1993; 71: 4252–66. 5. Elias D, Lasser P, Ducreux M, et al. Liver resection (and associated extrahepatic resections) for metastatic well-differentiated endocrine tumors: a 15-year single center prospective study. Surgery 2003; 133: 375–82. 6. Hughes K, Sugarbaker P. Resection of the liver for metastatic solid tumors. In: SA R, ed. Surgical Treatment of Metastatic Cancer. Philadelphia, PA: Lippincott, 1987; 125–64. 7. Leyvraz S, Spataro V, Bauer J, et al. Treatment of ocular melanoma metastatic to the liver by hepatic arterial chemotherapy. J Clin Oncol 1997; 15: 2589–95. 8. Albrecht T. Detection and characterisation of liver metastases. In: Lencioni R, ed. Enhancing the Role of Ultrasound with Contrast Agents. Milan: Springer, 2006; 53–67.

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9. Albrecht T, Hoffmann CW, Schmitz SA, et al. Phase-inversion sonography during the liver-specific late phase of contrast enhancement: improved detection of liver metastases. AJR Am J Roentgenol 2001; 176: 1191–8. 10. van Leeuwen MS, Noordzij J, Feldberg MA, Hennipman AH, Doornewaard H. Focal liver lesions: characterization with triphasic spiral CT. Radiology 1996; 201: 327–36. 11. Nino-Murcia M, Olcott EW, Jeffrey RB, Jr., et al. Focal liver lesions: pattern-based classification scheme for enhancement at arterial phase CT. Radiology 2000; 215: 746–51. 12. Danet IM, Semelka RC, Leonardou P, et al. Spectrum of MRI appearances of untreated metastases of the liver. AJR Am J Roentgenol 2003; 181: 809–17. 13. Kim KW, Kim AY, Kim TK, et al. Small (< or = 2 cm) hepatic lesions in colorectal cancer patients: detection and characterization on mangafodipir trisodium-enhanced MRI. AJR Am J Roentgenol 2004; 182: 1233–40. 14. Schima W, Kulinna C, Langenberger H, Ba-Ssalamah A. Liver metastases of colorectal cancer: US, CT or MR? Cancer Imaging 2005; 5 Spec No A: S149–56. 15. Nasu K, Kuroki Y, Nawano S, et al. Hepatic metastases: diffusion-weighted sensitivity-encoding versus SPIO-enhanced MR imaging. Radiology 2006; 239: 122–30. 16. Parikh T, Drew SJ, Lee VS, et al. Focal liver lesion detection and characterization with diffusion-weighted MR imaging: comparison with standard breath-hold T2-weighted imaging. Radiology 2008; 246: 812–22. 17. Badiee S, Franc BL, Webb EM, et al. Role of IV iodinated contrast material in 18F-FDG PET/CT of liver metastases. AJR Am J Roentgenol 2008; 191: 1436–9. 18. Cuenod C, Leconte I, Siauve N, et al. Early changes in liver perfusion caused by occult metastases in rats: detection with quantitative CT. Radiology 2001; 218: 556–61. 19. Hale HL, Husband JE, Gossios K, Norman AR, Cunningham D. CT of calcified liver metastases in colorectal carcinoma. Clin Radiol 1998; 53: 735–41. 20. Povoski SP, Klimstra DS, Brown KT, et al. Recognition of intrabiliary hepatic metastases from colorectal adenocarcinoma. HPB Surg 2000; 11: 383–90, discussion 390–1. 21. Kubo M, Sakamoto M, Fukushima N, et al. Less aggressive features of colorectal cancer with liver metastases showing macroscopic intrabiliary extension. Pathol Int 2002; 52: 514–18. 22. Schwartz LH, Gandras EJ, Colangelo SM, Ercolani MC, Panicek DM. Prevalence and importance of small hepatic lesions found at CT in patients with cancer. Radiology 1999; 210: 71–4. 23. van Erkel AR, Pijl ME, van den Berg-Huysmans AA, et al. Hepatic metastases in patients with colorectal cancer: relationship between size of metastases, standard of reference, and detection rates. Radiology 2002; 224: 404–9. 24. Eberhardt SC, Choi PH, Bach AM, et al. Utility of sonography for small hepatic lesions found on computed tomography in patients with cancer. J Ultrasound Med 2003; 22: 335–43; quiz 345–46. 25. Mueller GC, Hussain HK, Carlos RC, Nghiem HV, Francis IR. Effectiveness of MR imaging in characterizing small hepatic lesions: routine versus expert interpretation. AJR Am J Roentgenol 2003; 180: 673–80. 26. Bipat S, van Leeuwen MS, Ijzermans JN, et al. Imaging and treatment of patients with colorectal liver metastases in the Netherlands: a survey. Neth J Med 2006; 64: 147–51. 27. Bipat S, van Leeuwen MS, Comans EF, et al. Colorectal liver metastases: CT, MR imaging, and PET for diagnosis: meta-analysis. Radiology 2005; 237: 123–31. 28. Kinkel K, Lu Y, Both M, Warren RS, Thoeni RF. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology 2002; 224: 748–56. 29. Rappeport ED, Loft A. Liver metastases from colorectal cancer: imaging with superparamagnetic iron oxide (SPIO)-enhanced MR imaging, computed tomography and positron emission tomography. Abdom Imaging 2007; 32: 624–34.

LIVER METASTASES: DETECTION AND IMAGING 30. Ward J, Guthrie JA, Wilson D, et al. Colorectal hepatic metastases: detection with SPIO-enhanced breath-hold MR imaging: comparison of optimized sequences. Radiology 2003; 228: 709–18. 31. Ward J, Robinson PJ, Guthrie JA, et al. Liver metastases in candidates for hepatic resection: comparison of helical CT and gadolinium- and SPIOenhanced MR imaging. Radiology 2005; 237: 170–80. 32. Coenegrachts K, De Geeter F, Ter Beek L, et al. Comparison of MRI (including SS SE-EPI and SPIO-enhanced MRI) and FDG-PET/CT for the detection of colorectal liver metastases. Eur Radiol 2009; 19: 370–9. 33. Kong G, Jackson C, Koh DM, et al. The use of 18F-FDG PET/CT in colorectal liver metastases: comparison with CT and liver MRI. Eur J Nucl Med Mol Imaging 2008; 35: 1323–9. 34. Rappeport ED, Loft A, Berthelsen AK, et al. Contrast-enhanced FDG-PET/CT vs. SPIO-enhanced MRI vs. FDG-PET vs. CT in patients

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with liver metastases from colorectal cancer: a prospective study with intraoperative confirmation. Acta Radiol 2007; 48: 369–78. Onishi H, Murakami T, Kim T, et al. Hepatic metastases: detection with multi-detector row CT, SPIO-enhanced MR imaging, and both techniques combined. Radiology 2006; 239: 131–8. Ward J. New MR techniques for the detection of liver metastases. Cancer Imaging 2006; 6: 33–42. Gonzalez HD, Figueras J. Practical questions in liver metastases of colorectal cancer: general principles of treatment. HPB 2007; 9: 251–8. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008; 371: 1007–16.

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13

Surgery for metastatic colorectal cancer René Adam and E. Hoti

introduction Colorectal cancer (CRC) is a common malignancy with a very high incidence in Western countries. Approximately 150,000 new cases of CRC occur each year in the United States, accounting for more than 55,000 cancer-related deaths (1). Over half the patients diagnosed with CRC will develop liver metastases (CRLM) during the course of their disease (2), of which 15% to 25% will have liver metastases at the time of the diagnosis (3,4). In the absence of surgical treatment, 5-year survival is exceptional (5) and even with the best chemo- and bio-therapies, to date, median survival of unresected disease does not exceed two years (6,7). On the other hand, long-term survival and potential cure after surgical resection for CRLM has been demonstrated by numerous studies. Surgery is therefore considered as the treatment of choice for patients with resectable CRLM, yielding a 5-year survival between 35% and 52% (8,9). As a result, hepatic resection has evolved from a rare procedure associated with considerable mortality to a routine surgery with an operative mortality risk of around 2% (10,11). At present, the low operative mortality along with survival improvement has led to an expansion of more extensive liver surgery and to a clear change in surgical indications to a point where virtually no tumor should be considered unresectable provided that resection can be complete. These advances combined with novel systemic and regional ablative therapies have modified the course of the disease, transforming it from a uniformly fatal to increasingly curable for a majority of patients.

natural history of colorectal liver metastases The natural history of untreated CRLM has been well studied. The median survival untreated following diagnosis is 6 to 12 months and 5-year survival is extremely rare. Most studies indicate that the prognosis is most closely related to tumor burden. Wood et al. showed that while the 1-year survival was only 5.7% for patients with widespread disease, 60% of the patients with solitary liver metastases were alive at 1 year with a mean survival of 25 months (12). Wagner et al. (5) reported the 3- and 5-year survival for untreated resectable disease to be 14% and 2%, compared to 4% and 0% for unresectable disease. Wilson and Adson (13) in their case-controlled study (60 patients treated with hepatic resection versus 60 comparable patients not subjected to surgery) demonstrated that hepatic resection was associated with 5-, 10- year survival of 25% and 19% compared to no 5-year survival in the non resectable group. Two other case-control studies demonstrated almost identical results (5,14). Scheele et al. (14) reported a 5-year survival rate 40% in patients who underwent tumor resections compared to 0% in 62 patients who had potentially resectable tumors but did not undergo resection.

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Although long-term survival and potential cure after surgical resection has not been demonstrated by randomized controlled trials, the evidence (uniformly poor results observed in untreated patients in contrast to extensive data documenting long-term survival after hepatectomy) supports a significant survival benefit from resection and has provided the rationale for increasing indications for liver surgery as the most effective treatment of CRLM.

patient evaluation Patient Selection for Surgery In deciding which patient will tolerate liver resection, a number of factors will need to be considered, including patient comorbidities. Age per se is not an independent factor for increased operative risk (15). This is a very important fact, considering that an increasing proportion of patients being evaluated for surgery for malignant disease, are elderly. On the other hand, scores like the American Society of Anaesthesiology (ASA) (16) or the preoperative Acute Physiology and Chronic Health Evaluation score do significantly influence the incidence of postoperative complications. Patients with an ASA score > 1 have been shown to have more than three times the mortality and twice the morbidity compared to those patients with an ASA of 1 (16). Therefore, a major goal of the preoperative evaluation is to identify patients who are at high operative risk so those who have a prohibitive risk can be excluded from surgery whereas those with manageable comorbidities can have these conditions addressed preoperatively in an attempt to reduce their operative risk. Definition of Tumor Resectability The earlier definition of the resectability (based on factors such as number of lesions, size, distribution, etc.) has been progressively challenged resulting on a concept shift, which now focuses on whether a macroscopic and microscopic complete (R0) resection of the liver lesion as well as complete resection of any extrahepatic diseases can be performed. At present, CRLM are defined as resectable if two aspects are fulfilled: (1) oncological anticipation that the disease can be completely resected without any residual hepatic or extrahepatic disease; (2) maintenance of an adequate volume of the future remnant liver with preserved vascular inflow, outflow, and biliary drainage. In general, at least 25% of the total liver is the minimum safe volume that can be left after liver resection in patients with normal liver parenchyma (17). Preoperative Imaging The complex decision to determine resectability requires detailed anatomic imaging to determine tumor location, exclude unresectable extrahepatic metastases, and assess the adequacy of the liver parenchyma after surgery. There are a

SURGERY FOR METASTATIC COLORECTAL CANCER myriad of diagnostic capabilities available to date, including three-dimensional CT scanning, CT angiography, magnetic resonance angiography (MRI), and CT volumetry. Nevertheless, despite the evolution of imaging modalities, difficulties still exist, especially when trying to differentiate between metastases and benign liver lesions or to detect small metastatic lesions. The current approach to address these pitfalls is to use a multimodality strategy (18). For example, although helical CT scanning provides information for the entire chest and abdomen during a single breath hold, up to 25% of the lesion can still be missed (19). MRI, on the other hand, is currently the most effective imaging modality in detecting and characterizing liver lesions and is often ordered prior to liver resection to characterize indeterminate lesions seen on a CT scan as it has a higher sensitivity to detect and characterize small lesions (20). Using liver-specific contrast agents, MRI has equivalent sensitivity to CT angiography (21) (Level of evidence: 1). Positron emission tomography (PET) is another useful modality for detecting liver metastases, especially when combined with CT scann. However, it is no more sensitive than MRI in detection, and it lacks the special resolution and the ability to characterize lesions. Truant et al. (22) correlated PET and CT findings in 53 patients with final pathologic diagnoses. They found that PET detected significantly more extrahepatic, intraperitoneal metastases than CT, with a sensitivity of 63% versus 25%. Another meta-analysis study, comparing helical CT, MRI, and fluorodeoxy-glucose PET (FDG-PET) in the detection of colorectal liver metastases, showed that the sensitivities on a per-patient basis were 64.7%, 78.8%, and 94.6%, respectively (23). In contrast, there are other reports that have questioned the superiority of the FDG-PET and consider MRI and helical CT more sensitive in detecting small liver metastases (24,25). PET and FDG-PET are, however, more advantageous in identifying extrahepatic and possible unresectable metastases, which could be a contraindication to liver resection (26) (Level of evidence 1). In addition, the ability of the later investigation to detect occult disease prevents unnecessary surgery in 21.5% of patients and changes the overall management in 25% (26). Hence, despite their pitfalls, the use of image overlays, combining FDG-PET and helical CT or MRI, can increase the accuracy of preoperative staging before hepatic resection (27) (Level of evidence: 1).

prognostic factors and clinical risk scores Prognostic Factors The importance of prognostic factors lies in two aspects: evaluation of the prognosis and selection of candidates for surgery. With the evolution, some accepted negative prognostic factors are no more considered, while new ones appear as substitutes. Factors that have been consistently considered as absolute or relative contraindications to liver resection are number/location of liver metastases, resection margin, presence of extrahepatic disease, and tumor involvement of portal lymph nodes. ●

The number of metastases (≥4) is no longer considered a contraindication (28) to liver resection (based on the fact that long-term survival can be obtained for patients with four or more metastases treated with

●

surgery). When resecting ≥4 liver metastases, the limiting factor is not the number of metastases but whether it is possible to remove all of them (29–32). Similarly, the distribution (bilobar metastatic disease) is no longer considered as a prohibitive prognostic factor. Ercolani et al. (33) reported that the total tumor volume of liver metastases had a stronger influence on survival than did number and location. Also, data from LiverMetSurvey concerning patients with bilobar metastatic disease have demonstrated a 1-, 5-, and 10-year survival of 90%, 44%, and 22%, respectively (34). In general, if a complete resection of the metastases can be achieved with safe margins (R0 resection) while maintaining a sufficient volume of the residual liver, the number and location should not be considered as a contraindication to resection. Whereas achieving a negative resection margin is well established, the extent of this margin clearance remains controversial. Increasingly, studies are demonstrating that there is no significant difference in survival or recurrence related to the width of margin achieved. Elias et al. (35) demonstrated that the overall survival of patients with resection margins less than 1 cm was 27.8%, comparable to those with resection margins of ≥1 cm. Fong et al. (36), in his series of 426 patients undergoing hepatectomy for CRLM, reported an identical 5-year survival in the group with a clear margin of <1 cm compared to the group with a margin of 1 cm or greater. Similarly, Figueras et al. (37) reported that subcentimeter nonpositive surgical margin did not influence hepatic recurrence rates after hepatectomy for CLM. Kokudo et al. (38), in his study, went further on by demonstrating that a margin of 2 mm is clinically the minimum acceptable requirement, which carries approximately a 6% risk of margin-related recurrence. A recently published study from our center showed that despite a higher recurrence rate in patients with R1 resection (complete macroscopic resection with 0 mm free margin) compared to patients with R0 resection, the two groups had a similar overall and disease-free survival (61% vs. 57% and 28% vs. 17%) and recurrences were intrahepatic rather than being localized at the surgical margin (39).

Therefore, the absence of “safe” margins of resection should not be considered as an absolute contraindication to surgery provided that all tumors can be macroscopically resected. However, at the present surgeons should continue to plan hepatic resection with a preserved “safety zone” and avoid routine use of “minimum margin” surgery. ●

The presence of extrahepatic disease reduces the hope of long-term survival and it has been considered as a contraindication to liver resection. Lately, however, resection in patients with extrahepatic disease with curative intent has been advocated by some groups. In a French series (40) of 84 patients who underwent complete resection of extrahepatic disease concurrently with hepatic resection, the

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overall 5-year survival was 28% compared to 34% in the 224 patients undergoing liver resection alone. In addition, the study demonstrated that the total number of metastases has a stronger negative prognostic value after complete resection than their location. Other reports have suggested that patients with extrahepatic metastases may survive more than 5 years after a successful liver resection (41) (Level of evidence: 3). Encouraging results have been reported even after combined resection of concomitant liver metastases and peritoneal carcinomatosis, which has been traditionally considered as an absolute contraindication to liver resection (42,43). However, these results are observed in patients with a limited number of liver metastases (≤3 lesions). Involvement of the portal lymph nodes may be present in as many as 14% of patients with CRLM (44). Some authors have suggested that radical excision of involved portal nodes can produce a survival benefit (45). In a prospective study conducted by Jaeck et al. (46), the survival rate in patients with involved portal lymph nodes was significantly lower than in the control group (3-year survival 19% vs. 62%). However, patients with involved lymph nodes limited to the hepatoduodenal ligament and retropancreatic portion demonstrated a much better prognosis than those with involved lymph nodes around the common hepatic artery and celiac axis (3-year survival 38% vs. 0%). In a more recent study (47) conducted in patients responding to preoperative chemotherapy, we reported that combining liver resection and pedicular lymphadenopathy was justified in patients with involved pedicular lymph nodes (3- and 5-year survival 38% and 18%, respectively). Conversely, in patients with involved celiac or retroperitoneal lymph nodes, this approach was not justified (5-year survival 0%). In this group of patients, even the response to chemotherapy did not seem to change their usual poor prognosis.

is the impossibility to remove all metastatic disease, while leaving sufficient functional hepatic parenchyma, regardless of the location, distribution, number and size of the metastases. Clinical Risk Scores Over 10 years ago, Nordlinger (48) introduced the first scoring system for patients with CRLM, based on a multicenter data from 1568 patients who accepted potentially curative resections. In this large series, they identified three groups of patients with low, intermediate and high risk for poor prognosis based on seven high risk factors (see Table 13.1A). Since then, at least six more scoring systems have been developed among which the proposal from Fong et al. (49) based on a single institution series of 1001 patients attracted the most attention. Seven parameters were found to be independent predictors of prognosis. These include presence of extrahepatic disease; positive resection margin; nodal metastases from primary cancer; short disease free interval; largest tumor greater than 5 cm; more than 1 liver metastases; CEA greater than 200 ng/ml (see Table 13.1A). The data for the first two parameters are not available preoperatively. However, using the last five criteria, a preoperative clinical risk score system was created with each positive criterion counting as 1 point. The total score out of 5 is highly predictive of a poor outcome (5-year survival 14%). Patients with a score of 0, 1, and 2 have a highly favorable outcome (5-year survival 60%, 44%, and 40%, respectively). Table 13.1B demonstrates the survival rates for each score grade.

Table 13.1A Prognostic Scoring Systems Fong’s score*

Whereas preoperative factors may be generally instructive, these should not be used to exclude patients from surgical consideration. Patients with one or multiple negative prognostic factors can still derive a significant survival advantage from hepatic resection of their CRLM. To conclude, it is important to mention that at the present time the only unchallenged contraindication to liver resection

Nordlinger’s score*

Node-positive primary tumor Stage of the primary tumor Disease-free interval Disease free interval (≥2 years vs. (<12 months between colon <2 years) resection and appearance of metastases) Size of largest lesion >5 cm Size of the largest metastasis (<5 cm vs. ≥5 cm) More than 1 tumor Number of liver nodules (1–3 vs. 4 or more) CEA >200 ng/mL Resection margin (>1cm vs. <1 cm) Age (<60 years vs. ≥ 60 years *One point is assigned for each risk factor

Table 13.1B Survival Rates for Each Score Grade Survival (%) Fong’s score Score 0 1 2 3 4 5

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Nordlinger’s score

1 year

3 years

5 years

Median (mo)

93 91 89 86 70 71

72 66 60 42 38 27

60 44 40 20 25 14

74 51 47 33 20 22

Risk groups

Risk factors

2 years

Low risk

0–2

79

Intermediate risk

3–4

60

High risk

5–7

43

SURGERY FOR METASTATIC COLORECTAL CANCER The applicability of this score has been evaluated by independent investigators from Norway (50), indicating that the score is applicable to other populations outside of a large tertiary U.S. center. Recent data from Asia has shown that CRS is useful for predicting outcome after ablative therapy of liver metastases. Also the CRS can help to select the extent and sophistication of preoperative assessment (51) acting as a risk stratification tool in identifying patients who are most and least likely to have their management altered by the results of the test. In practice, although the scores are simple, easy to use and highly predictive of long-term outcome their clinical relevance in terms of indications and contraindications to surgery is low since even with poor prognostic factors, hepatic resection can provide a chance of long-term survival. Patients with poor scores could, however, be selected more appropriately for neoadjuvant and adjuvant therapy or for refined preoperative imaging (routine PET CT) to exclude those with contraindications to surgery. In addition, scores have proved useful for comparing results from different centers for surgical and ablative therapies as well as stratification of patients for trials.

after the surgery (58). The preoperative cycles induced a complete response in 3.8% of patients and a partial response in 40.1% with a decrease in the diameter of the nodules of 29.5%. At 3 years, the disease-free survival was 28.1% in the group treated with surgery alone and 35.4% in the group that received perioperative chemotherapy (p = 0.058). The reduction of the size of the nodules could modify and facilitate the liver resection with a minor hepatectomy instead of a major liver resection. In patients presenting with five or more bilobar metastases, Tanaka et al. (59) showed that the 5-year survival rate was 38.9% in the group receiving neoadjuvant chemotherapy compared to 20.7% of the group treated with hepatectomy alone. In addition, multivariate analysis revealed neoadjuvant chemotherapy to be an independent predictive factor for survival. These results suggest a survival benefit of neoadjuvant chemotherapy in patients with resectable metastases. Whether the use of adjuvant chemotherapy would translate as the “gold standard” practice is still a matter of debate. Obviously, multinodular metastases are very likely to benefit from neoadjuvant chemotherapy owing to the potential of missing small metastases.

management of patients with resectable colorectal liver metastases

Approaches to Surgery Assessment of Functional Hepatic Reserve The functional hepatic reserve can be assessed by Child–Pugh score and hepatic biological blood tests, however, to date the only test which has proven to have a good predictive value is the indocyanine green (ICG) clearance test (60). In candidates for liver resection with retention of less than 20% of ICG at 15 minutes, up to 60% of the volume of the parenchyma can be resected. Although liver metastases rarely develop in cirrhotic liver, with the ever increasing use of more efficient chemotherapy regimens and targeted agents, a rising number of patients are expected to present with damaged livers as a result of chemotherapy given before resection. Specific pathologic changes of the liver parenchyma (vascular changes and/or chemotherapy associated steatohepatitis) influencing the liver regeneration and function as well as the ability of the patient to recover have been observed, following administration of preoperative chemotherapy. Hence in this new context, evaluation of the functional reserve of the liver is becoming critical.

Preoperative management Neoadjuvant Chemotherapy Conventional first-line chemotherapeutic regimens for resectable colorectal liver metastases (CRLM) contain fluorouracil (5-FU) in addition to leucovorin. Using a bolus administration regimen for patients treated with 5-FU and leucovorin response rates ranging from 20% to 30% and a median survival of 11.5 months has been reported (52,53). No significant difference in median survival has been observed when the 5-FU was delivered by continuous infusion, despite improvement of the response rate and reduction of the toxicity. Combination of 5-FU with newer drugs such as irinotecan (topoisomerase I inhibitor) resulted in a higher response rate (39%), longer progression free and overall survival time (14.8) compared to 5-FU and leucovorin alone (54). In addition, it has been shown that irinotecan in combination with continuous infusion of 5-FU/ leucovorin (FOLFIRI) produces better response rates and longer progression free and overall survival compared to 5-FU/leucovorin alone (55). More recently, the combination of infusional 5-FU/leucovorin with oxaliplatin (cisplatin derivative) has been found to be less toxic and more efficacious than the bolus irinotecan/5-FU/ leucovorin regimen (56,57). Whether the combination of infusional 5-FU/leucovorin with oxaliplatin (FOLFOX) or FOLFIRI is better as first-line chemotherapy remains controversial as they have comparable response rates. What may be more persuasive is that when these regimens are used sequentially when progression or toxicity occurs, regardless the order, survival is prolonged. For patients with up to four liver metastases, a prospective trial conducted by the European Organization for the Research and Treatment of Cancer compared surgery alone versus surgery with perioperative chemotherapy (FOLFOX 4 – oxaliplatin/5-FU/leucovorin), six cycles before and six cycles

Preoperative Biopsies Currently routine biopsy of liver lesions as part of the diagnostic process for patients who are thought to have potentially resectable lesions is not recommended. Although the seeding along the needle track has been believed to be very rare (incidence 0.003–0.07%) (61,62), it appears that it has been greatly underestimated. An incidence of needle track metastases ranging from 10% to 19% has recently been reported (63,64). Therefore, the potential benefits of liver biopsy in suspected patients are outweighted by the risk of these serious complications as well as the risk of deriving false reassurance from a false-negative result. Role of Laparoscopy and Laparoscopic Ultrasound (LUS) Evaluation In the recent years, many surgeons have advocated the use of laparoscopy for evaluation of CRLM preoperatively in order to

121

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS reduce the number of unnecessary surgical explorations. This procedure has been reported to exclude 25% to 48% of patients from laparotomy with a false-negative rate of less than 15% (65,66). Grobmyer et al. (67) suggested that patients should be considered for laparoscopic evaluation if they have two of the following characteristics: lymph node positive primary tumor, CEA levels greater than 200 ng/mL, >1 hepatic lesion, diseasefree interval <12 months, and hepatic metastatic lesion >5 cm. Patients with two or more of these factors have a 30% chance of having occult extrahepatic disease. However, with increasingly sensitive preoperative imaging and the increasing use of ablation and resection of extrahepatic sites, fewer patients are subjected to nontherapeutic laparoscopy (Level of evidence: 3). Role of Intraoperative Ultrasound (IOUS) IOUS is an essential adjunct to conventional imaging and is widely used to guide surgery and ablative techniques. In experienced hands, IOUS has been shown to contribute to acquisition of precise details regarding tumor size, location, extent of local invasion, and may alter or guide the surgery in up to 67% of cases (68). Also, when compared with preoperative radiological findings, IOUS has been found to be able to identify at least one additional malignant lesion in 10% to 12% of cases (68–70). As such, the use of IOUS should be considered as mandatory not only for intraoperative diagnostics but also for determining the type of surgical procedure (resection). Types of Liver Resection Generally liver resection can be divided into two groups: anatomic (resection of one or several segments) and nonanatomic “wedge” resections (resection of a portion of parenchyma surrounding the metastatic lesion). If more than three segments are resected, the hepatectomy is defined as major. Different types of anatomic liver resection are performed: right hepatectomy (segments V–VIII), left lateral lobectomy (segments II, III), and left hepatectomy (segments II–IV). Other types include central resection (segments IV, V, VIII) and bisegmentectomies (segments V, VI or segments IV, V). Resections exceeding the boundaries of a normal right or left are defined as extended hepatic resections and are divided in six different types. Right hepatectomies extended to segment IV, segment I, or both. Similarly, extended left hepatectomies may include segment I, segments V and VIII, or segments I, V, and VIII. Selecting the Resection Type The principles of hepatic resection (including the oncological goal which is to remove all metastatic sites with tumor free margins) are no different for colorectal metastases than for any other hepatic surgery. Rather than dogmatically adhering to an anatomical versus nonanatomic approach, the hepatobiliary surgeons now guide their decisions aiming ultimately at resecting all metastases with negative histologic margins. Therefore, the type of resection chosen for a particular patient is and should be individualized based on the size, number, and location of the metastases, their relation to main vascular pedicles, and the volume of future liver parenchyma. Whereas a small, superficial metastasis can be best treated with a nonanatomic resection, a large metastasis deeply located within the

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Figure 13.1 Picture showing multiple metastasectomies with maximal preservation of the liver parenchyma.

liver may be treated with an anatomical, segment-oriented resection. The extent of liver resection (major vs. minor or anatomic vs. nonanatomic resection) is not by itself a prognostic factor. Therefore, independently of being anatomic or nonanatomic, resection should spare as much as possible the nontumoral parenchyma, bearing in mind that new recurrences could eventually develop for which surgery could possibly be indicated again (see Fig. 13.1).

postoperative management Adjuvant Systemic Chemotherapy At present, despite several chemotherapy regimens, data would support the use of 5-FU and leucovorin as adjuvant chemotherapy after liver resection if patients have not previously failed this regimen. Portier et al., in a multicenter trial that randomized 173 patients after hepatectomy for CRLM to surgery alone or to surgery followed by chemotherapy (5-FU/ Leucovorin), demonstrated that patients who received adjuvant chemotherapy had a significantly better disease-free survival compared to that of patients treated with surgery alone (34% vs. 27%; p = 0.03) (71). A year later, Park et al., in a large two-center study comparing 518 patients treated with no chemotherapy (379 American, 139 European) to 274 patients treated (240 American, 34 European) with 5-FU-based adjuvant chemotherapy, demonstrated that systemic adjuvant chemotherapy prolongs survival after hepatic resection for colorectal metastases (72). Patients subjected to adjuvant chemotherapy had improved survival (p = 0.007) even after stratification by clinical risk score (p = 0.001). In every clinical risk score category, patients subjected to adjuvant chemotherapy had a higher chance of survival (range 1.3–2.0 times). Meanwhile, for those who have previously failed this regimen, an oxaliplatin- or irinotecan-based regimen should be considered. Despite that there has not been a clear demonstration of efficacy of any regimen, the higher response rate observed in patients treated with FOLFOX or FOLFIRI over the 5-FU/leucovorin has resulted in many groups to preferentially use these regimens in adjuvant settings.

SURGERY FOR METASTATIC COLORECTAL CANCER Table 13.2 Reported Survival Outcomes after Resection of Colorectal Liver Metastases with Curative Intent Operative mortality (%)

Patient survival (%)

Author

Year

No. of patients

Postoperative morbidity (%)

1 year

3 years

5 years

10 years

Nordlinger et al. Fong et al. Minagawa et al. Suzuki et al. Choti et al. Adam et al. Kato et al. Abdalla et al. Tanaka et al. Fernandez et al. Pawlik et al. Wei et al.

1995

1568

2

–

–

–

28

–

1999 2000

1001 235

2.8 0.8

– –

89 –

57 51

36 38

22 38

2001 2002 2003 2003 2004 2004 2005

26 226 615 585 190 193 100

– 1 1 0 – 1 –

– 18.6 18 – – 26 1

– 93 91 – – 69 86

62 57 61 – 73 46 66

32 40 41 33 58 43 58

– 26 – – – – –

2005 2006

557 423

1 2

– 19.6

97 93

74 –

58 47

– 28

Adjuvant Intra-arterial Chemotherapy A number of studies have reported the safety, efficacy, and feasibility of adjuvant regional hepatic chemotherapy. Kusunoki et al. conducted a nonrandomized trial of HAI versus systemic chemotherapy after radical liver surgery. He showed that the 5-year survival was significantly better for the HAI group compared to the 5-year survival of the systemic group (59% vs. 27%, p < 0.001) (73). Kemeny et al., in an intergroup study of 109 patients randomized to surgery alone or surgery and HAI-FUDR, demonstrated that the 4-year disease-free survival was significantly better in the HAI group (67% vs. 43%) (74). In another larger study, 156 patients were randomized to resection and systemic 5-FU or resection and combined systemic 5-FU and HAIFUDR. The patients who were treated with regional therapy had a significantly better 2-year survival (86% vs. 72%) and markedly improved liver disease control (75). In conclusion, convincing evidence currently exist to support the use of adjuvant chemotherapy, either systemic or regional, to prevent to some extent the risk of recurrence following liver resection. Outcomes of Resection for Colorectal Liver Metastases Morbidity and Mortality Overall, the perioperative mortality of liver resection for CRLM does not exceed 2%, ranging between 0% and 5% in most published series (10,11,76) and is strongly influenced by perioperative blood loss, liver function, and extent of liver resection. In experienced units, even major hepatic resections, constituting around 50% of cases have perioperative mortality not exceeding 2% (76). The principal causes of death are liver failure and sepsis. It has been observed that the mortality has changed little over the last two decades, however, this does not mean that there has not been progress made. With improved safety, surgeons are increasingly performing more extensive resections,

which explain the fact why the operative mortality and longterm survival have plateaued. In contrast, the perioperative morbidity rate is reported to be greater than 20% (28,77). The major morbidity associated with liver resection includes hemorrhage (1–3%), bile leak and/or fistula (4%), pleural effusion/pneumonia (5–10%/5–20%), and hepatic failure (3–8%). Of the nonliver-related complications, intra-abdominal sepsis is found to be the most frequent major complication, and pulmonary infection is the most frequent minor complication. Among liver-related complications, liver failure is the most serious and occurs in 3% to 8% of all major liver resections often being lethal. Similarly, intraoperative hemorrhage, although rare, is another major complication with a mortality as high as 17% (78). Long-term Survival Results Large series have reported a 5-year survival after hepatectomy for CRLM of 35% to 52% with a 33- to 46-month median survival (8,9,46,79) (see Table 13.2). However, recent data have shown an improved 5-year survival rate of 58% after complete resection of CRLM (35). Also, a number of series with sufficiently long-term follow-up indicate that the 10-year survival after resection can be expected in 20% to 30% of patients (12,46,80) (see Table 13.2 and Fig. 13.1). Similarly the International Registry of Hepatic Metastases of Colorectal Cancer (LiverMetSurvey), which to date includes more than 8000 patients, has demonstrated a 5- and 10-year survival of 41% and 26%, respectively. An important oncologic question is whether the recently improved systemic therapies can achieve the same results as resection for CRLM? This seems unlikely considering that longterm survival beyond 5-years is rare without liver resection (5) (Fig. 13.2). Indeed, the survival results can be questioned if considering that the patients who undergo resection are selected and may have better outcomes due to less aggressive disease.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS However, there has never been a controlled trial to compare resection versus nonresection or conservative treatment of potentially resectable CRLM and this is unlikely to happen in the near future unless more efficacious systemic therapy regimens are discovered.

(Level of evidence: 3). A study conducted by our group (81) demonstrated that an additional 16% of patients who had initially unresectable liver metastases became candidates for hepatic surgery after receiving systemic chemotherapy. The 3and 5-year survival rates were 54% and 40%, respectively, close to those observed after resection of initially resectable nodules. These results were confirmed by other studies including ours (82,83). In 2004, we reported that subsequent rescue surgery for unresectable CRLM downsized by chemotherapy resulted in a 5- and 10-year survival rate of 33% and 23%, respectively, with a disease-free survival of 17% at 10 years (82) (Figs. 13.3 and 13.4). In contrast, patients with tumor progression during preoperative chemotherapy have a significantly worse outcome, with a 5-year survival of 8% versus 37% and 30% for patients with objective tumor response or tumor stabilization (84). Patients with tumor progression still had a poor prognosis even when a potentially curative hepatic resection was performed. Another aspect worth mentioning about is the combination of chemotherapy with new molecular-targeted drugs (bevacizumab, cetuximab). These agents have had a significant impact on the survival of patients with advanced CRC disease when integrated with chemotherapy in trials. Using them in combination with oxaliplatin- or irinotecan-based regimens, these agents have produced tumor response rates greater than 50% to 60% (85). Disease control rates (complete response; partial response or stabilization of disease) exceeded 90% in the report of a phase II study of FOLFOX combined with cetuximab in nonoperable patients with epidermal growth factor receptor-expressing metastatic CRC (86). The objective response rate was 79% according to independent expert review (87). Data from the Paul Brousse series showed that the use of targeted agents in second line therapy also increases the number of patients eligible for resection. A total of 131 patients with epidermal growth factor receptor-positive CRLM who had progressed following two or more lines of FOLFOX or

Management of Nonresectable Metastatic Disease Despite the advances made so far in liver surgery, approximately 80% to 90% of patients with CRC liver metastases are not candidates for liver resection at the time of diagnosis. Apart from the fitness of the patients, the unresectability of liver lesions is due to the following reasons: technically unable to completely remove the lesions due to the number, size, and their distribution; or due to ill location of the metastatic lesion (infiltration of IVC, confluence of hepatic veins). As the most frequent cause responsible for technical unresectability is multinodular bilobar metastatic disease, different approaches used alone or in tailored combinations have been developed to improve the resectability rate by either reducing the tumor burden (in turn the extent of the hepatic resection) or by increasing the volume of remnant liver parenchyma. Instead, ill-located metastases are being increasingly treated by radical surgery such as liver resection combined with total vascular exclusion (TVE). Chemotherapy to Downstage Nonresectable Metastatic Disease Systemic Chemotherapy The improved efficacy of chemotherapy agents has not only allowed increased patient survival in the noncurative setting, but has allowed a subset of previously unresectable patients to undergo liver surgery after “tumor downstaging,” a concept first introduced by our team (81). By reconsidering the initial unresectability of patients who strongly respond to chemotherapy, several investigators have shown that survival can be achieved by liver resection in a significant proportion of patients who otherwise would have had a poor outcome

Patient survival after a 1st liver operation for colorectal metastases: 8179 patients Log rank p = <0.0001

100 90 80 70 60 50

41%

40

7737 resected patients 26%

30 20 10

442 nonresected patients

7%

0 0

1

2 Resected

3

4

5 Resected

6

7

8

9

10

Nonresected

Figure 13.2 Five- and ten-year survival following hepatectomy for colorectal liver metastases. Source: www.livermetsurvey.org.

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SURGERY FOR METASTATIC COLORECTAL CANCER FOLFIRI regimens were treated with cetuximab, resulting in conversion of 7% unresectable patients to resectable. Certainly, recent results form the randomized trials (FOLFIRI vs. FOLFIRI/Cetuximab – CRYSTAL trial; and FOLFOX vs. FOLFOX/Cetuximab – OPUS trial) (88,89) add further evidence to the benefit conferred by cetuximab on the response and resection rates in patients with advanced CRLM treated with standard first-line therapies. As a result of using combined chemotherapy regimens, the

Paul Brousse Hospital – 473 patients (Apr. 88–Jul. 99) 100

91%

Resectable: 335 Initially non-resectable: 138 No surgery

80 Survival (%)

66% p = 0.01

60

48%

40

30%

52% 33%

20

23% No surgery

0 0

1

2

3

4

5 6 Years

7

8

9

10

Figure 13.3 Curves demonstrating 5- and 10-year survival for initially resectable patients and for patients who underwent rescue surgery. Source : From Ref. (82).

(A)

(C)

resection rates have significantly increased compared to regimens of FOLFOX or FOLFIRI alone. Furthermore, in two other studies, cetuximab conferred an increase in response rate and resection rate over standard chemotherapy alone, with the benefits being the greatest for patients with KRAS wild-type tumors; CRYSTAL 59% versus 43% and OPUS 61% versus 37% (90,91). Intra-arterial Chemotherapy The interest in using intra-arterial chemotherapy in neoadjuvant setting has also progressively increased as it has been demonstrated to have a high response rate in both the firstand second-line settings. Clavien et al., using HAI-FUDR with or without leucovorin, induced resectability in 6 (26%) of 23 previously treated patients. The actuarial survival rates at 3 years were 84% for responders to neoadjuvant therapy compared with 40% for nonresponders (92). In a Memorial Sloan-Kettering study (93), 44 patients with extensive liver metastases received HAI-FUDR and dexamethasone plus oxaliplatin-based systemic chemotherapy as part of two Phase I trials. The study population in this trial had a high number of patients with more than 4 metastases, metastases greater than 5 cm, more than 25% liver involvement with tumor, a CEA level greater than 10 ng/dl and previously chemotherapy exposure. Despite these negative parameters, the objective response rate was 82%, resulting in complete gross resection of tumor in 9 (20%) of the 44 patients and a median survival for all patients of 26 months. Recently, preliminary data from

(B)

(D) Figure 13.4 Unresectable colorectal liver metastases downsized by chemotherapy.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS several clinical trials using the oxaliplatin or irinotecan via HAI have been promising. In summary, regardless the type of chemotherapy used in unresectable patients, a significant proportion (15–30%) is switched to resectability. This proportion of patients will probably expand with the increasing efficacy of chemotherapy and biological agents, justifying a close collaboration of oncologists and surgeons in the multidisciplinary treatment of these patients. Techniques to Improve Resectability In addition to preoperative chemotherapy, a number of interventional/surgical techniques are available to achieve a situation of resectability include tumor ablation techniques, portal vein embolization, two-stage liver resection, and extended liver surgery (total vascular exclusion and cooling). Tumor Ablation Techniques Locally ablative modalities such as radiofrequency ablation (RFA) and cryotherapy are both techniques used either independently or as adjunctive to surgery. These techniques are regarded as complementary to hepatectomy when complete resection cannot be achieved. The strategy of using them can result in an increased number of initially unresectable patients in whom the curative treatment can be accomplished. ●

RFA is currently the most commonly applied ablation method. RFA involves localized application of conductive thermal energy to destroy tumor cells. Specifically alternating electric current in the range of radiofrequency waves (460 kHz) is applied from a generator through a needle electrode placed directly into the tumor.

Limitations of RFA are related to the lesion size (suitable for lesions ≤3 cm) or when a maximum of three tumors are present as well as the anatomical location of the tumor. In the vicinity of large hepatic vessels, the heat sink effect significantly increases the risk of incomplete ablation. Also, the risk of thermal injury is increased when nodules are close to main biliary structures or to extrahepatic organs. RFA procedure, when performed in combination with surgery, increases the resectability and curability for patients in whom hepatic resection alone is not curative. Adding RFA to hepatic resection has been reported to be well tolerated with a perioperative morbidity and mortality comparable to those seen after resection alone (94). For metastases considered as unresectable, RFA combined with hepatic resection can achieve a median survival as high 37 months (95). ●

126

Cryotherapy involves freezing and thawing of liver tumors by means of a cryoprobe. Tumor necrosis occurs by direct cellular freezing and indirectly through vascular thrombosis and tissue anoxia. Results of such treatment combined with hepatic resection for patients not eligible for hepatic resection alone have shown a 5-year survival rate of 24%, better than those obtained by palliative chemotherapy (96,97). Local recurrence at the site of cryotherapy occurs in 5% to 44% of patients and it has been

found that the rate increases when treating multiple lesions (>8), large lesions (>3 cm), or tumors located to major blood vessels (blood warmth may impair the freezing process).

Portal Vein Embolization Portal vein embolization (PVE), which was first described by Makuuchi (98), is used to trigger a compensatory hypertrophy of the future remnant liver. In patients with an otherwise normal liver, current guidelines recommend preoperative PVE when the ratio of the remnant liver volume is <30%. Patients submitted to prolonged chemotherapy with a high risk of induced hepatic lesions should benefit from this method when this ratio is less than 40%. PVE can be performed percutaneously or using the ilocolic vein approach via a limited laparotomy. After PVE, hepatic volume is routinely evaluated using CT scanner volumetry, which gives information about the degree of the compensatory hypertrophy as well as the status of the metastatic disease. The optimal time interval necessary to induce maximum hypertrophy after PVE has not been established yet, although some Japanese teams use to perform resection as early as 2 weeks after the PVE. The majority of groups, however, would usually use a 4 to 6 weeks of interval between PVE and surgery. PVE is safe and does not add significant morbidity. In our series, a significant increase of liver volume following preoperative PVE was observed in 43% of patients, allowing 63% of originally unresectable liver metastases to be subsequently operated (99). The feasibility and the influence on the outcome in patients requiring an extended hepatectomy has been reported by other investigators also. Farges et al. (100) published the results of a prospective study of PVE performed in patients undergoing right hepatectomy for either primary liver cancer or metastatic liver disease. They demonstrated significantly fewer postoperative complications when PVE was used to increase the FLR volume in patients with chronic liver disease whose anticipated FLR was <40%. In contrast, patients with normal liver function who underwent a right hepatectomy did not benefit from PVE, as it was expected, since the remaining liver usually represents more than 30% of the functional liver volume. In summary, the PVE needs to be performed only in patients who are being considered for an extended right hepatic resection. PVE is rarely necessary prior to extended left hepatectomy because the right posterior sector typically constitutes about 30% of the total liver volume (101,102). On the other hand, in patients who have been treated with heavy neoadjuvant chemotherapies with a high risk of induced parenchymal liver lesions the PVE should be performed when the ratio of the remnant liver volume to the total estimated liver volume is less than 40%. The selective use of PVE may enable safe and potentially curative hepatic resection in a subset of patients with advanced colorectal metastases who would otherwise have been marginal candidates for resection because of an inadequate FLR or significant underlying liver disease.

SURGERY FOR METASTATIC COLORECTAL CANCER Two-stage Hepatectomy The concept of “two-stage liver resection” to deal with multinodular CRC metastatic disease that cannot be resected in a single procedure owing to a too small volume of the future remnant liver was first described by our group (103). During the first stage, the less invaded hemiliver (usually left) is completely cleared of metastases by resection, which could be associated with a simultaneous portal vein ligation/embolization of the most involved hemiliver (usually right) – or percutaneous portal vein embolization 1 week later. The aim of this step is to minimize the risk of liver failure by performing a second and complete resection once regeneration induced by the portal vein

embolization has taken place. Finally a second stage hepatectomy will be carried out to completely remove the liver harboring the remaining metastases (Fig. 13.5). The success of this method relies on the liver regeneration between the two interventions, allowing the second hepatectomy to be performed with a lower risk of complications, including liver failure. Our experience, as well as that of others, has demonstrated that this strategy can be carried safely and effectively in selected patients with initially nonresectable multiple bilobar CRLM (104–107) (Table 13.3). In our latest study, the 3- and 5-year survival rates were 60% and 42%. It should be mentioned that during the first stage performing nonanatomic

(A)

(B)

(C)

(D)

Figure 13.5 Radiological follow-up of a patient treated with combination of neoadjuvant chemotherapy and two-stage hepatectomy. 1A, hepatic metastases before chemotherapy treatment. 1B, planning of surgery after tumor downstaging (before the first hepatectomy). 1C, first hepatectomy. 1D, liver remnant following the second hepatectomy (segments IV and I).

Table 13.3 Reported Survival Outcomes after Two-Stage Hepatectomy for Colorectal Liver Metastases Patient survival (%) Author/Institution

No of patients

Success rate (%)

Mortality rate (%)

Morbidity rate (%)

Median (months)

3 years

5 years

Adam et al. (2000) Jaeck et al. (2004) Shimada et al. (2004) Togo et al. (2005) Adam et al. (2007)

16 33 12 11 45

81 76 100 100 69

15 0 0 0 6.5

45 56 NA 18 48

31 – – 18 35

35 54 – 45 47

– – – – 28

NA, not available. The mortality rates concern the second operation.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS wedge resection is advantageous as it preserves a maximal amount of liver parenchyma that will hypertrophy after PVE to become the functional liver remnant. Also, our policy is to perform portal ligation and embolization with absolute alcohol during the first liver resection to avoid a second procedure before the definitive hepatectomy. Currently, the guidelines for two-stage hepatectomies include the following: ●

●

●

No residual tumor should be left in the future remnant liver at the first intervention. If the resection alone cannot remove all lesions, one of the ablative methods (RFA, cryotherapy) has to be used for local tumor destruction in order to prevent tumor progression during the regeneration of the remnant liver. At the first intervention, portal dissection and mobilization of the lobe that is to be resected during the second intervention should be avoided.

In summary, based on the nature of the metastatic disease (number, size, and distribution), the treatment strategies, which can be applied with the aim of achieving a complete treatment of CRC liver metastases include the following: ●

●

Patients with unilobar multinodular metastases requiring resection of more than 60% to 70% of the functional liver parenchyma should undergo preoperative portal vein embolization. Following PVE, the induced hypertrophy of the future remnant liver allows for a curative resection while minimizing the risk of postoperative hepatic insufficiency (Fig. 13.6A). Patients with bilobar multinodular metastases for which a planned resection would leave no more than three nodules and none larger than 3 cm in the remnant liver are preferentially treated with a multimodal approach consisting of hepatic resection combined with RFA or cryotherapy of the unresectable nodules (Fig. 13.6B).

Right lobectomy Remnant liver <30%

Portal vein embolization (A)

●

Patients with bilobar multinodular metastases for which a planned resection would leave more than three nodules or any nodule larger than 3 cm in the remnant liver could be candidates for two-stage hepatectomy (Fig. 13.6C).

Extended Liver Surgery (Total Vascular Exclusion and Cooling) Involvement of the IVC and/or the confluence of hepatic veins by liver metastases is another situation that can be considered as a contraindication to liver resection. Currently, employing total vascular exclusion (TVE) of the liver and vascular reconstruction techniques can make surgery possible without taking further risks for this specific group of patients. As the experience has grown with TVE, an increasing number of patients are being operated with acceptable morbidity and mortality. Conventional TVE consists of clamping of the liver inflow (Pringle maneuver) as well as clamping of the supra and infrahepatic vena cava. Alternatively, in cases with no caval involvement by the tumor, selective control of the hepatic veins can be achieved allowing preservation of the caval flow. In cases whereby the caval clamping is associated with hemodynamic disturbances (hypotension), a venovenous bypass is necessary through which venous blood from femoral and portal vein is diverted to axillary or internal jugular vein. A drawback of these techniques, however, is that almost inevitably would induce warm ischemia for which the maximal duration of tolerance is assumed to be around 60 to 90 minutes. For cases which require interruption of hepatic blood flow for more than 60 minutes, hypothermic perfusion of the liver should be instituted to prevent the consequences of a long warm ischemic time. Such combination was evaluated in a study conducted in our center, which demonstrated that TVE combined with hypothermic perfusion was associated with a better ischemic tolerance and liver function as well as significantly lower complication rates compared to TVE ≥ 60 min. Combined liver and vena cava resection is another procedure facilitated by combined TVE and hypothermic perfusion. In

Right hepatectomy ≤3 Metastases ≤ 30 mm (remnant liver)

Right hepatectomy >3 Metastases > 3 mm (remnant liver)

Hepatectomy + RFA or cryo (B)

Two – stage hepatectomy (C)

Figure 13.6 Diagrammatic illustration of the surgical strategies used when treating patients with “nonresectable” multimodal metastatic disease. (A) Multifocal unilobar metastases. (B) Multifocal bilobar metastatases. (C) Multifocal bilobar metastases. RFA, radio frequency ablation; Cryo, cryotherapy.

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SURGERY FOR METASTATIC COLORECTAL CANCER a series from our center (108), out of 22 patients who underwent such a procedure, one patient died (4.5%) during the perioperative course, whereas 14 patients (64%) developed complications. Overall 5-year survival for the operated patients was 38.3%, comparing favorably with other reported results. Hence, combining TVE with vascular reconstruction techniques has resulted in an increased number of patients undergoing surgery for CRC liver metastases involving vena cava and/or the confluence of hepatic veins (which not so long ago were considered as a contraindication to surgery). This approach, however, seems justified only for surgical teams experienced in both hepatobiliary and vascular surgery. Repeat Liver Resection for Recurrent Metastatic Disease Despite hepatic resections with a curative intent in wellselected patients, up to 60% subsequently will develop recurrent liver metastases. Of these, approximately 20% to 30% present with isolated recurrent liver metastases, which are potentially amenable to further resection.

Regardless of the technical challenges due to adhesions and altered anatomy of the liver, the repeat hepatectomy is safe with a postoperative mortality and morbidity not different from those reported after a first resection (median survival approaches 2 years) ( Table 13.4). Five-year survival rates ranging from 16% to as high as 41% have been reported (109–111). Not surprisingly, the same prognostic factors that predict favorable outcome after primary resection apply to the repeated liver resection, including complete removal of metastatic lesions with satisfactory margins and no extrahepatic disease. Furthermore, a study conducted by our team demonstrated that a third hepatectomy is safe, with complication rates and survival benefit similar to first and second hepatectomies (112) (Fig. 13.7). The overall 5-year survival following the third hepatectomy was 32% and disease-free survival was 17%. Similarly, Pessaux et al. showed overall 5-year survival rates of 33%, 21%, and 36%, respectively, after a first, second, and third hepatectomy (113). Also, in repeat resections, the general rule applies that it does not matter how many lesions the patient has, provided that an R0 resection

Table 13.4 Reported Survival Outcomes after Repeat Liver Resection for Recurrent Colorectal Metastases Patient survival (%) Author/Institution

Year

Fernandez et al. Adam et al. Yamamoto Muratore et al. Suzuke et al. Petrowsky et al. Adam et al. Shaw et al.

1995 1997 1999 2001 2001 2002 2003 2006

No of patients 170 64 75 29 26 126 199 66

1 years

3 years

5 years

– 87 48 – – 86 89 –

45 60 31 35 62 51 46 –

32 41 – – 32 34 32 44

(%) 100

89%

First hepatectomy Second hepatectomy

88%

80

Third hepatectomy

82% 54% 60

40

46%

36%

42%

32% 28%

20

0 0

1

Patients at risk First hepatectomy Second hepatectomy Third hepatectomy

2 No 416 139 6

3 1 yr 267 80 49

2 yrs 169 37 31

4 3 yrs 120 27 15

4 yrs 83 19 10

5 Year 5 yrs 60 13 6

Figure 13.7 Survival after 1st, 2nd, and 3rd hepatectomy from the time of the index operation. Source: From Ref. (112).

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS can be achieved within limits of safety in terms of liver volume and function. Therefore, hepatic recurrences should be regarded as oncologically similar to metastatic disease at initial presentation and repeat hepatectomies should therefore be offered to patients based on the same criteria as those used for initial hepatectomy. Special Considerations Despite the advances made in the management of CRLM, there are still some areas of uncertainty or debatable. For instance, it is not clear what type of treatment is needed after a complete clinical response (total disappearance of metastases while on chemotherapy). Similarly, the management of synchronous presentation of primary colorectal cancer and hepatic metastases is still disputed (chemotherapy or upfront surgery) and so is the issue of which site should be operated first—bowel or liver? Treatment of the Lesions That Have Disappeared After Neoadjuvant Treatment With the advances in chemotherapy efficacy, the frequency of “missing metastases” has increased. Nevertheless, the treatment strategies concerning such lesions are not well defined, particularly so when trying to decide about the necessity to resect, the time, and type of resection. In a study conducted by our team (82), we initially reported that up to 7.2% of the patients with unresectable CRLM treated with systemic chemotherapy developed complete metastatic necrosis. Hence, we recommended that preferably all tumor-bearing sites must be resected during the surgery for CRLM. And, while later on, it was suggested that “missing metastases” are cured in 70% of the cases (114), increasingly, the evidence indicates the contrary—a persistence of histologically active tumor in as many as 83% of the lesions, which have a complete radiological response on imaging (115). Furthermore, a subsequent report from our unit (116) demonstrated that the actual number of patients with no more residual tumor cells (complete pathological response, CPR) in CRLM after neoadjuvant chemotherapy was even smaller (4.5%) than the one previously reported rate, which is in keeping with reports from other centers (117). Considering these results, we can say that a complete radiological response does not mean complete histological response, and despite the favorable long-term results associated with the CPR (5-year survival of 76%) the utility of surgery remains unchallenged. This view is supported by several reasons: (1) Confirmation of CPR depends primarily on the accuracy of the pathologic examination and on the exhaustivity of histologic sampling as undetected malignant cells could still be present in the resected lesion/s. By resecting all metastases, the possibility of leaving residual tumor cells behind is greatly reduced; (2) During the laparotomy it is often possible to diagnose additional metastatic disease, which otherwise would have remained undetected by the standard investigative tools; (3) The diagnosis of the CPR is a retrospective one as there is no imaging technique, which can reliably diagnose CPR preoperatively, hence, only surgical resection with

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concomitant pathological examination is able to make a definite diagnosis. In practice, due to very low overall incidence of CPR (4%), patients who have a complete radiological response should be operated on. Patients treated with neoadjuvant chemotherapy should be referred to surgeons before the initiation of the treatment, so as to avoid eventual difficult decisional situations brought about by the inability to localize previously seen radiological lesions. Synchronous Metastases ● Neoadjuvant chemotherapy or upfront surgery? The interest in using preoperative chemotherapy for resectable patients has been increasing. The rationale for this policy has been supported by the better prognosis obtained with neoadjuvant chemotherapy and surgery, compared to upfront surgery in patients with synchronous CRLM. Administering neoadjuvant chemotherapy not only can be associated with a lower rate of positive surgical margins compared to the rates observed in patients treated with upfront surgery (118), but also such approach provides time to identify a subgroup of patients who will develop progressive disease while on chemotherapy (119). Concerning the later group (patients with progressive disease while receiving neoadjuvant chemotherapy), a study conducted by our team showed that such patients had a 5-year survival of 8% versus that of 37% observed on patients with an objective tumor response to neoadjuvant chemotherapy (119). In addition, a study conducted by Rubbia-Brandt et al. (117), using a tumor regression grade scoring system, identified that resected patients with a poor histological response to chemotherapy had a lower disease-free survival at 3 years and a lower overall survival at 5 years. Certainly taking into consideration these results, the utility (benefit) of surgical intervention in this subgroup of patients has to be questioned. Therefore, the decision to give neoadjuvant chemotherapy should be individualized and based on specific clinical situations. ●

●

●

●

In patients who are chemonaïve with four or more synchronous CRLM and a nonocclusive primary, neodjuvant chemotherapy can be appropriate followed by repeated MRI and PET CT. Neoadjuvant chemotherapy can also be administered in patients with two to three bilobar CRLM. By contrast, if a patient belonging to this group has comorbidities or there is a concern about chemotherapy-related hepatotoxicity at a time when an extended resection is required, initial surgery would be indicated. Instead for patients with one to two unilobar metastatic diseases, upfront surgery should be considered first. Single or staged intervention? The optimal timing for resection of synchronous CRLM and the primary tumor remains a matter of controversy. Most surgeons

SURGERY FOR METASTATIC COLORECTAL CANCER prefer a staged approach with initial resection of the colorectal primary followed by hepatic resection 8 to 12 weeks after. Supporters of this strategy argue that the combined approach is associated with increased morbidity and mortality (Level of evidence: 3). Nordlinger et al. (120) reported an operative mortality of 7% for combined resection compared to 2% for staged resection. Bolton and Fuhram (121) in their series reported a mortality rate of 12% for combined resections, which increased to 24% for those who underwent major liver resection. Reddy et al. (122), in a multi-institutional retrospective study comparing postoperative outcomes after simultaneous and staged colorectal and hepatic resections, concluded that caution should be exercised before performing simultaneous colorectal and major hepatic resections. For major hepatectomy, simultaneous colorectal resection increased mortality (8.3% vs. 1.4%, p < 0.05) and severe morbidity (36.1% vs. 15.1%, p < 0.05) as compared to combined minor liver and colorectal resection. Similarly, a recent study demonstrated that patients who underwent a combined resection had a higher mortality rate (10%) compared with patients treated by staged resection (1.1%), concluding that combined interventions should be performed in wellselected patients, <70 years old and not with rectal surgery (123). On the other hand, several studies have also reported that simultaneous resection of the colon and liver tumors results in morbidity and mortality comparable to staged resection (124,125). However, in the majority of these studies, the patients submitted to simultaneous resection, underwent limited liver resection, and were much more selected compared to those who underwent staged surgery by the same teams. In practice, simultaneous resections should be decided on an individual basis. Combined resections may be more appropriate in patients who require a straightforward colon resection and a limited liver resection (≤2 segments). Patients who require major liver resections particularly the elderly should be dealt with by staged resection. Ultimately, the final decision should be made by the operating surgeon based on the experience and the risk evaluation. In summary, it is recommended that colorectal and major liver resections (>3 segments) should not be performed during the same time. One-stage procedure (combined liver and colorectal resection) should be reserved for experienced teams sharing both colorectal and liver surgery expertise. Surgery for Synchronous Liver Metastases: Liver or Colon Resection First? The standard approach for synchronous CRLM consists of resection of the primary tumor followed by chemotherapy for 3 to 6 months with the goal of resecting the liver metastases if they stabilize or respond. However, this strategy has pitfalls as many patients have progression of their metastatic disease while being treated for their primary, precluding eventual

surgery with curative intent. Based on this observation, Mentha et al. (126) designed a management strategy that involves highinduction chemotherapy first, followed by liver surgery, and completed by removal of the primary colorectal tumor. Such strategy aims at controlling the CRLM at the same time as the colorectal primary, optimize the chances of curative liver resection, and allowing the administration of well-programmed chemoradiotherapy before rectal surgery (when indicated). The authors have shown that the new “reverse” approach produced resectability and survival rates better than those expected from the published data on patients treated “conventionally” for disease of similar severity (3-year survival of 86%). The obvious candidate for this treatment would be a patient with nonobstructive primary colonic tumor. The rationale of this approach is that in the majority of patients the most life-threatening site is represented by the liver. In summary, the first treatment should focus on the global metastatic disease rather than locally treat the primary tumor: primary chemotherapy seems to be better than primary resection. For unresectable liver metastases with a primary colorectal cancer in place, chemotherapy as the first treatment line does not alter the survival expectancy. The first surgical procedure should logically deal with the tumor site, which is more difficult to resect and more likely to be life threatening for the patient.

conclusions The surgical treatment of colorectal hepatic metastases represents the only potentially curative therapeutic option able to achieve long-term survival and a hope for cure. Newer treatment strategies have shifted from the traditional concept of successive lines of medical therapy to that of a continuum of care in which medical and surgical treatment combinations are tailored to the clinical settings. To optimize the treatment of CRLM, management by a multidisciplinary team consisting of oncologists, surgeons, and radiologists is of the utmost importance. Advances in body and hepatic imaging has allowed for more accurate selection of patients with colorectal liver metastases. Imaging modalities are now able to detect minimal metastatic, which not very long ago would have been very difficult to do so. The significance of the prognostic factors has changed, although helpful in stratifying patients with regards to prognosis, should not be used to exclude otherwise resectable patients from surgery. Data on the use of neoadjuvant and adjuvant therapy to decrease recurrence risk and improve survival in patients with initially resectable metastases are encouraging, while further evidence and assessment is needed. With newer chemotherapy regimens, a significant proportion of unresectable patients are currently switched to resectable, opening the way to a survival benefit, which is not very different to that of initially resectable patients. The use of modern surgical techniques has resulted in a reduction of perioperative mortality and morbidity, whereas tumor ablation techniques, PVE, and radical liver

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS surgery in combination with neoadjuvant chemotherapy have positively influenced the expansion of candidates for surgical resection. In addition, with the use of more active systemic chemotherapy as adjuvant therapy, we hope that an improved survival rate in resected patients will be observed. In patients with tumor recurrence following hepatectomy for CRLM, repeat hepatectomies provide long-term survival benefit similar to that of first hepatectomy. In future, better patient selection through improved imaging techniques and identification of genomic markers as well as further advances in pharmacotherapy will likely further improve the outcome for patients with CRLM.

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14

Chemotherapy for metastatic colorectal cancer Derek G. Power and Nancy E. Kemeny

introduction Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide and in Western countries, and it is the second most frequent cause of cancer-related death (1). The United States has the highest annual incidence of invasive CRC, and in 2008 an estimated 148,810 cases of CRC were diagnosed and 49,960 people died from the disease (2). At diagnosis, 20% to 25% of all patients will have synchronous liver metastases and at least another 60% of patients who develop metastatic disease will have metachronous liver metastases (3,4). The liver is the only metastatic site in about onethird of patients and this can be explained by the portal venous drainage of the colon and rectum to liver (5). Overall liver metastases are seen in approximately 20% to 70% of patients with CRC and lung metastases are seen in 10% to 20%. (6) For many years, the approach to patients with metastatic CRC was minimalist with fluorouracil-based chemotherapy being the only palliative option and median survival rarely exceeding one year (7). Surgical developments over the last 10 years in resection of liver metastases have resulted in improved long-term survival. Several large surgical series have shown 5-year survival rates averaging 30% to 40%, and in some patients a chance of cure, with 20% survival at 10 years after hepatic resection (8–10). Developments in chemotherapy, both systemic and regional, have resulted in a radically changed landscape for patients with metastatic CRC. Those patients who present with initially unresectable liver metastases, 80% to 85% of cases, may now have the chance of hepatic resection after chemotherapy downstaging. Even if liver resection is not possible, median survival has increased with modern chemotherapies (3,11). This review will focus on developments in chemotherapy and biologic therapy for the treatment of metastatic CRC and highlight how a true multidisciplinary approach has resulted in improved survival for this common disease.

systemic chemotherapy for unresectable liver disease (first and second line) The fluorinated pyrimidine antimetabolites have been the cornerstone of systemic treatment for CRC for over 50 years. Fluorouracil (5-FU) was the only chemotherapeutic agent available for nearly 35 years. Response rates with bolus 5-FU were 10% to 20% with median survival around 10 to 12 months (12). Modifications of the 5-FU dosing schedule were studied and it was found that a protracted infusion of the drug increased response rates to 20% to 30% and median survival to 12 to 14 months (13,14). The addition of the biomodulator folinic acid [leucovorin (LV)] to 5-FU similarly increased response rates and median overall survival (14,15), and it has now become standard to combine 5-FU bolus plus 48-hour infusion with bolus LV (deGramont – LV5FU-2) in a bimonthly

schedule as randomized data has shown the superiority of this regimen compared with other 5-FU/LV schedules (16). Over the last few years, three new chemotherapeutic agents—irinotecan, oxaliplatin, and capecitabine (an oral version of 5-FU)—have been approved for the treatment of metastatic CRC. Irinotecan is a topoisomerase inhibitor and activity in the metastatic setting was established in randomized studies comparing irinotecan with best supportive care. In patients who progressed on fluorouracil therapy, one-year survival rates were increased from 14% to 36% with the use of single agent irinotecan (17). Combinations of irinotecan and 5-FU/ LV were then studied in the first-line setting. A randomized trial of irinotecan added to infusional 5-FU/LV compared to 5-FU/LV alone demonstrated an increased response rate (35% vs. 22%, respectively, p = 0.005) and a survival benefit of 3 months (17 vs. 14 months, respectively, p = 0.031). Grades 3 to 4 toxicities were more common in the irinotecan group, e.g. diarrhea (44% vs. 26%) and neutropenia (29% vs. 2%) (18). A phase III study of 683 patients compared weekly irinotecan and bolus 5-FU/LV (IFL) to 5-FU/LV alone. The IFL regimen increased response rate (39% vs. 21%, p < 0.001) and survival (14.8 vs. 12.6 months, respectively, p = 0.04) (19). The FOLFIRI regimen, that is, irinotecan combined with the deGramont 5-FU/LV combination, has been shown to be safe and efficacious in the first-line setting and is now accepted as the optimal way to combine irinotecan and FU/ LV. Response rates approaching 40% and median overall survival of 17 to 23 months have been reported (20,21). The randomized BICC-C trial (before the addition of bevacizumab) reported a median OS of 23.1 months for FOLFIRI vs. 17.9 months for mIFL and 18.9 months for CapIRI (capecitabine and irinotecan) with response rates of 47%, 42%, and 39%, respectively (21). Oxaliplatin is a platinum derivative and works by alkylating DNA. As a single agent, oxaliplatin is not superior to LV5FU-2 and has limited activity in advanced CRC (22,23). In the firstline setting, the FOLFOX regimen, that is, combination oxaliplatin and LV5FU-2 given as the deGramont schedule, was shown to be safe, efficacious, and superior to LV5FU-2 with response rates of 50% and median overall survival of 16 months (24). FOLFIRI compared with FOLFOX showed response rates of 56% and 54%, respectively, and no difference in median overall survival 20.6 versus 21.5 months (p = NS) (25). A phase III trial by Colucci and colleagues comparing FOLFIRI and FOLFOX4 also showed essentially equal efficacy in terms of response rate, time to progression, and overall survival (26). The intergroup trial showed that patients receiving FOLFOX had a median survival of 19.5 months compared to 17.4 months for irinotecan plus oxaliplatin (IROX) or 15 months for IFL (p = 0.001) (27,28). Efficacy of the FOLFOX

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 14.1 Metastatic CRC Second-Line Regimens Study

First-line

Rothenberg (22) Rothenberg (32)

IFL FOLFIRI

Tournigand (25)

FOLFIRI

Souglakos (33) Park (137)

Oxaliplatin Irinotecan

Second-line

RR (%)

mTTP

FOLFOX4 FOLFOX4 XELOX FOLFOX6 FOLFOX6 FOLFIRI FOLFOX

9.9 12.4 15.3 15 FOLFIRI 18 15

4.6 4.8 4.7 4.2 4 7.5 2

mOS 12.6 11.9 2.5 14 5

RR, response rate; mTTP, median time to progression (in months). mOS, median overall survival (in months).

regimen was also shown in the randomized TREE1 study, which compared mFOLFOX6 to bolus FU/LV/oxaliplatin and to capecitabine/oxaliplatin. Response rates were 41%, 20%, and 27%, respectively, and median OS was 19.2, 17.9, and 17.2 months, respectively (29). Overall, the FOLFOX and FOLFIRI regimens have improved response rate, time to progression, and overall survival compared to 5-FU/LV (30). Replacing 5FU/LV with capecitabine and combining with oxaliplatin (XELOX) has been shown to be noninterior to FOLFOX and thus is a third alternative for first-line treatment (31). The combination of capecitabine and irinotecan, however, is not well tolerated and is associated with high rates of severe vomiting and diarrhea. Therefore the bolus/infusional schedule of FU, LV5FU-2 is the preferred mode of administration in combination with irinotecan (21). In the second-line setting, after treatment failure with oxaliplatin or irinotecan-based regimens, results are less impressive (Table 14.1). Response rates of up to 18% and median overall survival of 6 to 14 months have been reported (32,33). It is noteworthy that in those patients who are 5-FU refractory, there is no difference in outcome if second-line therapy begins with either FOLFOX or irinotecan. In a phase III study of 491 5-FU-resistant patients with mCRC, median overall survival with second line FOLFOX was 13.8 versus 14.3 months for irinotecan alone (p = 0.38) (34).

regional chemotherapy in unresectable liver disease The rationale for hepatic arterial infusion (HAI) of chemotherapy is that the hepatic metastases receive their blood supply from the hepatic artery and the normal liver parenchyma is fed by the portal vein (35). The development of an implantable pump allowing continuous infusion of chemotherapy and long-term patency of the catheter and hepatic artery made the development of HAI therapy possible (Fig. 14.1). Floxuridine (FUDR) is the ideal drug for use via HAI as it has a high hepatic extraction, a short half life, and a steep dose–response curve. These properties give FUDR a 400-fold advantage when given via HAI (36,37). Ten randomized phase III trials have compared HAI FUDR with systemic FUDR or FU/LV in patients with unresectable CRC liver metastases. All of these trials showed superior response rates with HAI administration (42–62%) compared to systemic (9–21%) (38). Overall survival has been difficult to prove in many trials due to crossover design of small numbers in

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Catheter in artery

Codman 3000 Pump

Figure 14.1 Implantable HAI pump.

the study, initial extrahepatic disease in some studies, and the fact that HAI was not used in all cases though the patients are included in the survival data. The CALGB 9481 study compared HAI FUDR + Dexamethasone (Dex) with systemic intravenous (IV) FU/LV and did not have a crossover (39). Dexamethasone was added to the FUDR in the pump as it had previously been shown to decrease FUDR toxicity and increase efficacy (40). There was a significant increase in overall survival in the HAI FUDR Dex arm versus the systemic FU/LV arm (24.4 vs. 20 months, respectively, p = 0.0034). Quality of life assessment showed that the HAI arm experienced significantly better physical functioning compared with the systemic arm. The 51% 2-year survival compared favorably with systemic combinations of Oxaliplatin/5FU/LV (25), or irinotecan/5FU/LV (41). The use of HAI alone, however, in a new meta-analysis using the old flawed studies did not show an increased survival (38). With new systemic therapies, it is more appropriate to think of a combination of these regimens with HAI FUDR/Dex.

CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER As over one-third of all patients with metastatic CRC will have liver-only disease, the combination of HAI FUDR to treat the liver disease and modern systemic chemotherapy to control potential extrahepatic micrometastases may show superior results as has been seen already in small studies. In a phase I study of 46 patients previously treated with systemic chemotherapy, HAI FUDR/Dex in combination with systemic irinotecan produced response rates of 74% and a median overall survival of 20 months (42). In an updated series of 49 patients with unresectable liver metastases treated with HAI FUDR/ Dex plus systemic oxaliplatin/irinotecan, 53% of whom were previously treated with systemic chemotherapy, Kemeny and colleagues report a 92% response rate and a median overall survival of 50.8 months and 35 months for chemotherapy in naive and pretreated patients, respectively. The resection rate in this study was 47%, in a population that was definitely unresectable at baseline (43) [see section “Converting unresectable liver disease to resection…” for further discussion on resection of liver metastases and for comment on using HAI with other chemotherapy besides FUDR, e.g., oxaliplatin].

systemic chemobiologic therapy for unresectable liver disease Our increasing understanding of molecular pathways in carcinogenesis has led to the development of novel targeted therapy. Vascular endothelial growth factor (VEGF) plays a crucial role in physiologic and pathologic angiogenesis. Preclinical data with bevacizumab, a humanized monoclonal antibody against VEGF, showed inhibition of growth of human tumor xenografts as a result of inhibition of tumor angiogenesis (44) and improved delivery of chemotherapy to the tumor by altering tumor vasculature and decreasing elevated interstitial pressure in tumors (45). In a randomized phase III trial, the addition of bevacizumab (bev) to IFL versus IFL alone resulted in increased response rates, progression-free and overall survival (20.3 vs. 15.3 months, respectively, p < 0.001) (46). The results were not as promising in a randomized phase III study of 1400 patients where the addition of bevacizumab to both FOLFOX4 and XELOX in the first-line setting improved progression-free survival (9.4 vs. 8.0 months for the bev and placebo groups, respectively, p = 0.0023), but not response rates (47% vs. 45%) or median overall survival (21.3 and 19.9 months) in the bevacizumab and placebo groups, respectively (p = 0.077). (47) The TREE and BICC-C studies showed an increased response rate and overall survival when bevacizumab was added to oxaliplatin- and irinotecan-based regimens. However, these studies were sequential and not randomized (29,48). There has been no trials comparing FOLFOX/bevacizumab with FOLFIRI/bevacizumab. However, based on the fact that FOLFOX and FOLFIRI have virtually identical activity in the first-line setting, the addition of bevacizumab to either regimen is reasonable. Bevacizumab has also shown activity in the second-line setting. The European Cooperative Oncology Group (ECOG) showed that patients treated with FOLFOX4 and bevacizumab after progression on irinotecan and fluoropyrimidines had improved survival compared with FOLFOX4 alone (12.9 vs. 10.8 months, p = 0.0011). (49)

The epidermal growth factor receptor (ERBB, EGFR) family compromises four molecules: EGFR, HER2, HER3, and HER4. EGFR is overexpressed in up to 70% of human CRCs and has been associated with advanced stage disease (50). EGFR activation mediates multiple cell-signaling pathways including PI3K/ AKT/mTOR and Ras/Raf/MEK/ERK resulting in resistance to apoptosis, proliferation, angiogenesis, and metastases. Two monoclonal antibodies that target the EGFR have been approved for the treatment of metastatic CRC. Panitumumab (Pmab) is a fully humanized IgG2 molecule, while cetuximab (Cmab) is an IgG1 chimeric molecule. A significant increase in response rate (22.9% vs. 10.8%) and time to progression (4.1 vs. 1.5 months), but not overall survival (8.6 vs. 6.9 months; p = 0.48) has been reported with Cmab in combination with irinotecan versus Cmab alone in patients refractory to irinotecan or oxaliplatin-based chemotherapy (51,52). The MABEL study of 1147 patients confirmed the results of the earlier Cmab studies. In patients who had progressed on previous irinotecan-containing regimens, the progression-free survival rate at 12 weeks was 61% with the irinotecan and Cmab combination and median overall survival was 9.2 months (53). Another secondline study, EPIC (Erbitux Plus Irinotecan in Colorectal Cancer), compared Cmab plus irinotecan with irinotecan alone in patients who had progressed on previous oxaliplatin-containing regimens. A significant improvement in PFS and response rate was found with the combination (3.98 vs. 2.56 months, p < 0.001; 16% vs. 4%, p < 0.001, respectively) with no difference in overall survival (10.7 vs. 10 months, p = 0.812) (54). The National Cancer Institute of Canada (NCIC) evaluated the effect of third-line Cmab in metastatic CRC patients who had previously received FU, irinotecan, and/or oxaliplatin. Compared to best supportive care, Cmab improved median overall survival from 4.6 months to 6.1 months (p = 0.005). (55) Results from these studies demonstrate that Cmab has activity as monotherapy, but is more effective when combined with irinotecan. This is likely due to modulation of irinotecan resistance by Cmab, which has been shown in preclinical work (56). Pmab was approved on the basis of an open label randomized phase III trial comparing Pmab with best supportive care in patients who had progressed on previous chemotherapies. Pmab significantly increased PFS (13.8 vs. 8.5 weeks, p = 0.001), but not overall survival (57). In the first-line setting, both Cmab and Pmab have shown activity as well. The phase III CRYSTAL trial of 1,217 patients compared FOLFIRI plus Cmab to FOLFIRI alone. Progression-free survival, the primary end-point, was significantly greater with the combination (8.9 vs. 8 months, p = 0.0479, respectively). Also there was a difference in response rate (47% vs. 39%, p = 0.0038) and median overall survival (19.9 vs. 18.6 months, p = 0.30) [intention to treat data] (58). The OPUS study randomized first-line FOLFOX4 plus Cmab with FOLFOX4 alone and showed a 10% increased response rate with the combination (46% vs. 36%, p = 0.084) and no change in median PFS (7.2 vs. 7.2 months) [intention to treat data] (59). Preliminary data from the phase III CALGB 80203 trial showed a higher overall response rate for FOLFOX/FOLFIRI plus Cmab versus chemotherapy alone (49% vs. 33%, p = 0.014) (60). There is less experience with Pmab, likely due to

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS its more recent approval. In a phase II study in the first-line setting, an objective response rate of 47% and a median survival of 16.8 months was reported when Pmab was combined with irinotecan-based regimens (61). Studies combing Pmab with oxaliplatin in the first- and second-line settings are ongoing (62). There are no data direct comparisons between Cmab and Pmab and the decision to use one over the other may well come down to physician preference or decreased rate of hypersensitivity reactions seen with Pmab (63,64). Many of the above trials with EGFR antibodies accrued patients who had EGFR-expressing disease. It has since emerged that there is a lack of correlation between EGFR expression based on immunohistochemistry, gene expression, or gene copy number and response to Cmab and Pmab (65–67). More recently, the predictive value of KRAS mutations downstream of the EGFR has helped to define a subset of patients more likely to respond to EGFR monoclonal antibodies and possibly explains why the overall efficacy to EGFR inhibition has been so poor. Retrospective analyses of many of the trials discussed above show that response rates to EGFR antibodies in patients who are KRAS mutant is very low (68–73). As a result the drug licensing body in Europe (EMEA) and the American Society of Clinical Oncology (ASCO) has restricted the use of EGFR antibodies to KRAS wild-type patients in the treatment of metastatic CRC. The CRYSTAL trial retrospectively performed KRAS analysis and reported an increased response rate (59% vs. 43%, p = 0.0025) and an overall survival benefit in KRAS wild-type patients (24.9 vs. 21.0 months, p = 0.22) for the Cmab and chemotherapy versus chemotherapy alone groups, respectively (58,74,75). The OPUS study also reported the effect of EGFR inhibition in the KRAS wildtype (wt) population. The addition of Cmab to FOLFOX in wild type patients increased response rate (61% vs. 37%, p = 0.11) and median PFS from 7.2 to 7.7 months (p = 0.02) compared to FOLFOX alone. In the mutant KRAS population median PFS decreased from 8.6 months to 5.5 months with the addition of Cmab to FOLFOX (p = 0.02), suggesting a detrimental effect with the addition of Cmab to FOLFOX in KRAS mutant patients (59). The benefit of Cmab even in the select KRASwt population, however, is modest with an overall survival benefit of 3.9 months (in KRAS wild type tumors, HR = 0.84 [95% CI: 0.64–1.11]), as reported in the CRYSTAL trial and an improvement in PFS of 1.2 months, or approximately 37 days. Genetic and biochemical evidence indicates that BRAF is the principal downstream effector of KRAS and recent data has shown that the BRAF mutation V600E (present in approximately 10% of CRCs, thus leaving at least 40% of nonresponsive patients with no mutations in EGFR or BRAF associated with resistance to EGFR antibody therapy) (76). Intact expression of PTEN and expression levels of EGFR ligands (amphiregulin, epiregulin) may also play a role in identifying those who will benefit from anti-EGFR therapies (71,77). As data emerged on activity with biologic agents, combinations of biologics with chemotherapy was investigated. The phase II BOND-2 study showed that adding bevacizumab and Cmab to irinotecan in patients who were irinotecan refractory suggested a benefit for the two antibodies versus one (overall

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survival 14.5 vs. 11.4 months, respectively) (78). The randomized phase III PACCE study investigated the addition of Pmab to a combination of bevacizumab and chemotherapy (either oxaliplatin or irinotecan-based regimens) in the first-line setting demonstrated a decreased PFS for the Pmab/bevacizumab plus oxaliplatin versus bevacizumab/chemotherapy combination (10 vs. 11.4 months, respectively, p = 0.044). In the irinotecan-based chemotherapy group, median PFS was 10.1 months for those the received two antibodies versus 11.7 months for those receiving one (79). A trend toward worse OS was observed with Pmab/Bev plus systemic chemotherapy vs Bev plus chemotherapy in the KRAS wt group, 20.7 versus 24.5 months, respectively. Additional toxicity was also seen in the Pmab/ bevacizumab/chemotherapy group. The CAIRO-2 study compared the combination of Cmab with bevacizumab and XELOX in the first-line treatment and showed that the Cmab/ bevacizumab/XELOX resulted in a decreased median PFS compared with XELOX/bevacizumab (9.4 vs. 10.7 months, p = 0.018) (80). KRAS analysis was performed retrospectively and when compared to patients with KRAS mutations in the chemotherapy/bevacizumab group, cetuximab-treated patients with KRAS mutated tumors had significantly shorter PFS (8.1 vs. 12.5 months, p = 0.003) and OS (17.2 vs. 24.9 months, p = 0.03). In those patients with KRAS wild-type tumors, there was no difference in either PFS or OS with the addition of cetuximab. Thus the addition of VEGF/EGFR antibody combinations to chemotherapy suggests a lack of benefit. The SWOG/ CALGB 80405 trial looking at FOLFIRI or FOLFOX in combination with Cmab or bevacizumab or both may help to answer this question (60). To date, therefore, dual biologic therapy with bevacizumab and an anti-EGFR antibody should not be used in combination with chemotherapy in the first-line treatment of metastatic CRC outside of a clinical trial.

converting unresectable liver disease to resection There is increasing literature supporting the use of modern systemic chemotherapy, as described above, to decrease the size and extent of liver disease, thus rendering previously unresectable metastases resectable (81–83). While this is not neoadjuvant therapy in the strictest sense of the word, the end point for patients with initially unresectable liver metastases from CRC should hopefully be hepatic resection. It has been shown that in nonresectable liver metastases, resection rate correlates with response (84). In the largest study to date, Adam and colleagues report an experience over 11 years in 1439 patients, of which 1104 had unresectable liver disease at presentation. Chemotherapy consisted of FOLFOX (70%), FOLFIRI (7%), or both (4%) and treatment was for an average of 10 courses. Hepatic resection was possible in 138 patients (12.5%) and the 5- and 10-year survival rates were 33% and 23%, respectively, which compares favorably to 335 patients who were resectable from the start and had 5- and 10-year survival rates of 48% and 30%, respectively (p = 0.01) (85). This study highlights the fact that modern chemotherapy can convert unresectable liver metastases to resection with good 5-year survival rates. Several other studies have looked at combinations/comparisons of FOLFOX, FOLFIRI, and FOLFOXIRI

CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER Table 14.2 Neoadjuvant Systemic Chemotherapy for Unresectable Liver Metastases Resectability rate (%)

Study

Regimen

Giacchetti (83)

5FU/LV/ Oxaliplatin

38

5 years, 50%

Bismuth (82)

16

Med, 48m 5years, 54%

Pozzo (138)

5FU/LV/ Oxaliplatin FOLFIRI

Alberts (139) Masai (140)

FOLFOX4 FOLFOXIRI

33.3 26

32.5

OS

All alive 19m f/u Med, 26m 4 years, 37% Med, 37m

m, months; Med, median; OS, overall survival; f/u, follow-up.

(oxaliplatin, irinotecan and bolus/infusional 5FU/LV) in patients with initially unresectable (or not optimally resectable) disease and report increasing rates of R0 hepatic resections and overall survival (Table 14.2). In a phase III study of 244 patients, conducted by the Gruppo Onclogico Nord-Ovest (GONO) group, FOLFOXIRI was compared with FOLFIRI. The rate of R0 hepatic resections was 36% for the triplet compared with 12% for the doublet (p = 0.017) (86). This group recently updated the long-term outcome of 196 patients with initially unresectable mCRC treated with FOLFOXIRI in two phase II and one phase I trials. The overall R0 resection rate was 19% and at 5 years, 29% of patients are free of disease (87). Another phase III study of 283 patients showed that the addition of oxaliplatin to FOLFIRI increased the resection rate of lung and liver metastases from 4% to 10%. Of those who underwent surgery after FOLFOXIRI, 86% had an R0 resection (88). Subset analysis of the oxaliplatin stop-go OPTIMOX-1 study showed that FOLFOX4 was superior to FOLFOX7 in terms of overall survival after an R0/R1 resection (51 vs. 38 months, respectively) (89). HAI combined with systemic therapy in nonrandomized studies has demonstrated high response and resection rates. In a retrospective series examining HAI FUDR Dex in patients who had all received prior oxaliplatin/5FU/LV and some had prior irinotecan as well, the response rate for 39 patients was 44%, and median OS from the time of initiation of HAI was 20.1 months, while it was 32 months from the initiation of treatment of their metastatic disease. Eighteen percent of patients proceeded to surgical resection or ablation (90). HAI FUDR/Dex combined with oxaliplatin and irinotecan based regimens produced resectability rates of up to 47% in patients who were definitely unresectable at presentation and 53% had received prior systemic therapy. The median survival for all patients was 41 months. Survival for the chemotherapy naive group was 50 months while it was 38 months for those previously treated (43). The benefit of HAI therapy given in a “neoadjuvant” setting has also been highlighted by Auer and colleagues. Radiologic complete response of liver metastases in patients treated with HAI FUDR was more likely to represent a true CR when

compared to systemic neoadjuvant chemotherapy (68% vs. 29%), and the liver recurrence rate was 14% in the HAI group versus 42% in the preoperative systemic chemotherapy group (p < 0.001) (91,92). The benefit of HAI in the “neoadjuvant” setting has also been reported with the use of other drugs besides FUDR. In a phase II study, Ducreux and colleagues reported the efficacy and relative safety of HAI Oxaliplatin plus 5FU/LV in 26 patients with initially unresectable liver metastases. Median overall survival and median disease free survival was 27 months and 27 months, respectively (93). The intention to treat response rate was 64% and 5 patients proceeded to R0 liver resection. Recent work by Boige and colleagues used HAI Oxaliplatin combined with systemic FU/LV after systemic failure with either FOLFOX or FOLFIRI or both (94). Median PFS and overall survival were 7 months and 16 months, respectively, and 7 out of 39 patients previously deemed unresectable were able to undergo an R0 liver resection. The use of preoperative HAI Oxaliplatin has also been reported by Elias and colleagues to be significantly associated with a true pathologic complete response even when “missing” metastases are left in place at hepatectomy (95). These studies suggest that regional therapy may produce a higher rate of true cured lesions than systemic therapy as described in the Benoist study where persistent macroscopic or microscopic residual disease or early recurrence in situ was observed in 83% of liver metastases having a complete response on imaging (96). The toxicity profile of HAI Oxaliplatin is abdominal pain (grades 3–4, 14%) and neutropenia (grades 3–4, 43%) (97). Irinotecan is not more useful via HAI route as the systemic levels of the active metabolite SN-38 are similar to that seen when irinotecan is given systemically (97–99). Biologic agents are also being used in combination with systemic chemotherapy in patients with initially unresectable liver disease. Recent data has shown that bevacizumab in combination with chemotherapy may increase hepatic resection rates and does not appear to impact adversely on surgical outcome or liver regeneration. In a nonrandomized phase II trial by Gruenberger and colleagues, the addition of bevacizumab to XELOX in patients with potentially resectable liver metastases resulted in an objective response rate of 73%, a resection rate of 93%, and no intraoperative or wound healing complications (100,101). To evaluate whether preoperative bevacizumab affects patients going for liver resection, the Bevacizumab Expanded Access Trial (BEAT) was designed and has thus far concluded that metastatectomy is feasible after bevacizumab treatment (102). Combination of EGFR antibodies with systemic chemotherapy may also have the potential to increase resection rates of unresectable or possibly resectable liver metastases. Adam and colleagues reported that combining Cmab with oxaliplatin- or irinotecan-based chemotherapy in chemorefractory patients with unresectable liver metastases can result in salvage liver resection rates of 17%. With a median follow-up of 16 months, 92% of resected patients (23/25) were alive and 10 patients (40%) were disease-free. There was no significant increase in operative mortality or liver injury. Median overall (OS) and progression-free survival (PFS) from initiation of cetuximab therapy was 20 and 13 months, respectively

139

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS (for resected patients) (103). A phase II study of FOLFOX4 plus cetuximab in the treatment of patients with EGFRexpressing initially unresectable liver metastases resection rates were 23.8% (8/10 of whom had liver metastases only), PFS of 12.8 months and median OS of 30 months (104). The CRYSTAL trial compared FOLFIRI + Cmab versus FOLFIRI alone and reported liver a resection rate (R0) of 9.8% for the investigational arm versus 4.5% for the control arm (58). The CELIM study reported an R0 resection rate of 34% for initially unresectable liver metastases (n = 106) with “neoadjuvant” FOLFOX/Cmab (n = 20) or FOLFIRI/Cmab (n = 16) (105). The NSABP is currently planning a trial to study the rates of conversion from unresectable to resectable liver disease using an EGFR antibody. Ongoing phase II trials in our institution are investigating the rate of conversion to complete resection with initially unresectable liver metastases after treatment with HAI FUDR Dex in combination with best systemic chemotherapy plus bevacizumab. Such studies will help to further define the role of HAI in the neoadjuvant setting and should lead to adequately powered phase III trials comparing HAI plus systemic chemobiologic therapy with chemobiologic therapy alone in this setting. Presently initial systemic chemotherapy with or without biologic therapy is reasonable as first-line therapy. If the liver disease is not resectable at this stage, then consideration should be given to HAI in combination with further systemic chemotherapy. If HAI therapy is not available, then chemotherapy with EGFR inhibitors should be used.

scheduling strategies for treatment of metastatic disease Various strategies have been used in an attempt to improve the inconvenience and toxicity of chemotherapy. An especially troublesome toxicity is oxaliplatin-associated neurotoxicity. The OPTIMOX1 study compared FOLFOX4 [ARM A] given until progression with a “stop and go” regimen of FOLFOX7 (high-dose oxaliplatin and no bolus dose 5FU) X 6 cycles followed by maintenance 5FU X 12 cycles and then reintroduction of FOLFOX7 [ARM B] (89). There was an insignificant difference in prevalence of sensory neuropathy between the two arms, and median PFS (9 and 8.7 months for arms A and B, respectively) and overall survival (19.3 vs. 21.3) were equivalent. Maintenance 5FU (without oxaliplatin) is therefore a valid treatment option after initial exposure to FOLFOX. The OPTIMOX2 study evaluated a chemotherapy-free window compared to the “stop and go” schedule of OPTIMOX1. The maintenance chemotherapy group had significantly superior PFS and overall survival, the difference being especially seen in those patients with a poor prognosis (overall survival in the “stop and go” group versus chemotherapy free groups was 28.7 vs. 14.5 months, respectively), suggesting stopping all therapy was not effective (106). The OPTIMOX3 study will evaluate the use of targeted therapy with bevacizumab and erlotinib during the maintenance phase. Stopping irinotecan has been studied by Labianca and colleagues comparing FOLFIRI for 6 months with FOLFIRI X 2 months followed by 2 months of no treatment and then FOLFIRI for another 2 months. There was no significant difference in terms of efficacy between the two groups (107).

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The CAIRO (Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer) and FOCUS (Fluorouracil, Oxaliplatin, and CPT11 [irinotecan]-Use and Sequencing) trials investigated the strategy of sequential use of single agents and combination chemotherapy (108,109). The CAIRO study showed no significant difference in overall survival between sequential capecitabine followed by irinotecan followed by XELOX compared to XELIRI followed by XELOX (17.4 vs. 16.3 months, respectively, p = 0.3281). The FOCUS trial was a three-arm study comparing 5-FU/LV followed by irinotecan (control group) with either 5FU followed by 5-FU in combination with either irinotecan or oxaliplatin (group 1), or 5FU in combination with either irinotecan or oxaliplatin from the outset (group 2). Groups 1 and 2 achieved a longer overall survival time than the control group (13.9 months), but only the FOLFIRI regimen in group 2 achieved significance (16.7 months, p = 0.01). Both the CAIRO and FOCUS trials challenge the thinking that upfront combination regimens should be preferentially used. The staged approach upgraded to combination regimens has a role to play and can be considered. The literature on bevacizumab in first-or second-line setting has raised the question of continuing use of bevacizumab beyond progression of disease. Grothey and colleagues reported results from the large prospective observational study of 1445 patients who were enrolled in the BRiTE registry (Bevacizumab Regimens: Investigation of Treatment Effects and Safety). In multivariate analysis, bevacizumab beyond first progression (BBP) was strongly and independently associated with improved survival compared with no-BBP (31.8 vs. 19.9 months, p < 0.001) (110). Due to the substantial potential for selection bias in the BRiTE analysis such as patients with better performance scores or less disease receiving more Bev after progression, a phase III SWOG 0600 study bevacizumab continuation trial is planned to further investigate bevacizumab continuation beyond progression (Irinotecan Bevacizumab Continuation Trial iBET).

systemic therapy for resectable and unresectable liver disease Reasons for giving neoadjuvant chemotherapy to those patients with clearly resectable liver metastases at presentation are (1) decreasing tumor size may make the surgery easier and (2) control micrometastatic disease. If a patient progresses in an extrahepatic site while on chemotherapy before liver resection, one can eliminate these patients from the risks and morbidity associated with hepatic resection. The LiverMetSurvey group found that those patients with ≥5 liver metastases survived longer if they were given neoadjuvant chemotherapy, with 5-year survival rates of 22% and 12% (p = 0.07) for the preoperatively and nonpreoperatively treated groups, respectively (3,111). (3) Assessment of chemotherapy activity preoperatively may help design appropriate postoperative therapy. (4) Preliver resection patients may tolerate chemotherapy better and full-dose treatment may impact on the ability to treat microscopic disease. (5) Response to neoadjuvant chemotherapy may reflect prognosis after liver resection (112). Adam and colleagues studied 131 patients (74% with synchronous CRC and resectable liver metastases) who underwent liver resection

CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER for multiple lesions (>4) after systemic chemotherapy. In a multivariate analysis, tumor progression on chemotherapy and the number of chemotherapy regimens were independently associated with shorter survival duration (113). In contrast to this, a retrospective series at MSKCC of 111 patients with synchronous CRC and resectable liver metastases who received neoadjuvant chemotherapy were identified and it was shown that response to chemotherapy was not related to overall survival after hepatic resection. The median overall survival after liver resection was 62 months with a median follow-up of 63 months. Comparing response in three categories, that is, complete or partial response, stable disease, or progression of disease, median overall survival was similar (58 months – 65 months – 61 months, respectively, p = 0.98). Thus if response to neoadjuvant chemotherapy is used as a criterion for proceeding to liver resection, some patients may be denied potentially curative liver resection and therefore long-term survival (114). When patients with CRC and synchronous resectable liver metastases are undergoing treatment with neoadjuvant chemotherapy, it is important to scan frequently and consider short duration of preoperative chemotherapy. Potential disadvantages of neoadjuvant chemotherapy include: (1) liver toxicity from systemic chemotherapy, which includes steatosis, portal fibrosis, sinusoidal alterations, peliosis, and hemorrhagic centrilobular necrosis (3,115). These toxicities may increase the risk of liver resection, prevent liver resection, and impair the functioning of the remaining hepatic tissue (11). Oxaliplatin-based regimens are associated with a higher risk for vascular lesions and sinusoidal dilation, and irinotecan-based regimens are associated with higher risks for steatosis and steatohepatitis (116,117). There is relatively little data on the frequency or gravity of liver toxicity with the use of biologic agents prior to liver resection. D’Angelica and colleagues report no statistically significant increase in perioperative complications between perioperative bevacizumab versus matched-control groups (118). Klinger reports that when bevacizumab is added to oxaliplatin-based chemotherapy there was no impact on chemotherapy-induced hepatic steatosis and fibrosis, and bevacizumab decreased the severity of sinusoidal obstruction syndrome (101). (2) Secondary splenomegaly and resulting portal hypertension (3). (3) A complete radiologic response that may make it difficult for surgeons to resect appropriate areas (3). Benoist and colleagues report that persistent residual disease or early recurrence in situ were observed in 55 of 66 (83%) liver metastases having a complete response on imaging (119). The use of perioperative chemotherapy (FOLFOX) in patients with initially resectable liver metastases (≤4 metastases) was studied by the European Organization for the Research and Treatment of Cancer (EORTC 40983 study). In a 364-patient population, this trial showed that perioperative FOLFOX was compatible with major liver surgery, however, there was increased toxicities in treated group. The absolute increase in PFS in patients who underwent liver resection and perioperative FOLFOX was 9.2% (42.4% vs. 33.2%, p = 0.025). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs. 27/170 [16%]; p = 0.04) and included, biliary fistulae [output >100 ml/day

for >10 days] (8% vs. 4%), hepatic failure [bilirubin >100 mg/ day for >3 days] (6% vs. 3%), and wound infection (3% vs. 2%). The clinical impact of these complications was not significant (120). Survival data are not yet available and the longterm benefit of neoadjuvant chemotherapy in those patients with initially resectable liver metastases is still not clear, especially since both pre- and postchemotherapy was given. At present, the EORTC 40051 BOS (Biologics, Oxaliplatin and Surgery) trial is assessing perioperative chemotherapy with FOLFOX6 and cetuximab with or without bevacizumab in patients with resectable hepatic metastases form CRC. Our advice, in clearly resectable lesions, is resection should be preformed first or if systemic chemotherapy is given, it should be for a short a period as possible (no more than six treatments at two-weekly intervals) to avoid liver toxicity, and liver lesions should be resected as soon as possible if the patient is a suitable surgical candidate. Consideration should then be given to “adjuvant” systemic chemotherapy in combination with HAI (see below).

˝adjuvant˝ systemic therapy after liver resection The role of “adjuvant” systemic chemotherapy after liver resection is even more uncertain as the majority of data is with 5-FU/LV and it has been difficult to show a significant difference in disease-free and overall survival (121). Mitry and colleagues recently reported the combined results of two phase III trials comparing adjuvant FU/LV after liver resection with surgery alone. Median progression-free survival was 27.9 months in the chemotherapy (CT) arm as compared with 18.8 months in the surgery (S) arm (hazard ratio = 1.32; 95% CI: 1.00–1.76; p = .058). Median overall survival was 62.2 months in the CT arm compared with 47.3 months in the S arm (hazard ratio = 1.32; 95% CI: 0.95–1.82; p = .095). Adjuvant chemotherapy was independently associated with both progression-free survival and overall survival in multivariable analysis. Ychou and colleagues report no benefit with the addition of irinotecan to FU/LV after liver resection compared to FU/LV alone. The overall HR for DFS adjusted for the stratification factors was 0.89 (95% CI: 0.66–1.19, log-rank p = 0.47). Median DFS was 21.6 for FU/LV vs 24.7 months for FOLFIRI (122). No randomized data to support the use of “adjuvant” biologic therapy after liver resection have been published so far.

adjuvant regional therapy after liver resection Recurrence of liver disease after liver resection is a significant problem with nearly 70% of patients developing recurrence in either hepatic or extrahepatic sites. It is estimated that up to 60% of recurrences will be in the liver (123). As microscopic liver disease is the most likely cause of this recurrence, there has been much interest in “adjuvant” HAI. Level I evidence for the role of HAI FUDR Dex in this setting is provided by Kemeny and colleagues. In a population of 156 patients who underwent complete liver resection, a phase III randomized trial was performed that compared HAI FUDR Dex plus systemic FU/LV with systemic FU/LV. After a median follow-up time of 10 years, 41% of the HAI arm are alive at 10 years

141

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS compared to 27.2% of the FU/LV alone arm. The median hepatic PFS has not yet been reached in the HAI arm and is 32.5 months in the systemic-only group (124,125). Other groups have also shown a clear benefit to “adjuvant” HAI plus systemic chemotherapy after liver resection (Table 14.3) (126–130). HAI FUDR Dex has been combined with modern systemic chemotherapy after liver resection. Kemeny and colleagues reported a two-year survival of 89% with HAI FUDR Dex in combination with irinotecan at a median follow-up of 26 months (131). A phase I trial examining adjuvant HAI FUDR Dex combined with systemic FOLFOX has been reported. Disease-free survival at 2 and 5 years was 59% and 50%, respectively, and 2- and 5-year overall survival rates were 90% and 86%, respectively (132). Based on this evidence, we recommend placement of an HAI pump at the time of liver resection and a 4 to 6 months period of “adjuvant” HAI FUDR/ Dex in combination with best available chemotherapy. Biologic therapy may be added in as part of a clinical trial.

The benefits of adjuvant HAI after liver resection were recently demonstrated in a 1000-patient retrospective review by Ito and colleagues (133). In a multivariate analysis, one of the significant factors associated with survival after liver resection was HAI therapy. The median overall survival was 68 months with HAI therapy and 50 months for those that did not receive HAI (p = 0.0001). Another retrospective study of 250 patients who underwent liver resection compared adjuvant HAI FUDR + best available systemic chemotherapy (n = 125) with adjuvant systemic FOLFOX or FOLFIRI (n=125). Adjuvant HAI-FUDR plus modern systemic chemotherapy was associated with an improved liver recurrence-free survival (liver RFS) and disease-specific survival (DSS). For the adjuvant HAI-FUDR plus modern systemic group, the 5-year liver RFS, overall RFS, and DSS were 75%, 46%, and 72%, respectively, compared to 52%, 26%, and 55% for the modern sys alone group (p < 0.01) (134).

Table 14.3 True Randomized Trials of Adjuvant HAI FUDR Chemotherapy Study

HAI

Tono (141) MSKCC (124) ECOG (126) Lorenz (128) Lygidakis (129)

No. Patients IV

FU FUDR+IV FU/LV FUDR+IVFU/LV FU/LV Multidrug**

po FU FU/LV FU None None

2-year HPFS (%)

2-year OS(%)

MS (Mths)

HAI

IV

HAI

IV

HAI

IV

HAI

IV

9 74 45 113 20

10 82 30 113 20

78 90 67 67 –

30 60 43 63 –

78^ 86 62 62 –

50^ 72 53 65 –

63 72 64 44.8 20!

40 59 50 39.7 11!

PFS, hepatic progression-free survival; OS, overall survival; MS, median survival. ** Interleukin, carboplatin, mitomycin, epirubicin, LV, urographin. ! Mean survival. ^ 3-year overall survival.

Table 14.4 Dose Reductions for HAI FUDR AST *

Ref value (ref) Current value$

If held,restart when: Ref value (ref) * Current value$

If held,restart when: Ref value (ref)* Current value$

If held, restart when: *

≤50 U/L 0 to <3 X ref 3 to <4 X ref 4 to <5 X ref ≥5 X ref <4 X ref Alk Phos ≤90 U/L 0 to <1.5 X ref 1.5 to >2 X ref ≥2 X ref <1.5 X ref Total Bilirubin ≤1.2 mg/dl 0 to <1.5 X ref 1.5 to <2 X ref ≥2 X ref <1.5 X ref

FUDR dose >50 U/L 0 to <2 X ref 2 to <3 X ref 3 to <4 X ref ≥4 X ref <3 X ref >90 U/L 0 to <1.2 X ref 1.2 to 1.5 X ref ≥1.5 X ref <1.2 X ref >1.2 md/dl 0 to <1.2 X ref 1.2 to <1.5 X ref ≥1.5 X ref <1.2 X ref

Reference value is the value obtained on the day patient received the last FUDR dose. Current value is that obtained at pump emptying or on the day of planned treatment (whichever is higher).

$

142

100% 80% 50% HOLD 50% off last dose FUDR 100% 80% HOLD 25% off last dose FUDR 100% 50% HOLD 25% off last dose

CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER As preoperative chemotherapy for resectable or unresectable liver metastases becomes more effective, surgeons may be faced with the problem of “missing metastases,” that is, radiologic complete response of liver lesions. As mentioned above, radiologic response is more likely to be a true pathologic response when preoperative HAI is used. In the adjuvant setting, treatment with HAI is also more likely to result in a true pathologic complete response when “missing” liver metastases are left in place at hepatectomy. Elias and colleagues reported, in a series of 228 patients, that adjuvant HAI Oxaliplatin is significantly correlated with definitive eradication of “missing” metastases (p < 0.01) (95). Insertion of the implantable pump can be performed at the time of liver resection. The pump is placed percutaneously in the left lower quadrant and is fixed in position. The pump chamber is filled by accessing a subcutaneous septum and injecting. An expanding and contracting propellant liquid pushes on a bellows and infuses the drug, for example, FUDR, from the pump chamber via the hepatic artery catheter to the liver. It takes 2 weeks for the chamber to empty and it is then filled with glycerol or saline to keep the catheter patent. The cycle is then repeated after another 2 weeks, that is, 2 weeks of drug and 2 weeks of glycerol. Before insertion of the pump, hepatic arterial anatomy is viewed with a CT angiogram to make sure no aberrant vessels are present. Complication rates are low. Allen and colleagues reported a series of 544 patients with HAI pumps and complications were divided into early, for example, misperfusions and late, for example, dislodgement (135). Rates were less than 7% in both cases. A macroaggregated albumin nuclear scan is performed after all pump insertions to make sure the perfusion of the liver is adequate. Hepatotoxicity from HAI therapy depends on the drug being used and the duration of therapy. Raised transaminase is not uncommon (up to 70% of cases) and can be an early sign of liver damage. Raised bilirubin or alkaline phosphatise are a more serious sign of liver damage and may indicate sclerosing cholangitis (136). The addition of dexamethasone to FUDR has decreased the incidence of this side effect. An algorithm for does reductions based on liver blood tests has been drawn up and FUDR doses can be adjusted accordingly (Table 14.4).

conclusions Liver resection should now be considered in all patients with liverconfined metastatic disease from CRC. Modern systemic chemotherapy with irinotecan- and oxaliplatin-based regimens can increase resection rates is a significant number of patients. The addition of biologic agents in patients with the appropriate molecular signature may increase repose rates and resectability rates even further. Long-term cures are possible in patients who undergo liver resection and series with 10-year survivors have been reported (10). In those patients in whom resection is not possible, overall survival has increased from less than 1 year with fluorouracil regimens to over 2 years with chemobiologic regimens (74). Hepatic arterial infusion with FUDR has consistently demonstrated increased response rates and hepatic progression-free survival compared to systemic chemotherapy. The combination of HAI FUDR with modern chemotherapy and perhaps chemobiologic therapy can result in increased resection rates of initially unresectable liver disease and also has a role to play after liver resection.

Treatment paradigms for metastatic CRC have changed dramatically over the last decade and involvement of a multidisciplinary team of surgeons, oncologists, radiologists, and pathologists can result in long-term survival becoming a reality.

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CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER 137. Park SH, Sung JY, Han SH, et al: Oxaliplatin, folinic acid and 5-fluorouracil (FOLFOX-4) combination chemotherapy as secondline treatment in advanced colorectal cancer patients with irinotecan failure: a Korean single-center experience. Jpn J Clin Oncol 2005; 35: 531–5. 138. Pozzo C, Basso M, Cassano A, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 2004; 15: 933–9. 139. Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases

from colorectal cancer: A North Central Cancer Treatment Group phase II study. J Clin Oncol 2005; 23: 9243–9. 140. Masi G, Marcucci L, Loupakis F, et al. First-line 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the feasibility and the activity of second line treatments in metastatic colorectal cancer. Ann Oncol 2006; 17: 1249–54. 141. Tono T, Hasuike Y, Ohzato H, et al. Limited but definite efficacy of prophylactic hepatic arterial infusion chemotherapy after curative resection of colorectal liver metastases: A randomized study. Cancer 2000; 88: 1549–56.

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15

Multimodal approaches to the management of colorectal liver metastases Gerardo Sarno and Graeme J. Poston

This chapter focuses on the recent development of multimodal strategies intended to increase the pool of patients with colorectal liver metastases (CRLMs) for whom curative treatment may be possible. These strategies include improved preoperative staging, new standards for surgical resection, novel surgical strategies, the application of modern systemic chemotherapy in the neoadjuvant setting, an emerging role for ablative therapies, greater emphasis on the collaborative, multidisciplinary management of this disease, and most recently, the question of whether to resect the liver disease before the primary bowel tumor. It is now clear that an aggressive multidisciplinary approach to the management of this problem can result in one-third of these patients now being considered for treatment that even if not achieving complete cure, offers significant long-term survival. Colorectal cancer is globally a growing cause of public health concern (1,2). The prevalence is increasing at 5% per year among the burgeoning middle classes in both China and India, and in western society is expected to increase in incidence by over 30% over the next 20 years because of evergrowing elderly (>70 years of age) population (1,2).The liver is frequently the only site in 30% to 40% of patients with advanced disease (3). By the time of initial diagnosis of colorectal cancer, nearly a quarter of patients will have clinically detectable CRLMs, despite increasing patient and clinician awareness of the disease (1,4,5). Historically, these patients have a poorer prognosis when compared to those who subsequently develop metachronous diseases (1,5). Of those who undergo apparently successful resection of the primary tumor, nearly half will develop liver metastases, usually within the first 3 years after colectomy (1,4,5). Until recently, surgery was the only treatment that offered the chance of cure for CRLM, and until recently, only far less than 20% of these patients were considered suitable for attempted curative resection; historically, the remaining patients being offered palliative and symptomatic treatment (6). Recent data suggest that ablation therapy (radiofrequency or RFA, microwave) might achieve long-term survival, but with poorer overall results compared to surgical resection (7). The other major advance in recent years has been the availability of medical oncology strategies using chemotherapeutic and biologic agents not only to significantly prolong survival in incurable disease, but also to bring initially inoperable patients to surgical resection with curative intent (8). Recently, it has become a legal requirement in a number of European countries (UK, France, Belgium, and Spain) for all cancer patients to be discussed within the setting of a multidisciplinary team (MDT) before any treatment intervention commences. In order for such an MDT to be effective in the management of colorectal cancer liver metastases, the team must undertake a number of specific steps in determining the extent of spread of the cancer, and the best modalities for this

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purpose, and then the role(s) of each of the possible treatment modalities (surgery, ablation, systemic chemotherapy, regional chemotherapy/radiotherapy, and biological therapies) as well as the strategy of which treatment to use in which sequence.

building an effective multidisciplinary team An effective MDT needs to be built around a designated core membership. Once this core group is established, then other professionals from many disciplines can attend and become involved. For the management of patients with CRLM, the key disciplines of the core group include hepatobiliary surgery, medical oncology, diagnostic radiology, interventional radiology, and palliative care. It is essential that there is a designated team member from each of these disciplines. Other disciplines that we have found helpful in support of our CRLM MDT include gastroenterology/hepatology, our specialist nursing colleagues, and histopathology. However, having a dedicated clerical coordinator who can pull together all the relevant correspondence, documentation and investigations for each and every patient to be discussed is absolutely essential for the successful operation of such an MDT. With regard to diagnostic radiology, it is our experience that the radiologist presenting the images to the MDT will require at least 3 hours preparation time for every 20 patients to be discussed. This requirement for radiology time has major cost implications for the running of a busy radiology department.

preoperative staging: the key to selection of candidates for curative treatment The uses of individual imaging techniques for diagnosing and staging CRLM have differing strengths and weaknesses. However, with all modalities we are rapidly improving our ability to detect low-volume metastatic disease much earlier in the disease process. It must be remembered that all metastases (those found at the time of initial presentation, and those subsequently found metachronously after apparently “curative” resection of the primary tumor) are synchronous to the time of diagnosis of primary colorectal cancer. There is now emerging consensus on the optimal choice of technique, and the sequence with which they should be employed (9–12).

computeed tomography Recent advances in computed tomography (CT) technology (helical CT and multidetector row helical CT) have improved performance in speed of acquisition, resolution, and ability to image the liver during various phases of contrast enhancement with greater precision (9,12). Using intravenous iodinated contrast media these techniques characterize liver lesions based on their enhancement patterns during the various phases of contrast circulation in the liver (12). CT has limitations, including

MULTIMODAL APPROACHES TO THE MANAGEMENT OF COLORECTAL LIVER METASTASES the need for a high radiation dose and low sensitivity in detecting and characterizing lesions smaller than 1 cm.

magnetic resonance imaging Magnetic resonance imaging (MRI) is highly effective in detecting and characterizing smaller (<1 cm) liver lesions because of the high lesion to liver contrast, most frequently using gadolinium (9,12). The use of liver-specific contrast media, such as super paramagnetic iron oxide (SPIO), further improves the contrast between normal liver tissue and metastases (12,13). However, MRI is limited by low sensitivity for detecting extrahepatic disease, especially in the peritoneum and chest.

positron emission tomography Positron emission tomography (PET-CT) has emerged as an important diagnostic tool in detecting and staging metastatic colorectal cancer. Although the modality appears to be highly sensitive, specificity is lower because any focal area of hypermetabolism (including inflammation and abscesses) can generate false-positive results. Other disadvantages include higher cost, poorer lesion localization and limited sensitivity for lesions smaller than 1 cm. (13,14).

surgery There are many substantial prospective and retrospective series of surgical resection of CRLM consistently show 5-year survival rates following liver resection of 30% to 50%, depending on selection criteria (15). The problem encountered when attempting to interpret these reports is that although there are more than 600 in the literature, barely 30 series are prospective studies, reporting more than 100 patients from reliable high-volume centers, and with median follow-up of >24 months (15). However, from these reports nearly all patients who survive for more than 5 years can usually be considered cured of the disease.

defining resectability of liver only disease Historically, resectability of CRLM was relatively straightforward. The definition of resectability was based of old studies that identified certain adverse clinicopathological factors, and so liver resection was only attempted in patients who had one to three unilobar metastases, preferably presenting at least 12 months after resection of the primary tumor, whose disease was resectable with at least a 1 cm margin of healthy liver tissue and who had no hilar lymphadenopathy or extrahepatic disease (16). Such patients accounted for <10% of the total population with liver only metastatic disease (16). We now know that patients outside these traditionally accepted criteria can benefit from long-term survival following hepatectomy (17,18). Resectability is now based on whether a macroscopically and microscopically complete (R0) resection of the liver can be achieved. Therefore resectability is now defined by what healthy liver volume will remain. Our definition of liver resectability is now (19): 1. Disease can be completely resected. 2. At least two adjacent liver segments can be spared with adequate vascular inflow and outflow and biliary drainage.

3. The volume of the liver remaining after resection, i.e., the “future remnant liver” (FRL) will be adequate (13). Clearly, the FRL limit for safe resection varies from patient to patient, and from institution to institution but in those with an otherwise normal liver, the safe FRL volume is 20% to 30% (19).

resection margins Historically, resection was only considered if the hepatobiliary surgeon believed that the metastasis could be resected with a margin of healthy surrounding liver that was >1 cm. The new standards challenge the “1 cm rule.” More recent studies show that size of the resection margin has no effect on survival, as long as the margin is microscopically clear of disease (20,21).

new strategies to improve resectability Other strategies are being increasingly employed in patients with unresectable CRLM to improve resectability. Portal vein embolization induces atrophy of the liver to be resected with hypertrophy of the liver that is to remain (i.e., increases the FRL). Similarly, two-stage hepatectomies, employing delayed rehepatectomy after hypertrophy of the residual liver, may be used for large bilateral lesions in which a single-stage resection of all involved segments would result in acute liver failure (22,23). Disease outside the liver that may be resected with curative intent includes direct diaphragmatic invasion, adrenal metastases and lung metastases when few in number and readily resectable (1). Recent reports demonstrate that up to 35% of patients are still alive 5 years after resection of pulmonary colorectal metastases (24).

combining chemotherapy and surgery Modern chemotherapeutic regimens utilizing oxaliplatin with 5-FU and folinic acid (FOLFOX), also irinotecan (FOLFIRI) are associated with high response rates of up to 50% and median survival in incurable disease that exceeds 2 years (25,26). Most significantly, such high response rates can now bring 10% to 30% of patients with disease initially considered unresectable to subsequent secondary liver resection (22,25,26). Within a consecutive series of 1104 patients with CRLM initially considered unresectable and treated with chemotherapy, 138 (12.5%) had a sufficiently good response to chemotherapy to enable potentially curative liver surgery to be performed in 93% of these cases (22). Survival was 33% and 23% at 5 and 10 years, respectively, with a median survival of 39 months, although this was significantly lower than that for patients resected primarily within the same period at the same institution (48% and 30% at 5 and 10 years, respectively) (22). Evaluation of these and other data suggest that the ability to achieve secondary liver resection of initially inoperable CRLM is directly proportional to the degree of response to the chemotherapy regimen (26). Phase II and III studies evaluating novel biological agents, such as the monoclonal antibodies directed against vascular endothelial growth factor (VEGF) (bevacizumab) and the epidermal growth factor receptor (cetuximab and panetumumab), suggest even greater response rates (and possibly higher

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 100

HR = 0.73; CI:0.55–0.97, p = 0.025

90 80 70

+9.2% At 3 years

Periop CT

60 50

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1

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Number of patients at risk: 85 59 39

24

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2

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Figure 15.1 Three-year progression-free survival comparing surgery alone to surgery with perioperative chemotherapy in the EORTC 40983 (EPOC) trial (30).

secondary CRLM resection rates) when compared to conventional chemotherapy alone. Therefore, even more patients with initially unresectable CRLM may respond to treatment with combinations of systemic treatments in the future (27–29). Recent data from the German Phase II CELIM study have suggested that as many as 40% of patients with unresectable kras wild type colorectal cancer metastases confined to the liver may now be brought to liver resection with curative intent using combinations of cetuximab with either oxaliplatin-based or irinotecan-based chemotherapy regimens (30). Recent data have suggested that the addition of perioperative (both neoadjuvant with adjuvant) chemotherapy using FOLFOX to surgical resection confers improved disease-free survival when compared to surgery alone (31). These data need to be interpreted with caution since the study did not demonstrate its primary endpoint (3-year disease-free survival on intention to treat at the point of initial randomization), and only achieved significance on the analysis of operated patients, when ineligible patients were excluded (Fig. 15.1).

the role of tumor ablation Much interest in tumor ablation (mostly using RFA) derives from its low morbidity and mortality (32). A recent metaanalysis of 95 published series reported complication rates of <9% (33), the commonest complications being intra-abdominal bleeding, sepsis, and biliary injury. Mortality rates range from 0% to 0.5%. However, the most reported disadvantage of RFA are the higher rates of local recurrence, ranging from 1.8% to 12% using the surgical approach, to as high as 40% with radiologic guided percutaneous placement of the probe. Undoubtedly, some of this higher local failure rate relates to the type of lesions being treated by percutaneous RFA. Ablative therapies are often used for the treatment of metastases that

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are often too close to major vascular structures to be considered resectable with a clear margin. Just as a surgical margin would be likely to be compromised, high blood flow immediately adjacent to the tumor will conduct away heat, leading to incomplete ablation and tumor recurrence (2). The efficacy of RFA in unresectable CRLM has been established by several large cohort studies with median survivals of 28.9 to 36 months being achieved (32,33). Presently the dearth of prospective randomized controlled trials comparing RFA with chemotherapy over chemotherapy alone in unresectable CRLM is being addressed by the EORTC CLOCC trial (EORTC 40004). Early progression-free survival data from this study have suggested that the addition of RFA to FOLFOX-based chemotherapy confers a statistically significant improved progression-free survival of 17 months compared to 10 months for FOLFOX alone (T Ruers, personal communication). Microwave ablation therapy is now becoming commercially available. The major advantage of microwave ablation over RFA is speed. Whereas it may take 20 to 30 minutes to achieve an adequate ablation of a 3-cm metastasis using RFA, microwave can achieve the same degree of tumor destruction in only 3 to 4 minutes.

management strategies for synchronously detectable crlm Patients who present with technically “easily” resectable primary tumor (right, transverse, left, and sigmoid colon) and peripherally placed, low-volume liver disease (segments 2, 3, 4B, 5, 6, and subcapsular lesions in segments 4A, 7, and 8) are amenable to synchronous resection of both primary tumor and metastatic liver disease at the same procedure, without significantly increased morbidity or mortality (34–37). Those patients (a decreasing minority) who present with large bowel obstruction, perforation or life-threatening hemorrhage and

MULTIMODAL APPROACHES TO THE MANAGEMENT OF COLORECTAL LIVER METASTASES CRC metastases

Up-to-date CT or MRI of chest, abdomen, and pelvis

Hepatic metastases only

Extrahepatic disease

Determine if patient is candidate for hepatic resection or HR and RFA or RFA alone

Consider chemotherapy

Not candidate for HR or RFA Response

No response

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HR and RFA Some tumor(s) resectable and some ablatable (Laparotomy – HR and RFA)

RFA alone All tumor(s) ablatable but not resectable Lapartomy, Laparoscopic or Percutaneous)

No response

Consider HR and/or RFA Consider HR and/or RFA

Follow-up CT or MRI of the chest, abdomen, and pelvisand CRC surveillance

Incomplete ablation or new metastases

Consider repeat or serial RFA and/or repeat HR

Figure 15.2 The possible treatment strategy algorithm for patients with colorectal liver metastases (40).

synchronous CRLM should have immediate definitive lifesaving treatment (endoscopic stenting, resection with either a stoma or immediate reconstruction). Most surgical oncologists would recommend that in situations where resection of the primary tumor may be more demanding (T2–T3 rectal carcinoma), or when the management strategy for the primary tumor requires neoadjuvant treatment (chemoradiotherapy for T3–T4 rectal carcinoma), or the liver disease (albeit technically resectable) is of such an extent that it requires at least a hemi-hepatectomy or more, then planned sequential staged procedures carry lower perioperative risk (36,37). However, when considering staged sequential treatment strategies, concerned must remain about the risk of tumor progression at both sites during treatment (31,38–40). For

patients presenting with asymptomatic primary tumors in the presence of unresectable liver metastases, it would be reasonable to propose a course of systemic chemotherapy and base subsequent treatment strategies on the degree of response (38). Those patients whose chemotherapy response is sufficient that their liver disease is now amenable to potential hepatectomy can now be considered for surgery with curative intent (31,38–40). For the 6% to 10% of patients with present with inoperable disease and continue to progress while on chemotherapy (23,31), consideration can be given to further lines of chemotherapy, but overall the outlook is poor and futile surgery can be avoided. For patients with primary colon cancer (as opposed to primary rectal tumors) with initially unresectable liver whose disease responds so well that an R0 resection of all tumor sites

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS can be achieved using a relatively minor liver resection, then synchronous liver–bowel surgery is feasible (38).

should the liver resection take precedence over the bowel surgery? The fundamental question is now whether or not, having achieved a window of therapeutic opportunity to deal with the liver disease, does the liver disease takes precedence over the primary tumor (39,40)? It has been proposed that the liver disease should be resected first, and then following eradication of the liver disease, subsequently deal with the primary bowel tumor. Using this strategy, potentially curative surgery for both primary and secondary disease has been achieved in 16 of 20 (80%) such patients in small singlecenter series (38).

conclusions If feasible, surgical resection remains the gold standard of treatment for CRLM. Unfortunately, patients still present with advanced colorectal cancer. Modern chemotherapy regimens offer increasing numbers of patients with initially unresectable CRLM the chance of being brought to potentially curative liver surgery (Fig. 15.2) (41). The remaining controversies in this field are the timing of such surgery and the strategic decisions of which operation (bowel first, liver first, or synchronous combined surgery) is now the first procedure of choice? The role of the MDT in the management of colorectal cancer liver metastases is to collate all the available data that can lead to an accurate assessment of disease spread and stage, then using these data, to plan an effective treatment strategy that ideally is focused on possible cure, but in any event is aimed at gaining maximal survival advantage for our patients.

references 1. Poston GJ. Surgical strategies for colorectal liver metastases. Surg Oncol 2004; 13: 125–36. 2. Primrose JN. Treatment of colorectal metastases: Surgery, cryotherapy or radiofrequency ablation. Gut 2002; 50: 1–5. 3. Weiss L, Grundmann E, Torhorst J, et al. Hematogenous metastatic patterns in colonic carcinoma: An analysis of 1541 necropsies. J Pathol 1986; 150: 195–203. 4. Sugarbaker PH. Surgical decision making for large bowel cancer metastatic to the liver. Radiol 1990; 174: 621–6. 5. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet 1994; 343: 1405–10. 6. Geoghegan JG, Scheele J. Treatment of colorectal liver metastases. Br J Surg 1994; 86: 158–69. 7. Abdalla E, 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: 818–25. 8. Bismuth H, Adam R, Levy F, et al. Resection of nonresectable metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996; 224: 509–20. 9. Sahani DV, Kalva SP. Imaging the liver. Oncologist 2004; 9: 385–97. 10. McLoughlin JM, Jensen EH, Malafa M. Resection of colorectal liver metastases. Cancer Control 2006; 13: 32–41. 11. Vauthey JN. Patients with hepatic colorectal metastases. Program of the AHPBA 2006 consensus conference; January 25, 2006; San Francisco, CA.

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12. Martinez L, Puig I, Valls C. Colorectal liver metastases: Radiological diagnosis and staging. Eur J Surg Oncol 2007; 33(S2): S5–S16. 13. Charnsangavej C. Selection for resection: Preoperative imaging evaluation. Program of the AHPBA 2006 consensus conference; January 25, 2006; San Francisco, CA. 14. Israel O, Mor M, Gaitini D, et al. Combined structural and functional evaluation of cancer patients with a hybrid camera based PET/CT system using (18) F-FDG. J Nucl Med 2002; 43: 1129–36. 15. Simmonds PC, Primrose JN, Colquitt JL, et al. Surgical resection of hepatic metastases from colorectal cancer: A systematic review of published studies. Br J Cancer 2006; 94: 982–99. 16. Hughes KS, Simon R, Songhorabodi S, et al. Resection of the liver for colorectal carcinoma metastases: A multi-institutional study of patterns of recurrence. Surgery 1986; 100: 278–284. 17. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 1999; 230: 309–18. 18. Minagawa M, Makuuchi M, Torzilli G, et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: Long-term results. Ann Surg 2000; 231: 487–99. 19. Vauthey JN, Pawlik TM, Abdalla EK, et al. Is extended hepatectomy for hepatobiliary malignancy justified? Ann Surg 2004; 239: 722–32. 20. Scheele J, Stangl R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg 1995; 19: 59–71. 21. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005; 241: 715–24. 22. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 2004; 240: 644–57. 23. Petrowsky H, Gonen M, Jarnagin W, et al. Second liver resections are safe and effective treatment for recurrent hepatic metastases from colorectal cancer: A bi-institutional analysis. Ann Surg 2002; 235: 863–71. 24. Kanemitsu Y, Kato T, Hirai T, Yasui K. Preoperative probability model for predicting overall survival after resection of pulmonary metastases from colorectal cancer. Br J Surg 2004; 91: 112–20. 25. Pozzo C, Basso M, Cassano A, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 2004; 15: 933–39. 26. Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant chemotherapy of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005; 16: 1311–9. 27. Wicherts DA, de Haas RJ, Adam R. Bringing unresectable liver disease to resection with curative intent. Eur J Surg Oncol 2007; 33(S2): S42–S51. 28. Adam R, Aloia T, Levy F, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic chemotherapy. J Clin Oncol 2007; 25: 4593–602. 29. Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine and oxaliplatin as neoadjuvant treatment for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008; 26: 1830–5. 30. Folprecht G, Gruenberger T, Hartmann JT, et al. Cetuximab plus FOLFOX6 or cetuximab plus FOLFIRI as neoadjuvant treatment of nonresectable colorectal liver metastases: a randomized multicenter study CELIM-study. ASCO GI, San Francisco 2009, abstract 296. 31. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX-4 and surgery for respectable liver metastases from colorectal cancer. Lancet 2008; 371: 1007–16. 32. Feliberti EC, Wagman LD. Radiofrequency ablation of liver metastases from colorectal cancer. Cancer Control 2006; 13: 48–51. 33. Mulier S, Mulier P, Ni Y, et al. Complications of radiofrequency coagulation of liver tumors. Br J Surg 2002; 89: 1206–22. 34. Poston GJ, Byrne C. Decision making for patients with colorectal cancer liver metastases. Ann Surg Oncol 2006; 13: 10–1. 35. Verghese M, Pathak S, Poston GJ. Increasing long-term survival in advanced colorectal cancer. Eur J Surg Oncol 2007; 33(S2): S1–S4. 36. Nesbitt C, Glendinning RJ, Byrne C, Poston GJ. Factors influencing treatment strategies in advanced colorectal cancer. Eur J Surg Oncol 2007; 33(S2): S88–S94.

MULTIMODAL APPROACHES TO THE MANAGEMENT OF COLORECTAL LIVER METASTASES 37. Weber JC, Bachellier P, Oussoultzoglou E, Jaeck D. Simultaneous resection of colorectal primary tumour and synchronous liver metastases. Br J Surg 2003; 90: 956–62. 38. Benoist S, Pautrat K, Mitry E, et al. Treatment strategy for patients with colorectal cancer and synchronous irresectable liver metastases. Br J Surg 2005; 92: 1155–60. 39. Mentha G, Majno PE, Andres A, et al. Neoadjuvant chemotherapy and resection of advanced synchronous liver metastases before treatment of the colorectal primary. Br J Surg 2006; 93: 872–8.

40. Mentha G, Majno P, Terraz S, et al. Treatment strategies for the management of advanced colorectal liver metastases detected synchronously with the primary tumour. Eur J Surg Oncol 2007; 33(S2): S76–S83. 41. Blokhius TJ, van der Schaaf MP, van den Tol MP, et al. Results of radiofrequency ablation of primary and secondary liver tumors: Longterm follow-up with computed tomography and positron-emission tomography-18F-deoxyglucose scanning. Scand J Gastroenterol 2004; 241: 93–7.

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16

Management of neuroendocrine tumor hepatic metastasis Kaori Ito

introduction Neuroendocrine tumors (NET), including both carcinoid tumors and islet tumors, are derived from primitive neuroectodermal cells that are distributed throughout the body during embryonic development (1–4). Therefore, NETs originate from various organs but most commonly involve the lungs, bronchi, and gastrointestinal tract (2,5). NETs were traditionally classified into foregut, midgut, and hindgut derivatives based on their presumed origin of gut. Currently, it is replaced by the WHO classification system of 2000 according to the histological differentiation (6). Clinical presentations widely differ depending on both their organ and excess hormone production (e.g., serotonin, histamine, tachykinins, and prostaglandins) (3,5). The overall incidence of NET has been reported to be 1 to 2 cases per 100,000 people (5) (Tables 16.1 and 16.2). Hepatic metastasis is the second common metastasis following lymph node metastasis in NETs (3) (Fig. 16.1). Up to 45% of patients with abdominal carcinoid will present with bowel obstruction and more than half of patients who were explored for bowel obstruction due to NETs are found to have hepatic metastases. Despite of the fact that liver is the common metastatic site of NETs, primary hepatic NET is extremely rare (0.6% of all NETs) (2). In this chapter, we describe specifically about the management of hepatic metastases of NETs.

diagnosis Clinical Features Hepatic metastases of NET could be diagnosed preoperatively following investigation of a specific hormonal syndrome or following the incidental finding of hepatomegaly or an abdominal mass. Or it could be discovered at the abdominal exploration for primary gastrointestinal NETs. Besides hormonal symptoms, patients will complain local symptoms due to tumor bulk (pain, early satiety, or palpable mass). Subclinical hepatic metastasis does not require treatments, however, lifestyle-altering symptoms or biologically aggressive tumors require treatment (7). Demographics, presentation, symptoms, tumor histology, and primary tumor location of patients with NET-hepatic metastasis are summarized in Table 16.3 (8). The most representative symptom of patients with NETs is carcinoid syndrome. It is caused by systemic circulation of hormonal products from bulky metastatic NETs. This syndrome is a manifestation of late stage of NET and 5% to 10% of all NET patients present with this syndrome (1,5,9,10). In patients with NET-hepatic metastasis, carcinoid syndrome is frequently evident, at least biochemically (1). Common symptoms and signs include cutaneous flushing (71–80%), diarrhea (76–80%), hepatomegaly (71%), carcinoid heart disease (41–70%), asthma (9–25%), pellagra (2%) (3,11–15).

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Wessels et al. proposed the Carcinoid Symptom Severity Scale (Table 16.4) (16). This scaling system well illustrates the disease severity and is used to evaluate the symptomatic change before/after treatment (17). Carcinoid crisis is an acute life-threatening presentation, which is precipitated by anesthesia or interventional procedures (18,19). When large amounts of hormonal products are suddenly released into the systemic circulation, they trigger hypotension, tachyarrhythmias, bronchospasm, and neurological abnormalities. Carcinoid crisis is treated by the intravenous administration of somatostatin (SST) (50–100 μg). Premedication with SST analogs before interventional therapies can prevent crisis (19–23). Carcinoid-associated fibrosis should also be of concern. Carcinoid tumors cause fibrosis of the surrounding tissue. The pathogenesis of fibrosis is not well studied. Fibrosis in the peritoneum leads to bowel ischemia or mechanical bowel obstruction (24,25), in the retroperitoneum leads to hydronephrosis (24,26), in heart leads to tricuspid/pulmonary valve disease (carcinoid heart disease) (27), and in the thorax leads to thickening of pleura (28). These lesions can be the major cause of morbidity and mortality of the patients in the advanced stage. Laboratory Investigation Blood Patients with suggestive symptoms of NET should undergo laboratory tests to confirm the diagnosis of NET. Elevated plasma chromogranin A (CgA) level is the most sensitive marker of carcinoid tumors. CgA is a water-soluble acidic glycoprotein, which is stored in the secretory granules of NET cells. The sensitivity of plasma CgA level in NETs is reported up to 100%, however, it is not specific because the elevation of CgA is observed in prostate carcinoma too (1,29–31). Other biomarkers include bradykinin, serum substance P, neurotensin, human chorionic gonadotropin (hCG), neuropeptide K, and neuropeptide PP (1). Urine The measurement of 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) can provide a summation of paroxysmal tumor secretion activity. 5-HIAA is a metabolite of serotonin, which is released by carcinoid tumors. The specificity of this test is around 90%. False-positive can will occur with consumption of serotonin-rich foods (bananas, avocados, plums, eggplant, tomatoes, plantain, pineapples, and walnuts) (32,33). If the laboratory findings were equivocal, a provocative test such as a pengastrin test (injection) or alcohol ingestion might be performed under the careful monitoring (31) (Grade III. Recommendation C).

MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS Table 16.1 WHO Classification of Neuroendocrine Tumors (NET) of the Gastrointestinal Tract with Portal Venous Drainage Stomach, ileum, colon

Pancreas

Well-differentiated Endocrine Tumor (Carcinoid) (1) Benign behavior Non-functioning Confined to mucosa-submucosa, nonangioinvasive Size ≤1 cm (stomach or small intestine) or ≤2 cm (colon) (2) Uncertain behavior Nonfunctioning Confined to mucosa-submucosa, nonangioinvasive Size >1 cm (stomach or small intestine) or >2 cm (colon) Well-differentiated Endocrine Carcinoma (Malignant Carcinoid) Low-grade malignant tumor Deeply invasive (muscularis propria or beyond) or with metastases (liver) Poorly-differentiated endocrine carcinoma Small-cell carcinoma High-grade malignant tumor Mixed Endocrine/Exocrine Carcinoma Moderate to high-grade malignant tumor

Well-differentiated endocrine tumor (1) Benign behavior Confined to the pancreas, non-angioinvasive Size: <2 cm Mitosis: ≤2 Ki67 positive cells/10 HPF: ≤2% (2) Uncertain behavior Confined to the pancreas Size: ≥2 cm Mitosis: >2, or angioinvasive Ki67 positive cells/10 HPF: >2% Well differentiated Endocrine Carcinoma Functioning or non-functioning Low-grade malignant tumor with gross local invasion and/or metastases (liver) Ki67 positive cells/10 HPF: >5% Poorly-differentiated Endocrine Carcinoma Small cell carcinoma High-grade malignant tumor Ki67 positive cells/10 HPF: >15%

Source: Adapted from Ref. (6).

Table 16.2 Anatomical Location of NETs (Carcinoid Only, Except for Islet Cell Tumors) from SEER 1973–1999 % Lung, bronchi, and trachea Stomach Duodenum Jejunum Ileum Appendix Cecum Colon Rectum Other

28 5 3 2 15 5 4 5 14 6

Source: Adapted from Ref. (2).

Diagnostic Imaging Somatostatin Receptor (SSTR) Scintigraphy Given the clinical presentation and biochemical confirmation of NETs, topographical localization of primary tumor and metastases should be pursued. SSTR scintigraphy utilizing 111 In-labelled SST analog (octreotide) can detect NETs that express SSTRs. Sensitivity of this test is reported as 84% (57– 93%) (1,34,35) (Fig. 16.2). The simultaneous use of single positron emission computed tomography (SPECT) can enhance the sensitivity. This is the first choice of diagnostic imaging test to find the primary site of carcinoid tumors (Grade III. Recommendation C). Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) CT and MRI are utilized to obtain more precise image of local extent of tumor if surgery is contemplated, but not to look for

the primary site. Sensitivity of CT/MRI is reported to be about 80%. The detection rates are 76% to 100% for CT alone and 67% to 81% for MRI alone (31). Triple phase spiral CT is the most informative to evaluate NET-hepatic metastasis. NEThepatic metastasis-associated findings are defined as mass lesions with calcification and radiating strands of fibrosis (36) (Fig. 16.3) (Grade III. Recommendation C). Positron Emission Tomography (PET) [18F]Fluoro-2-deoxy-d-glucose (FDG)-PET scan became an essential tool for many cancers to detect cancer cells, which were not seen in other imaging, or to quantify metastatic sites by the whole body image. The utility of 18F-PET scan for NETs is not well supported. Because typically NETs are slow growing with a low metabolic rate, the uptake of 18F by NETs cannot be visualized (37,38). The detection rates are reported as 25% to 73% (1,39). Instead, PET scan with the radioactive serotonin precursor 11C-5 HT, and 68Ga/64Cu coupled to octreotide revealed an excellent detection rate (40). Since there were no large studies to assess the efficacy of PET scan compared to other diagnostic imaging (41), the role of PET scan for NETs is still unclear (Grade III. Recommendation C). Radiolabeled Metaiodobenzylguanidine (MIBG) Because NETs concentrate MIBG, the administration of 123 I-MIBG is another option to detect metastatic NETs. Sensitivity and specificity were reported as 55% to 70% and 95%, respectively (42,43). Although the accuracy of this test is inferior to that of SSTR scintigraphy, MIBG is a useful alternative of SSTR scintigraphy in patients on long-acting SST analog in whom SSTRs may have been occupied by SST analogue already (42,43) (Grade III. Recommendation C).

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Figure 16.1 Macroscopic (A) and microscopic (B) views of large resected hepatic neuroendocrine liver metastasis (stained for chromogranin-A). Note the hypervascularity of the metastasis compared to the background liver and comparable colorectal liver metastases.

Table 16.3 Clinical Features of NET-Hepatic Metastasis Demographics Gender Men Women Age Metastatic presentation Synchronous Metachronous Symptoms Hormonal Pain Mechanical, progressive tumor growth Weight loss Jaundice Asymptomatic with progressive tumor growth Gastrointestinal bleeding Tumor histology Carcinoid Nonfunctional islet cell tumor Functional islet cell tumor Primary tumor location Pancreas Gastrointestinal bleeding Lung Unknown

% 40 60 52 years % 74 26 % 55 55 36 15 5 4 1 % 48 31 21 % 49 25 9 16

Source: Adapted from Ref. (8).

treatment Treatment of NET-hepatic metastasis is required for patients with lifestyle-altering symptoms, or biologically aggressive tumors. The principal requirements are to remove the primary and metastatic sites in order to reduce levels of bioactive agents (27,44–46). Therefore, surgical resection is the first choice as long as patients fit to surgery. Treatment options include hepatic resection, hepatic artery occlusion, radiofrequency ablation, cryoablation, liver transplantation, and medical therapy. Indications and timing of therapy are still controversial.

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Hepatic Resection Surgical resection of NET-hepatic metastasis is categorized into curative intent resection or palliation intent resection (debulking/cytoreductive surgery). Both of approaches contribute to the improvement of symptoms and the prolonged survival. Curative intent resection is indicated for patients with solitary or localized hepatic metastasis. Only 10% to 25% of NET-hepatic metastasis is found in this category. Palliation intent resection is applied to patients with considerable symptom due to multiple, bulky extended tumor. The removal of more than 90% of the tumor bulk allows a significant palliation. Concurrent resection of extrahepatic tumors is often performed. Regional lymphadenectomy should be done because lymph node metastasis is common in NETs. Administration of SST analogs will be required for patients with residual tumors. Curative resection is associated with longer survival than noncurative resection (91% vs. 76% at 5 years; median 30–50 vs. 16–32 months, respectively). Summary of literature review regarding postoperative outcomes is shown in Table 16.5 (8,47–58). Postoperative morbidity and mortality rates are 22% (3-26%) and 3% (0–6%). Although perioperative carcinoid crisis is not very frequent (0–3%), precaution should be always taken. Relief of symptom was achieved in 92% (46–100) of patients. Disease-free survival is 17 to 60 months (median 41 months) and 36% (16–42%) at 5 years. Hepatic recurrence is reported in 82% of patients (52). Survivals have an estimated median of 67 (52–81) months. Five-year survival rate extends up to 73% (31–85%). Ten-year survival is reported as 35% (Grade III. Recommendation C).

Hepatic Artery Embolization Hepatic artery embolization (HAE) is a rational approach against liver malignancies by using the discrepancy of blood supply between liver tumor and normal liver. The selective occlusion of hepatic artery causes hypoxic damage of tumor. Patients with NET-hepatic metastasis who don’t fit for surgery will benefit from this therapy. Indications include (i) rapid enlargement of tumor mass, (ii) increasing symptoms, and (iii) patient preference for the procedure in lieu of other treatment (46). Occlusive and/or chemotherapeutic agents are infused into the hepatic artery through an angiography catheter (5).

MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS Table 16.4 Carcinoid Symptom Severity Scale Score

Description

Description

1

No symptoms

2

Mild symptoms

3

Symptoms impact daily living

4

Sever symptoms

5

Disabling symptoms

Symptoms: None Frequency: None Lifestyle effects: None Symptoms: Diarrhea, flushing, or wheezing Frequency: Up to 4 times daily Lifestyle effects: None to minimal Symptoms: Diarrhea, flushing, or wheezing Frequency: 5–7 times weekly Lifestyle effects: Restricts patient from leaving home for prolonged periods of time. Symptoms: Diarrhea, flushing, or wheezing Frequency: Multiple daily episode Lifestyle effects: Symptoms require significant recognization of daily activities to accommodate for these symptoms; patients rarely leave home, must be close to bathroom facilities and medical supplies. Symptoms: Diarrhea, flushing, or wheezing (severe) or of sufficient severity to warrant hospitalization for treatment of dehydration, electrolyte imbalance, refractory hypertension, or asthma Frequency: Numerous (>4) daily Lifestyle effects: Symptoms are disabling; patients are unable to leave home or require hospitalization.

Source: Adapted from Ref. (16).

Figure 16.3 Computed tomography scan of multiple neuroendocrine hepatic metastases from a primary small bowel carcinoid. Figure 16.2 Indium-111 Octreotide scan demonstrating octreotide avid liver metastases.

A diagnostic angiography should be obtained from a femoral approach to confirm the anatomy of artery and the patency of portal vein before the administration of the therapeutic agents (Fig. 16.4). Patients should receive SST analogs before the procedure to prevent hormonal adverse events (59). There are no definitive data to support the agents for embolization such as Gelfoam, Ivalon, starch particles, lipidol, or radio isotope-loaded spheres. Selection of chemotherapeutic agents is also still inconclusive. Cisplatin, doxorubicin, and mitomycin are most commonly utilized. Almost all of patients experience postprocedural abdominal pain, nausea, vomiting, and fever. Transaminase levels will shoot up dramatically, and then followed by the elevation of

alkaline phosphatase and or serum bilirubin. Tumor-related hormone level will increase temporarily, however, it can be obviated with SST analogs administration (59). Major complications include gastrointestinal bleeding, gastric and duodenal ulceration, hepatic abscess, ischemic necrosis of gallbladder or small intestine, pancreatitis, sepsis, renal failure, hepatorenal syndrome, portal vein thrombosis, sclerosing cholangitis, arterial thrombosis, and arrythmias (60). Since these complications are common and even can be fatal, patient selection should be strict and postprocedural hospital stay with careful monitoring is warranted. Overall, morbidity rate ranges from 3% to 20%, mortality rate ranges from 0% to 7% (Table 16.6). Successful symptomatic relief and the reduction of tumor size can be achieved; however, the duration of palliation may

157

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 16.5 Hepatic Resection (Literature review: 1996–2008) Follow-up period Morbidity Mortality (months) (%) (%)

Relief of symptoms (%)

Disease free survival (%)

Disease free survival (months)

Disease specific survival (%)

Disease specific survival (months)

Year

No. of patients

Dousset (Paris, France) (47)

1996

17

6–108

24

6

100

36% at 5 years

17

46% at 5 years

NA

Chen (MD, USA) (48) Chamberlain (NY, USA) (8) Jaeck (Strasbourg, France) (49) Yao (IL, USA) (50)

1998

15

27

NA

0

NA

NA

21

2000

34

27

NA

6

86–100

NA

NA

2001

13

42

NA

0

46

NA

not reached not reached NA

2001

16

30

12

0

100

Chung (CA, USA) (51) Sarmiento (MN, USA) (52) Knox (TN, USA) (53)

2001

31

26

26

3

90

69% at 3 years 42% at 5 years NA

2003

170

NA

14

1

96

46

2004

17

NA

24

0

82

16% at 5 years NA

Mazzaferro (Milan, Italy) (54) Osborne (FL, USA) (55) Musunuru (WI, USA) (56) Landry (KT, USA) (112) Eriksson (Uppsala, Sweden) (58) Median

2007

36

NA

NA

0

NA

2006

61

NA

3

2

73% at 5 years 76% at 5 years 68% at 6 years 73% at 5 years 31% at 5 years 61% at 5 years 85% at 5 years 59% at 10 years NA

2006

13

20

NA

NA

2008

23

NA

2008

42

83% at 3 years 75% at 5 years NA 73% at 5 years

67

60

9–104 NA

92

19% at 10 years NA

NA

100

NA

50

26

0

NA

NA

NA

18

20

0

71

NA

NA

27

22

3

92

36% at 5 years

41

35

not reached NA 81 135 NA 43

52 NA

be limited due to recurrence or rearterization of tumors. The occlusive agent alone is associated with a relief of symptom rate 49% (33–100%), median disease-free survival at 15 (8–37) months, and median disease-specific survival at 24 (24–120) months (55,56,61–68). Whereas the embolization with chemotherapeutic agents results in a relief of symptom rate 75% (61–92%), median disease-free survival is 14 (10–19) months, and median disease-specific survival 33 (25–49) months. The summary of recent literature review is shown in Table 16.7 (Grade III. Recommendation C).

Figure 16.4 Typical angiogram of multiple neuroendocrine hepatic metastases prior to embolization.

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Hepatic Radiofrequency Ablation Radiofrequency ablation (RFA) can be performed percutaneously or laparoscopically for patients who are unfit for hepatic resection or intraoperative RFA in addition to hepatic resection is also advantageous. High-frequency alternating current causes ionic agitation that is converted into heat, and leads coagulation necrosis of tumor. The probes can deploy 4 to 5 cm in a single session with up to 200 W of power (Fig. 16.5).

NA 17 0 5 0

NA

2008

Christante (OR, USA) (118)

Median

Musunuru (WI, USA) (56)

2006

2005

2007

Bloomston (OH, USA) (117)

Median HAE and HACE Gupta (TX, USA) (66)

2003 2007

Roche (Villejuif, France) (115) Ho (MO, USA) (116)

18

123

59

122

14 46

24 15

Median Combination with chemotherapeutic agents (HACE) Ruszniewski (Paris, France) (114) 1993 Drougas (TN, USA) (60) 1998

HAE, polyvinyl alcohol particle or gelfoam powder. HACE, for carcinoid tumor: cisplatin+doxorubicin. For islet cell tumor: 5FU+streptozocin NA

Doxorubicin, Lipiodol Doxorubicin, cisplatin, mitomycin C +5FU Doxorubicin, Lipiodol Cisplatin, doxorubicin, mitomycin, Lipiodol Cisplatin, doxorubicin, mitomycin, ioxaglate sodium, Lipiodol Cisplatin, doxorubicin, mitomycin

9

0

NA

0

9

NA

5

7

5

0 4

0 0

7

5 9

0

0 6 0 0 0

0

Mortality (%)

20

NA

23

14 20

8 60

12

12 NA

111 23

1994 2003

NA, including surgical ligation N-Butyl-2-cyanoacrylate, Lipiodol

Gelfoam Polyvinyl alcohol particles Lipiodol/Gelfoam Polyvinyl alcohol particles Trisacryl gelatin microsphere (embosphere)

Gelfoam

Morbidity (%)

HAE with systemic chemotherapy Moertel (MN, USA) (68) Loewe (Vienna, Austria) (67)

55 35 24 59 15

8

Agent(s) used

3

1998 1999 2002 2006 2007

1989

No. of patients

Median

Eriksson (Uppsala, Sweden) (64) Brown (NY, USA) (113) Schell (FL, USA) (17) Osborne (FL, USA) (55) Granberg (Uppsala, Sweden) (65)

Occlusive agent alone (HAE) Nobin (Lund, Sweden) (63)

Year

Table 16.6 Hepatic Artery Occlusion (Literature Review: 1989–2008)

83

83

NA

75

61

92

64 78

NA 75

98

98.0 NA

49

38–52 89–100 64 59 33

38

Relief of symptoms (%)

31% at 3 years 31% at 3 years

NA

5% at 5 years

NA

5% at 5 years

NA NA

NA NA

NA

NA NA

38% at 1 year

38% at 1 year NA NA NA NA NA

Disease free survival (%)

24

25

23

14

19

10

17 14

13 NA

NA

NA NA

15

8 15 NA 37 NA

NA

Disease free survival (months)

NA

NA

NA

29% at 5 years

27% at 5 years

28% at 5 years

83% at 5 years 29% at 5 years

NA NA

65% at 5 years

NA 65% at 5 years

72

13% died in 5 months 83% at 5 years 54% at 5 years 72% at 5 years NA NA

Disease specific survival (%)

34

NA

34

33

39

33

48 33

NA 25

44

49 39

24

80–120 24 NA 24 NA

NA

Disease specific survival (months)

MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS

159

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 16.7 Milan Criteria Inclusion criteria 1. Confirmed histology of carcinoid tumor (low-grade neuroendocrine tumors) with or without syndrome 2. Primary tumor drained by the portal system (pancreas and intermediate gut: from distal stomach to sigmoid colon) removed with a curative resection (pre-transplant removal of all extra-hepatic tumor deposits) through surgical procedures different and separate from transplantation 3. Metastatic diffusion to liver parenchyma < or + 50% 4. Good response or stable disease for at least 6 months during the pre-transplant period 5. Age < or + 55 years Exclusion criteria 1. Small-cell carcinoma and high-grade neuroendocrine carcinomas (non-carcinoid tumors) 2. Other medical/surgical conditions contraindicationg liver transplantation, including previous tumors 3. Non-gastrointestinal carcinoids or tumors not-drained by the portal system Source: Adapted from Ref. (54).

Figure 16.5 CT guided radiofrequency ablation of single small liver metastasis 1 day after arterial embolization.

This treatment is suitable for relatively small tumors. Indications for RFA include (i) fewer than 4 in number, (ii) smaller than 5 cm, (iii) accessible location in liver, and (iv) not in contiguity to vascular structures, bowel, or the gall bladder (46). Complications include bleeding, sepsis, and intrahepatic biliary duct damage. Morbidity rate is around 5%. No RFArelated mortality has been reported (58,69). RFA is associated with the high incidence of the recurrence at previously ablated sites (58,70,71). Local recurrence rate is reported to be 5 to 6% (69,70,72). The assessment of outcome of this procedure is somewhat difficult to be specific because many of RFA are combined with surgical resection. A large

160

study by Mazzaglia et al. (69) detailed the outcomes of 80 laparoscopic RFA sessions in 63 patients who underwent RFA alone for NET-hepatic metastasis (54). Relief of symptoms was achieved more than 90% of the patients. Median diseasefree survival was 11 months. Median disease-specific survival was close to 4 years. Five-year survival rate was 48% (Grade III. Recommendation C). Hepatic Cryoablation Cryoablation can be applied for patients with unresectable refractory NETs. Intraoperative approach combined with hepatic resection is common rather than cryoablation alone. The cryoprobe is inserted into tumor under ultrasound guidance. The freezing temperature of cryoprobe is maintained liquid nitrogen perfusing in the uninsulated tip. Tumor is monitored until the “ice ball” enveloped the tumor with a 1-cm margin of normal tissue. Multiple freezing–thaw cycles lead to tumor destruction (73). Indications for this procedure are still unclear. Complications include coagulopathy, bleeding, acute renal failure, and pulmonary embolism. Morbidity rate is reported variously but at a minimum of 23%. Mortality rate is 0% to 2% (74–76). Of note, this procedure is usually combined with hepatic resection; therefore, the outcomes of reported studies are not specific for cryoablation. Almost all patients experienced the relief of symptoms and biochemical response. Local recurrence at the ablated site is reported as 17% in a study from Seifert et al. (75). Median recurrence-free survival is 10 months. Median disease-specific survival is 20 to 49 months. Three-year survival rate is up to 91% (74–76) (Grade III. Recommendation C). Liver Transplantation Liver transplantation is a therapeutic alternative of hepatic resection for unresectable NET-HM patients. Whereas the results of liver transplantation for other metastatic tumors are poor (77), patients with NET-hepatic metastasis have been more likely benefit from liver transplantation (57,78–85). Although this approach is still controversial, “Milan criteria” for indication to liver transplantation in patients with NEThepatic metastasis are widely referred (Table 16.7) (54). Patients will receive a full graft, a split graft or a domino graft from deceased or living donor (78). The general principle of complete resection of both primary and metastatic tumor has to be pursued in the setting of this treatment. Therefore, transplantation could be performed with concurrent resection of extrahepatic tumor including lymphadenectomy of hepatic pedicle and hepato-duodenal ligament (54,78,86). Standard immunosuppression should be administered postoperatively. Adjuvant chemotherapy or long-acting SST analogs will be applied as appropriately (54). Table 16.8 shows the summary of literature review. Postoperative morbidity includes acute rejection episodes, acute cholangitis, and bacteremia. Overall morbidity rate are reported as 56% (32–75%). Mortality rate is 10% (5–44%). Recent studies report that 5-year survival of 21% (36–90%), with symptomatic relief occurring in all of the patients.

MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS Table 16.8 Liver Transplantation (Literature Review, 1996–2008)

Dousset (Paris, France) (47) Lang (Gottingen, Germany) (57) Lehnert(Heidelberg, Germany) (87) Rosenau (Hannover, Germany) (88) Florman (NY, USA) (89) V.Vilsteren (MN, USA) (86) Mazzaferro (Milan, Italy) (54) Olausson (Goteborg, Sweden) (90) Marin (Murcia, Spain) (91) Le Treut (Marseille, France) (78) Median

Year 1996

No. of patients 9

1997

12

1998

103

2002

19

2004

11

2006

19

2007

24

2007

15

2007

10

2008

85

FollowDiseaseup Relief of free period Morbidity Mortality symptoms survival (months) (%) (%) (%) (%) NA NA 44 NA Rec rate 11% NA NA 8 100 Rec rate 57.1% 60 NA 14 NA 24% at 5 years 60 NA 5 NA 21% at 5 years 34 NA 27 NA 9% at 5 years 22 32 5 NA 80% at 1 years 60 NA NA NA 77% at 5 years 54 NA 7 NA Rec rate 33.3% 36 75 10 NA 57% at 3 years 46 NA 14 NA 20% at 5 years 50 56 10 100 21% at 5 years

Disease-free survival is 21% (9–77%) at 5 years. Median time to recurrence is 25 (1.5–58) months (47,54,57,78,86–91) (Grade III. Recommendation C). Medical Treatment SSTR-targeted Therapy SST analogs are effective in improving hormonal symptoms due to NETs. SST inhibits the release of serotonin and other hormones from NETs (92). Because SST has a short half-life (about 2 minutes), it is not suitable for clinical use (92). Longacting SST analogues (octreotide and lanreotide) are widely applied. The response rate ranges 70% to 80% when administered subcutaneously every 6 to 12 hours (93,94). Dosage should be adjusted with clinical use from 50 to 500 μg 3 times a day. Adverse effects include gallstones, steatorrhea, sinus bradycardia, cardiac conduction abnormalities, arrhythmias, hypothyroidism, hypoglycemia, and hyperglycemia (92,95). SSTR analogs are utilized for preoperative symptomatic control, preprocedural medication to prevent carcinoid crisis, and postoperative supportive therapy if residual tumors were evident (1) (Grade III. Recommendation C). Chemotherapy Chemotherapeutic agents for NETs include streptozotocin, 5-FU, doxorubicin, cyclophosphamide, etoposide, cisplatin, temozolomide, thalidomide, paclitaxel, and docetaxel (1,4). Overall response rate of chemotherapeutic alone is reported to be only 20% to 40%. At least there is one randomized trial comparing streptozocin +5FU and doxorubicin +5FU (96). The patients were enrolled this study were 249. Response rate

43.795 pt 58 6 weeks to 48 months NA 11 NA NA NA 25 NA NA 25

Disease specific survival (%) NA

Disease specific survival (months) 24

NA

55

47% at 5 years 80% at 5 years 36% at 5 years 87% at 1 years 90% at 5 years NA

NA

57% at 3 years 47% at 5 years 47% at 5 years

NA

NA NA NA NA NA

56 55

in two groups were similar (16% vs. 15.9%). Streptozocin + 5 FU was associated a subtle increase of survival (24.3 vs. 15.7 months), however, renal toxicity was significantly frequent in that group. Unfortunately, there are no data existing to reveal the benefit of each chemotherapeutic agent, or the combination of agents (92,97–99) (Grade Ib. Recommendation B). Interferon Interferon inhibits tumor growth by directly blocking the G0/G1 phase of cell cycle. Applications of interferon to NETs have been investigated since 1982 (100–103). Interferon alpha alone resulted in biochemical response rate of 7% to 66%, and tumor response rate 0% to 25%. The combination of interferon alpha and SST analogs failed to be effective (104) (Grade III. Recommendation C). Radionuclide Therapy Receptor targeted therapy with radionuclides is an emerging treatment for patients with disseminated NET metastases. 131 I-MIBG, [111In-DTPA-D-Phe] octreotide, 90yttrium, and 177 lutetium-labeled SST analogs are utilized (35,105–111). Agents will be selected by uptake at diagnostic imaging. This treatment is specific and tolerated. Fair levels of biochemical response and volume reduction are reported. Symptomatic relief can be achieved. Reported adverse effect is renal damage. Adequate renal protection should be added before treatment (Grade III. Recommendation C).

summary Summary of treatment for NET-hepatic metastasis is shown in Table 16.9.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 16.9 Summary of Treatment for NET-Hepatic Metastasis

Indication Hepatic resection (8,47–56,58,112) Hepatic artery occlusion HAE (17,55, 63–65,113) HACE (60,114–118)

Hepatic radiofrequency ablation (58,69,119,120)

Hepatic cryotherapy (74–76) Liver transplantation (47,54,57,78,86–91)

Tumor restricted to one lobe (1) Rapid enlargement of tumor mass, (2) Increasing symptoms, (3) Patient preference for the procedure in lieu of other treatment, (4) Patients with adequate liver function and patent portal vein (1) Fewer than 4 in number, (2) Smaller than 5cm, (3) Accessible location in liver, and (4) Not in contiguity to vascular structures, bowel, or the gall bladder Small lesions. Usually combined with hepatic resection Milan criteria. See Table 16.7.

●

●

●

●

● ●

●

3

92

36% at 5 years

41

73% at 5 years

67

3

0

49

15

5

75

72% at 5 years 29% at 5 years

24

20

38% at 1 year 5% at 5 years

5

0

82

NA

11

NA

48

23

0

95

32% at 3 years

10

91% at 3 years

45

56

10

100

21% at 5 years

25

47% at 5 years

55

Hormonal symptoms (carcinoid syndrome) and/or symptoms due to hepatic mass Laboratory investigations: CgA (blood) and 5-HIAA (urine) Identify the primary and metastatic sites by SSTR scintigraphy Assess the resectability of hepatic metastasis by CT or MRI

Surgical resection (curative or palliative) Other liver targeted therapy (HAE/HACE, RFA, and cryotherapy) Liver transplantation for selected unresectable patients SST analogues for symptomatic control Radionuclide therapy is emerging for the disseminated disease No proven survival benefit in chemotherapy

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Diseasespecific survival (months)

22

Treatment: ●

Diseasespecific survival (%)

Mortality (%)

Diagnosis:

●

Diseasefree survival (months)

Morbidity (%)

key points ●

Diseasefree survival (%)

Relief of symptoms (%)

14

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MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS 117. Bloomston M, Al-Saif O, Klemanski D, et al. Hepatic artery chemoembolization in 122 patients with metastatic carcinoid tumor: lessons learned. J Gastrointest Surg 2007; 11(3): 264–71. 118. Christante D, Pommier S, Givi B, et al. Hepatic artery chemoinfusion with chemoembolization for neuroendocrine cancer with progressive hepatic metastases despite octreotide therapy. Surgery 2008; 144(6): 885–93; discussion 893–4.

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17

Noncolorectal, nonneuroendocrine metastases C. Kahlert, R. DeMatteo, and J.Weitz

introduction

gynecological tumors

Approximately 90% of malignant hepatic lesions are metastases of extrahepatic primary tumors. Despite enormous progress of multimodal therapeutical options, surgical resection remains the only option for curative treatment in most of these cases. However, in contrast to colorectal or neuroendocrine hepatic metastases, the surgical approach for noncolorectal and nonneuroendocrine hepatic metastases is highly controversial. From a critical point of view, it is argued that noncolorectal, nonneuroendocrine liver metastases often belong to very aggressive types of cancer. In addition, they partly derive from extraabdominal primary tumors. In contrast to intraabdominal tumors metastasizing through the portal vein with the liver theoretically being the first filter organ, liver metastases of extraabdominal primary tumors imply a simultaneous systemic spread of tumor cells. However, resection of hepatic tumors can be accomplished safely with an appropriate risk of perioperative mortality and morbidity, and patients with favorable tumor biology might benefit from a surgical approach. Therefore, proper selected patients should be offered resection of noncolorectal, nonneuroendocrine liver metastases. Since noncolorectal, nonneuroendocrine hepatic metastases encompass a heterogeneous group of primary tumors, the management of these metastases needs to be discussed individually for each primary tumor type.

The most common gynecological types of cancer comprise of ovarian cancer, endometrial cancer, and cervical cancer. Ovarian cancer is the leading cause of tumor-related death among gynecological malignancies. Epithelial tumors are the most frequent, followed by sarcomas, germ cell and stromal tumors (10). These tumors commonly metastasize to the peritoneal cavity and lymph nodes, however, liver metastases are also a common site of systemic spread (10). Since there is an inverse correlation between the volume of the residual tumor and the overall patient survival, resection of liver metastases should be performed with optimal cytoreduction of extrahepatic lesions (11,12). By this, median overall survival can be prolonged significantly (11). Despite a significant decline of the incidence of uterine cancer for the last 70 years, it still remains the fourth most frequent tumor among women (1). Endometrial cancer usually metastasizes by lymphatic vessels. The most common sites for hematogenous dissemination are bone, lung, and liver (13). Recently, a multicenter study by Adam et al. reported that resection of uterine liver metastases resulted in a 5-year survival of 35% and a median overall survival of 32 months. Similar results were observed in smaller study by Kollmar et al. (14). Cervical cancer, similar to uterine cancer, spreads most frequently via the lymphatic system, whereas hematogenous dissemination is a rare event. This may explain why liver metastases occur only in 1.2% to 2.2% of the patients (15,16). Furthermore, in many cases, liver metastases are accompanied by uncontrolled locoregional disease or extrahepatic lesions (15). Only in 0.3% to 5% of cases, isolated liver metastases are found. Up to date, only a few case reports report data regarding liver resection in hepatic metastasized cervical cancer (17–19), proving the feasibility of hepatectomy in this tumor stage, but still lacking profound data regarding the medical benefit. In summary, as for other noncolorectal, nonneuroendocrine liver metastases, liver resection for hepatic lesions of gynecological tumors can be accomplished safely. For evaluating the benefit of a surgical intervention, more data should be acquired by further clinical studies. Despite the lack of more data, liver resection is offered to carefully selected patients with secondary liver disease of these types of cancer.

breast cancer Breast cancer is the most frequent malignant tumor and the second most common cause of cancer death in women (1). Patients with breast cancer rarely present with isolated liver metastases, in only 10% to 20% of metastatic breast cancer, metastases are restricted solely to the liver (2,3) (Fig. 17.1). Therefore, the risk of systemic tumor relapse after removal of liver metastases is high and ought to be accounted before a surgical liver resection is contemplated. Retrospective studies report a median survival between 36 and 63 months (4–6) ( Table 17.1) when patients underwent surgical treatment in addition to systemic chemotherapy. In contrast, in patients treated with chemotherapy alone, the median overall survival will rarely exceed two years (7). Predictive risk factors, which should be considered for selecting appropriate patients, are lymph node status, extensive hepatic lesions requiring a major resection (8), recurrence of liver metastases within one year after resection of the primary tumor (9), R2 resection, and failure to respond to preoperative chemotherapy (4). Applying these criteria on patients with breast cancer and isolated hepatic metastases enables to select a subset of patients where liver resection may improve progression-free and overall survival compared to systemic treatment alone.

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renal cell cancer Since 1950, the incidence of renal cell cancer (RCC) has more than doubled. Based on advances in renal imaging, improved staging, and refinement in surgical technique the 5-year survival has notably improved (20). The clinical outcome in early-stage RCC is excellent with a high probability of complete remission. However, since renal cell carcinoma is characterized by high resistance to chemotherapy, the median

NONCOLORECTAL, NONNEUROENDOCRINE METASTASES

Figure 17.1 Solitary liver metastases originating from breast cancer.

Table 17.1 Selected Retrospective Studies Reporting Clinical Outcome in Patients after Resection of Liver Metastases from Breast Cancer

Author

Year

Number of patients included

Caralt et al. (5) Adam et al. (4) Vlastos et al. (6)

2008 2006 2004

12 454 31

Median overall survival (months)

5-year survival

35.9 45 63

33% 41% 61%

Figure 17.2 Solitary liver metastases originating from renal cancer.

overall survival in metastatic disease remains still unsatisfactory. Even by introduction of immunotherapy and targeted therapy, median overall survival reaches approximately only two years (21), making systemic therapy a merely palliative approach. Resection of isolated liver metastases (4,22) (Fig.17.2) as well as other distant metastases of renal cell cancer (23,24) resulted in 5-year survival rates between 38% and 88%. Though the results of these retrospective studies are certainly influenced by a selection bias, they should be used to evaluate carefully whether in patients with metastatic renal cancer a complete surgical resection of the distant disease is possible. These patients will most likely benefit from a surgical approach if all disease can be resected. Whether the results of surgical resection can be further improved by a multimodal therapeutic regimen including immunotherapy and moleculary targeted therapy needs to be further evaluated.

pancreatic cancer Pancreatic cancer is one of the most aggressive tumors. It is the fourth leading cause of cancer death in females and the fifth leading cause in males worldwide (1). When pancreatic cancer is first diagnosed, the majority of patients are not amenable to surgical treatment according to the established standard criteria. Approximately only 15% to 25% of patients are eligible to curative operation procedures. One of the most frequent exclusion criteria for a curative surgical intervention is the presence of distant metastases, namely, liver metastases. In metastasized pancreatic cancer, palliative systemic chemotherapy is considered to provide the best therapeutical option. Yet, in many cases, R0 resection of liver metastases in addition to resection of the primary tumor would be technically feasible. By palliative systemic chemotherapy, median overall survival reaches approximately 6 months (25–27). The impact of a curative-intent surgical intervention is still unanswered. In several retrospective studies of resection of liver metastases of pancreatic cancer, the median overall survival ranges from 6 months to 20 months (4,19,28–37) (Table 17.2). In single cases, single patients have even survived longer than 5 years (30). Though, despite some encouraging results, the decision for the resection of pancreatic cancer liver metastases should be made on an individual basis where the patient is aware of a nonstandard treatment approach. Currently, resection of liver metastases is highly controversial and certainly far from being accepted by the medical community.

gastric cancer Table 17.2 Selected Retrospective Studies Reporting About Clinical Outcome in Patients after Resection of Liver Metastases from Pancreatic Cancer

Author

Year

Gleisner et al. (29) 2007 Shrikande et al. (28) 2006 Adam et al. (4) 2006

Number of patients included

Median overall survival

5-year survival

17 10 40

5.9 11.4 20

Not published Not published 25%

The incidence of gastric cancer has steadily decreased in Europe and the United States, however, it still remains the second most common cancer worldwide. For locally advanced gastric cancer, the overall survival has been improved by treating patients with perioperative chemotherapy (38). However, for gastric adenocarcinoma with distant metastases, overall survival is still not favorable. The presence of liver metastases (Fig. 17.3) is generally considered to define a noncurative state of the disease. Patients treated by palliative chemotherapy survive approximately 9 to 10 months on average

167

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS in two retrospective multicenter studies with an appropriate number of patients (4,49). In general, the histological type of these tumors was squamous cell carcinoma. The clinical outcome after hepatic resection was unfavorable with median overall survival of 16 and 18 months, respectively, and a 5-year survival below 20%. This may lead to the conclusion that for hepatic metastasized tumors of the lungs and the head and neck region, nonsurgical interventions should be favored for management of these patients. However, bearing in mind that surgical resection is the only hope for cure, patients should not be categorically excluded, but carefully evaluated for a surgical approach as an individual curative attempt.

sarcoma

Figure 17.3 Solitary liver metastases originating from gastric cancer.

Table 17.3 Selected Retrospective Studies Reporting about Clinical Outcome in Patients after Resection of Liver Metastases from Gastric Cancer

Author

Year

Koga et al. (41) Adam et al. (4) Ambiru et al. (46)

2007 2006 2001

Number Median of patients overall included survival 42 64 40

34 15 12

5-year survival Not published 27% 18%

(39,40). Retrospective studies, reporting outcome after hepatic resection as treatment for liver metastases of gastric adenocarcinoma, estimate the overall survival between 19 and 34 months (41–45) (Table 17.3). These numbers exceed the outcome of patients having merely received systemic chemotherapy. As each of these studies have included only a small number of patients probably affected by a selection bias, the data are still insufficient. To select patients with liver metastases of gastric cancer who might benefit from a surgical approach, different strategies have been implemented. Summarizing the available literature, resection of hepatic metastases seems to be associated with a better survival if solitary or metachronous lesions are being resected. As in many other tumor types, patient selection therefore seems to be the most important factor ensuring a benefit for the patients undergoing liver resection for liver metastases of gastric cancer.

respiratory tract⁄head and neck tumors Both tumors deriving from the lungs and from the head and neck regions are usually associated with poor prognosis in the presence of distant metastases. Therefore, albeit tumors from these sites often form liver metastases (46–48), only recently the impact of surgical resection has been documented

168

For surgical evaluation, liver metastases originating from sarcomas can be divided into two subtypes: gastrointestinal stromal tumors and non-GIST sarcomas. Gastrointestinal stromal tumors emerge most often in the stomach, second most in the small bowl and in the colon and most rarely in the duodenum, the esophagus or nonintestinal organs (50). Almost half of the patients suffer from distant metastases and in more than 50%, the metastatic disease is isolated to the liver (51). One decade ago, a large retrospective study regarding hepatic resection for GIST metastatic to the liver reported about a median overall survival of 39 months and 5-year survival of 30% (52). Since the introduction of imatinib mesylate in the therapy of GIST (53), the oncological management has changed in favor of a multimodal treatment, improving the patient outcomes significantly. In recent retrospective studies including patients treated with imatinib mesylate, the 5-year survival was 70% (4) and median overall survival was not reached despite long periods of followup (54) (Table 17.4). However, DeMatteo et al. and Gronchi et al. observed in two retrospective studies that mainly patients with metastatic GIST responding to a preoperative tyrosine kinase inhibitor therapy profit by a surgical approach whereas nonresponder do not seem to benefit by tumor resection (55,56). These data should be taken into account when selecting appropriate patients for surgery with liver metastases of gastrointestinal stromal tumors. In summary, gastrointestinal stromal tumors metastatic to the liver require interdisciplinary therapy regimens. Besides to surgical resection, this should involve application of new medical agents such as imatinib or radiofrequency ablation for small lesions not accessible to surgical resection (54,57). Non-GIST sarcomas have a worse prognosis than gastrointestinal stromal tumors. While extremity and trunk soft tissue sarcomas most frequently metastasize to the lung, primary visceral and retroperitoneal sarcomas often disseminate to the liver (51) (Fig. 17.4). After surgical resection of liver metastases, patients have a median overall survival of 32 to 37 months and 5-year survival probability of 27% to 32% (4,54) (Table 17.4). These data demonstrate that most patients with hepatic metastases of sarcomas will succumb to their disease. Patients with a disease-free interval exceeding two years, however, seem to have a better prognosis after hepatic resection (52). These data again point to the fact that selected patients should be offered

NONCOLORECTAL, NONNEUROENDOCRINE METASTASES Table 17.4 Selected Retrospective Studies Reporting about Clinical Outcome in Patients after Resection of Liver Metastases from GIST- And Non-GIST Sarcoma Author

Year

Adam et al. (4)

2006

Pawlik et al. (54)

2006

DeMatteo et al. (52)

2001

Histological type

Number of patients included

Median overall survival (months)

33 125 54 12 34 22

Not reached 32 Not reached 37

70% 31% Ca. 50% No survivor after 5 years

39*

30%*

GIST Non-GIST sarcoma GIST and leiomyosarcoma Non-GIST sarcoma GIST Non-GIST sarcoma

5-year survival

*Including patients with GIST- and non-GIST sarcoma.

Figure 17.4 Solitary liver metastases originating from a non-GIST-sarcoma.

resection of liver metastases, as they most likely will benefit from this treatment.

melanoma Melanomas belong to the most frequent types of tumors with an increasing incidence over the last 30 years. Of the melanomas, 90% derive from the skin, 5% have an ocular origin, and 5% develop at other sites (58). Noteworthy, depending on the primary site, melanomas display a different metastasizing pattern. Cutaneous melanomas disseminate to the liver only in 15% to 20% of patients with metastatic disease (Fig. 17.5). This often happens with simultaneous metastatic decay of other organs (59). By contrast, in 40% of patients with liver metastases from uveal melanoma, the liver is the only site of the disease (60). Therefore, the number of liver metastases resected from uveal melanoma is nearly equivalent to that of cutaneous melanoma. While excision of early stage melanoma results in an excellent prognosis, chemotherapy achieves barely a median overall survival of 12 months in disseminated tumor stage (60,61). Hence, surgical resection of metastases offers the only chance for cure. However, patients amenable to a surgical intervention at the liver account for approximately only 2% to 3% of all patients representing with liver metastases of melanoma (62,63). In these cases, the median overall survival is estimated to be between 19 and 28 months and the median 5-year survival reaches 20% (4,49,62) (Table 17.5). This may justify the

Figure 17.5 Solitary liver metastases originating from cutaneous melanoma.

resection of liver metastases from cutaneous or uveal melanoma in individual patients.

predictive factors determining clinical outcome For a successful preoperative assessment, several predictive factors can be taken into account to decide whether a patient with noncolorectal, nonneuroendocrine hepatic metastases might benefit from surgical resection. Several studies examined factors associated with improved survival after resection of noncolorectal, nonneuroendocrine liver metastases. In the study of Weitz et al. (19), 141 patients undergoing hepatic resection between April 1981 and April 2002 were analyzed, length of disease-free interval, primary tumor type, and completeness of resection were independent prognostic factors regarding cancer-specific survival (Table 17.6). Adam et al. analyzed the outcome of 1452 patients from 41 centers undergoing hepatectomy between 1983 and 2004. The majority of primary tumors were breast cancer (32%), gastrointestinal cancers (16%), and urologic cancers (14%). Five-year overall survival for the entire cohort of patients was

169

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 17.5 Selected Retrospective Studies Reporting About Clinical Outcome in Patients After Resection of Liver Metastases from Cutaneous and Ocular Melanoma Author

Year

Site of melanoma

Number of patients included

Median overall survival (months)

5-year survival

Pawlik et al. (49)

2006

Herman et al. (62)

2001

Cutaneous Ocular Cutaneous

24 16 5

24 29 22*

No survivor 20% 70%†

*Including patients with both cutaneous and ocular melanoma. † Within a mean follow-up of 25.4 months.

Table 17.6 Analysis of Prognostic Factors for Cancer-Specific Survival

Gender Age (years)

Male Female ≤50 >50 Synchronous (1) Metachronous ≤24 mo

Presentation Disease-free interval

>24 mo Adrenocortical Breast Gastrointestinal Reproductive tract Melanoma Renal Other Unknown

Primary minor

Primary tumor

Reproductive tract Nonreproductive tract Yes No Yes No ≤5 cm >5 cm I >l Unilobar Bi lobar RO Rl R2 Minor major*

Prior metastases* Extrahepatic disease Size Number Distribution Margin status

Resection type Blood transfusion Postoperative complies (1)

Lions

Yes No Yes No

Multivariate

Median CSS

Hazard Ratio

No.

(mo)

p-Value

48 93 55 86

52 40 42 41 37 48

NS NS

34

0.04

39 102 71 70 15 29 12

52 40 48 21

39 17 II 13 5 39 102

115 17 48 32 11 115 36

24 117 41 100

48 40 42 46 42 37 49 34 46 40 49 17 10 40 52 52 37 40 49

88 53 88 53 100 41 116 19 6 65 76 79 62 46 95

Source: From Ref. (19). *Major liver resection: resection of 3 or more liver segments. Prior extrahepatic metastases. Presentation of the liver metastases: the same time as the primary tumor. CSS indicates cancer-specific survival; CI, confidence interval; NS, not significant.

170

Univariate

(95% CI)

p-Value

1.4(1.0–1.8)

0.03

NS

0.0!

Reference 0.7(0.4–1.3) 1.0(0.6–1.7) 0.8 (0.3–1.5)

0.02

0.4 (0.2–0.7) 1.5(0.7–2.7) 0.7 (0.3–1.3) 1.7(0.3–1.3) Reference 0.02

NS NS NS NS NS <0.0I

NS NS NS

Reference 2.1 (1.1–4.1) 2.7 (0.8–7.9)

<0.01

NONCOLORECTAL, NONNEUROENDOCRINE METASTASES 36% and the 10-year overall survival of 23%. The following independent adverse prognostic factors could be identified: patient age over 60 years, nonbreast origin, melanoma or squamous histology, disease-free interval of less than 12 months, extrahepatic disease, incomplete macroscopic resection, and major hepatectomy. The authors went on to stratify patients according to the number of adverse prognostic factors present and stratified them into low-risk patients (0–3 points, 5-year survival: 46%), mid-risk patients (4–6 points, 5-year survival: 33%), and high-risk patients (>6 points, 5-year survival of less than 10%). This model may help to guide the decision regarding the best approach to patients with noncolorectal, nonneuroendocrine liver metastases.

summary Resection of noncolorectal, nonneuroendocrine liver metastases is associated with an improved progression-free and overall survival in a selected subgroup of patients. However, until now, these data have been mainly obtained by retrospective studies and probably are affected by selection bias, as patients with lower performance status and poorer prognosis are less likely to have undergone surgery. Due to these limitations, a conclusion regarding a direct comparison to nonsurgical approaches cannot be drawn. Each individual case needs to be carefully assessed prior to a decision regarding a surgical approach. Furthermore, to reduce the risks of postoperative morbidity and mortality, it is recommendable to perform the surgical intervention on the liver at high-volume centers (64).

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18

Chemotherapy-associated hepatotoxicity Martin Palavecino, Daria Zorzi, and Jean-Nicolas Vauthey

introduction Hepatic resection is the only therapy that offers a chance for cure in patients with colorectal liver metastases, but only 20% of the patients are candidates for resection at the time of diagnosis (1–3). For those patients who are resected, the 5-year survival has been reported up to 58% (4–8). After hepatic resection, the majority of patients will develop recurrence within the liver with or without extrahepatic metastases. Systemic chemotherapy has been used preoperatively (9) or as an adjuvant therapy after surgery to decrease the risk of disease recurrence (10). During the last decade, an increasing number of new therapeutic agents has been developed to improve the response rates of the existing drugs (Fig. 18.1). Initially, 5-fluorouracil (5-FU)-based chemotherapy had a 20% response rate with a modest improvement in survival (11). Capecitabine was introduced as an oral alternative to intravenous 5-FU. The addition of oxaliplatin and irinotecan in combination with 5-FU increased the response rate to 50% and the conversion of unresectable metastases to resectable was subsequently reported in up to 38% of patients (12,13). Most recently, bevacizumab and cetuximab, antibodies vascular endothelial growth factor and an antiepidermal growth factor receptor, respectively, have been associated with response rates of up to 70%, when combined with standard chemotherapy (14). The rationale for preoperative chemotherapy includes (i) the downsizing of metastases, thus decreasing the amount of resected parenchyma and increasing the rate of curative resection; (ii) the identification of patients who will not benefit from surgical resection due to disease progression during chemotherapy; (iii) the early treatment of micrometastases (8–10). Nordlinger et al. (15) reported the results of a multicentric randomized controlled trial (EORTC Intergroup trial 40983), evaluating the outcome of patients with resectable colorectal liver metastases (no more than four metastases, no extrahepatic disease) with two arms: surgery alone versus six cycles of FOLFOX4 before and after surgery. The trial showed an increased progression-free survival at 3 years of 8.1% (from 28.1% to 36.2%, p = 0.041) in all eligible patients; and 9.2% (from 33.2% to 42.4%, p = 0.025) in all patients undergoing resection (15). Clinical and pathological studies have established associations between specific chemotherapeutic agents and histologic changes in the liver. Current evidence suggests there are two broad categories of chemotherapy-induced liver injury: nonalcoholic fatty liver disease (NAFLD), including steatosis and steatohepatitis, and sinusoidal obstruction syndrome (9) (Figs. 18.2 and 18.3). The use of sequential or combined treatments may result in mixed patterns of injuries. The objective of the present chapter is to summarize the changes induced in the liver parenchyma by chemotherapy and its effects on surgical outcomes.

chemotherapy-associated nonalcoholic fatty liver disease Nonalcoholic fatty liver disease (NAFLD) encompasses different types of pathological changes in the liver, ranging from steatosis to steatohepatitis. NAFLD affects up to 24% of the general population and increases to 75% in patients with a body mass index equal or greater to 30 kg/m2 (16). Usually, NAFLD is asymptomatic, but it may progress to cirrhosis and develop hepatocellular carcinoma in later stages of disease (17,18). The diagnosis of NAFLD can be suspected by laboratory routine tests and imaging findings. However, the gold standard diagnostic method is the histological assessment of the liver. Steatosis is defined as the fat accumulation in the hepatocytes. It can be graded according to the percentage of affected cells (mild when less than 30% of the hepatocytes are involved, moderate with involvement of 30% to 60% of the hepatocytes, and severe with >60% hepatocytes involved). Steatohepatitis is defined as steatosis associated with inflammation (neutrophilic portal and lobular infiltration, perisinusoidal fibrosis, hepatocellular ballooning, glycogenated nuclei) (8). Kleiner et al. proposed a score based on three features (steatosis, lobular inflammation, and ballooning) evaluated semiquantitatively. A Kleiner score of 5 or greater correlates with a diagnosis of steatohepatitis, while a score of 3 or 4 is considered borderline (19). Steatosis Different chemotherapeutic regimens, such as intraarterial floxuridine (20), 5-FU and folinic acid (21), interferon α and 5-FU (22), 5-FU, and levamisole (23) were reported to induce steatosis. However, none of these early studies reported the effects of steatosis on surgical outcomes (8). In 1998, Behrns et al. (24) evaluated outcomes after major hepatectomy in patients with steatosis. The authors found that patients with moderate to severe steatosis (>30%) had a higher BMI, longer operative times, and higher rates of postoperative morbidity, mortality, and intraoperative blood transfusion. Similarly, Kooby et al. (25) analyzed a cohort of patients with steatosis who underwent liver resection. Steatosis was associated with infectious complications but not with major complications or postoperative mortality. Two studies were carried out at The University of Texas M.D. Anderson Cancer Center. The first showed an increased rate of steatosis in patients treated with irinotecan, but Parikh et al. found no increased mortality in patient with steatosis, even when severe (26). In the second study, Vauthey et al. (9) studied 406 resected patients using the Kleiner’s score (19), and no agent was found to be associated with steatosis and there was no increased postoperative morbidity or mortality rate (Table 18.1). However, many patients with steatosis have other

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS comorbid conditions, such as obesity and diabetes that can increase the risk of complications. In a recent study of patients who underwent major hepatectomy, patients with steatosis had increased blood loss, morbidity, and intensive care unit stays compared to matched control patients with normal livers (27). The prevalence of obesity (BMI ≥ 30 kg/m2) was 26% in the steatotic patients compared with 2% in controls, which may have contributed to the poorer outcome in steatotic patients. Steatohepatitis An increased rate of steatohepatitis in patients undergoing preoperative chemotherapy was first observed by Fernandez et al. (28). Multivariate analysis showed that treatment with irinotecan or oxaliplatin and high BMI were independent risk

1980

1985

1990

1995

2000

2005

5-FU

RR% Median survival (months)

Capecitabine

20–25

13

Irinotecan Oxaliplatin

~55

20–22

~70

>24?

Cetuximab Bevacizumab

Figure 18.1 During the last 10 years, several new drugs were incorporated to the armamentarium for the treatment of colorectal liver metastases. 5-FU, 5-fluorouracil; RR, response rate. Source: Modified from Ref. (33).

factors for steatohepatitis. In the previously mentioned study, Vauthey et al. (9) analyzed the relationship between preoperative chemotherapy and liver injury. Using the Kleiner’s score (19), 8% of the patients had steatohepatitis. Steatohepatitis rate was higher in those patients treated with irinotecan-based chemotherapy (20% vs. 4%, p < 0.001). The incidence of steatohepatitis was higher in patients with BMI higher than 25 kg/m2. The 90-day mortality rate for patients with steatohepatitis was 15%, compared to 2% for patients without steatohepatitis (p = 0.001). The main cause of death was liver failure. The conclusion of the study was to cautiously use irinotecan in patients with BMI higher than 25 kg/m2, especially in patients undergoing major hepatic resections (Table 18.1). Unlike simple steatosis, which does not significantly impact postoperative outcome, steatohepatitis is an ominous finding and a relative contraindication to major liver resection. Given the associations between irinotecan, steatohepatitis, and increased postoperative mortality, major hepatic resection should probably not be performed in patients with known steatohepatitis, and irinotecan should be avoided in patients with known steatosis or steatohepatitis or the features of metabolic syndrome if major hepatic resection is anticipated. Sinusoidal obstruction syndrome The association between sinusoidal obstruction syndrome and oxaliplatin-based chemotherapy was first described by Rubbia-Brandt et al. (29) in 2004. Changes associated with

(A)

(B)

(C)

(D)

Figure 18.2 Nonalcoholic fatty liver disease (NAFLD). (A) Macroscopic view of a fatty liver (yellow liver). (B) Pathology specimen showing the aspect of a fatty liver. (C) Microscopic view of a simple steatosis: accumulation of large globules of fat in the cells. (D) Microscopic view of steatohepatitis: different degrees of inflammation in the field (ballooned and apoptotic cells). Source: Modified from Ref. (8).

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CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY

(A)

(B)

(C)

Figure 18.3 Sinusoidal obstruction syndrome. (A) Macroscopic view of a liver with oxaliplatin-related sinusoidal injury (blue liver). (B) Pathology specimen showing the aspect of a liver with sinusoidal injury. (C) Microscopic view of sinusoidal injury: centrilobular sinusoidal dilatation with scattered macrovesicular steatosis. Source: Modified from Ref. (8).

Table 18.1 Published Data on Chemotherapy-Associated Hepatotoxicity and Its Effect on Postoperative Outcomes Author, year Behrns, 1998 (24) Kooby, 2003 (25) Parikh, 2003 (26) Fernandez, 2005(28) Karoui, 2006(39) Vauthey, 2006 (9) Nordlinger, 2008(15) Nakano, 2008(40) Reddy, 2008 (44)

Number of patients 135 325 chemo, 160 controls 61 chemo, 47 controls 37 45 chemo, 22 controls 248 chemo, 158 controls 151 chemo, 152 controls 36 chemo 39 chemo, 57 controls

Major hepatectomy 100% 69% chemo, 63% controls 100% 49% 100% 68% N/A 100% 69%

Drugs

Type of liver injury

Morbidity

Mortality

5-FU ± irinotecan

Steatosis Steatosis

NS Higher

NS NS

5-FU ± irinotecan

Steatosis

NS

NS

5-FU ± irinotecan/ oxaliplatin 5-FU ± irinotecan/ oxaliplatin 5-FU ± irinotecan 5-FU ± oxaliplatin 5-FU ± oxaliplatin

Steatohepatitis

N/A

N/A

Sinusoidal injury

Higher

NS

Steatohepatitis Sinusoidal injury N/A

NS NS Higher

NS+ NS NS

Sinusoidal injury N/A

Higher NS

N/A NS

5-FU ± oxaliplatin Bevacizumab + oxaliplatin

Source: Modified from Ref. (45). NS, not significant; chemo, chemotherapy; 5-FU, 5-fluorouracil; N/A, not available. + Subset of patients with steatohepatitis had increase 90-day mortality.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS sinusoidal injury (dilation and congestion, venous occlusion, and fibrosis) were in found in 78% of patients treated with oxaliplatin. This study did not analyze the effects of the injury on outcomes after resection. The association between oxaliplatin and sinusoidal injury has been confirmed in other studies, in which the incidence of sinusoidal injury in patients treated with oxaliplatin ranges from 19% to 52%. In the study by Vauthey et al. (9), the incidence of sinusoidal dilatation was higher in those patients with oxaliplatin-based chemotherapy compared to patients with other chemotherapy regimen (19% vs. 2%, p < 0.001). The analysis also demonstrated that oxaliplatinbased chemotherapy for a median of 12 weeks preoperatively was not associated with increased morbidity or mortality after surgery. Likewise, the pathological findings of sinusoidal injury itself were not associated with an increased rate of perioperative complications. In patients receiving preoperative 5-FU ± oxaliplatin, Aloia et al. (30) found severe forms of vascular alterations, specifically hemorrhagic centrilobular necrosis and regenerative nodular hyperplasia in patients treated for greater than 6 months preoperatively (12 cycles). In these patients, a higher rate of preoperative blood transfusions was noted. The EORTC Intergroup trial 40983 showed an increase in postoperative complications with perioperative chemotherapy with oxaliplatin plus surgery compared to surgery alone (26% vs. 16%, respectively, p = .04). However, this complication rate of 26% for combined chemotherapy and surgery compares favorably with the 36% complication rate previously reported for resection without preoperative chemotherapy in single center studies (31). Of note, in the surgery only arm of the EORTC Intergroup Trial 40983, 18 patients (11%) underwent an unnecessary laparotomy (open and close) compared to only 8 patients (5%) in the perioperative chemotherapy arm. If the total open and close is added to the total complications in each arm of the study, the difference between the two arms becomes nonsignificant for all unfavorable events (surgical complications plus open and close) in the comparison between perioperative chemotherapy plus surgery versus surgery alone (30% vs. 26%, p = 0.5). Taken together, limited preoperative chemotherapy (four to six cycles preoperatively) remains a valid option and is used at major centers in patients with resectable and unresectable liver metastases. Short-course preoperative chemotherapy is currently used at our institution in most patients with colorectal liver metastases considered for resection (Fig. 18.4) (32).

the effects of monoclonal antibodies Targeted biologic agents are increasingly being used for the systemic treatment of colorectal liver metastases. In the past 5 years, bevacizumab and cetuximab were approved by the Food and Drug Administration for the treatment of colorectal liver metastases (33). Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF). D’Angelica et al. (34) studied the effects of bevacizumab on outcomes after liver surgery. The authors compared patients who underwent surgery with or without preoperative bevacizumab. They found no increase in morbidity and suggested a waiting time of 6 to 8 weeks between the last dose of bevacizumab and

176

Diagnosis of colorectal liver metastasis

Resectable Preoperative therapy 2–3 months

Unresectable

Resectable

First-line chemotherapy re-evaluate 2–3 months

Hepatectomy (one-stage or two-stage) ± PVE*

Second-line chemotherapy

Postoperative therapy 3–4 months

Third-line chemotherapy

Figure 18.4 Treatment recommendation for liver metastases of colorectal cancer. Source: Adapted from Ref. (32).

surgery. More recently, a study by Gruenberger et al. provided evidence to suggest that this interval may be shortened to 5 weeks without increase in perioperative complications (35). Ribero et al. (36) analyzed the effect of bevacizumab in patients receiving oxaliplatin-based chemotherapy. The response to therapy was measured with the percentage of viable cells in the surgical specimen. Patients who received preoperative bevacizumab had a significant lower rate of viable cells compared to those patients who did not receive preoperative bevacizumab (33% vs. 45%, p = 0.02). The incidence and severity of sinusoidal injury were lower in patients receiving preoperative bevacizumab (27% vs. 54%, p = 0.006). The antiangiogenic effects of bevacizumab have raised concerns regarding potential effects on bleeding, wound healing, and liver regeneration. A study from the MDACC reported that the addition of bevacizumab to chemotherapy before portal vein embolization did not impair liver regeneration (37). Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR). No specific liver injury has been so far identified and related to the preoperative administration of cetuximab. Preclinical data in animal models investigated the effects of anti-EGFR antibodies after partial hepatectomy in mice and found that their blockade does not impair liver regeneration (38). Future investigations are needed to further study possible specific histologic changes in the liver in patients treated with biologic agents.

diagnosis Liver function tests cannot be used to assess chemotherapyassociated liver injury, since many patients have normal laboratory values despite significant hepatic injury. A heightened index of suspicion for chemotherapy-associated hepatic injury is necessary in patients at risk for NAFLD due to obesity, diabetes, or hyperlipidemia, as well as patients who have received prolonged courses of chemotherapy. Computed tomography can identify patients with fatty infiltration by determining the density of the liver compared to the spleen (at least 10 Hounsfield units lower than the spleen). Magnetic resonance

CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY imaging (MRI) accurately predicts steatosis on the basis of signal differences between fat and water. However, modern imaging methods cannot differentiate between steatosis and steatohepatitis. For these reasons, liver biopsy is the gold standard diagnostic procedure to confirm liver injury. Percutaneous liver biopsy may be associated with false-negative results, due to the patchy distribution of the injuries. To overcome this issue, laparoscopy with direct inspection and core biopsy may be an alternative to image-guided percutaneous biopsy in patients suspected of chemotherapy-associated liver injury, especially in those patients who are candidates for major hepatic resection. Grossly, sinusoidal injury results in the so-called blue liver syndrome, characterized by a bluish, edematous, spongiform appearance and consistency (Fig. 18.3), while steatosis results in a yellow liver (Fig. 18.2).

prevention Several issues should be taken into account to prevent chemotherapy-associated liver injuries. First of all, prolonged unnecessary courses of preoperative chemotherapy should be avoided. Different studies demonstrated that hepatotoxicity is strongly related to chemotherapy duration. Karoui et al. (39) analyzed two groups of patients who underwent liver resection with or without chemotherapy (5-FU ± irinotecan/oxaliplatin). In the chemotherapy group, five patients developed liver insufficiency versus none in the control group. Morbidity was higher in patients who received at least six cycles of chemotherapy compared to those who received five cycles or less (54% vs. 19%, p = 0.047). In another study, Aloia et al. (30) concluded that patients who received more than 12 cycles of oxaliplatin-based chemotherapy had a higher rate of reoperations and a longer length of stay compared to patients who received 12 or fewer cycles. The optimal duration of preoperative chemotherapy to maximize therapeutic benefit, while avoiding hepatotoxicity, is likely up to 4 months (i.e., 8 cycles). In the study from MDACC, patients received relatively short-course oxaliplatin for 3 to 4 months, which was not associated with increased morbidity or mortality after hepatic resection (9). Another issue to be considered is the duration of the interval between chemotherapy and liver resection. Several studies show that a longer interval between chemotherapy and hepatic resection for CLM reduces hepatotoxicity and surgical complications. However, this interval should be balanced with the risk of tumor progression during the treatment-free interval. In the European trial, Nordlinger et al. (15) reported an interval between the last dose of chemotherapy and liver resection (in the chemotherapy arm) of 2 to 5 weeks. Nakano et al. (40) observed a mean interval between the last chemotherapy and surgery of 6.5 months in patients without sinusoidal injury compared to 3.6 months in patients with sinusoidal injury. Welsh et al. (41) observed a morbidity rate of 2.6%, 5.5%, and 11% when the intervals between the last chemotherapy and surgery was 9 to 12 weeks, 5 to 8 weeks, and ≤5 weeks, respectively (p = 0.009). In patients with suspected chemotherapy-associated liver injury, the functional future liver remnant should be assessed prior to major liver resection to minimize postoperative complications. The future liver remnant (FLR) can be assessed using three-dimensional contrast-enhanced computed

tomography. Briefly, the contours of the FLR are delineated on the screen, and volume is calculated by adding each slice’s volume, determined by the surface area, slice thickness, and space between slices (42). To calculate the total liver volume, Vauthey et al. (42) determine a formula based on body surface area. The estimated liver volume is calculated using the following formula: total liver volume = –794.41 + 1267.28 × body surface area. The ratio of the FLR to total estimated liver volume is defined as the standardized FLR (sFLR), which has been shown to reflect the function of the remnant liver and correlate with surgical outcome. When the sFLR is predicted to be insufficient for safe hepatic resection, portal vein embolization (PVE) is a strategy to induce hypertrophy of the FLR (42). In normal livers, if the standardized future liver remnant is ≤20% of total liver volume, portal vein embolization (PVE) should be considered. In patients who received extensive chemotherapy, preoperative PVE should be considered when the standardized future liver remnant is ≤30% of total liver volume (13). In this context, PVE is used as a procedure to test the capacity of the injured liver to regenerate. In a study by Ribero et al. (36), a degree of hypertrophy (DH = sFLR post-PVE – sFLR pre-PVE) ≤ 5% predicted the occurrence of postoperative complications, either overall, liver-related complications, or liver dysfunction. Patients with significant chemotherapyassociated liver injury who have inadequate liver hypertrophy after a technically successful PVE are not candidates for a major liver resection. Another strategy for patients with chemotherapy-associated hepatotoxicity to undergo complete resection of metastases is two-stage liver resection. This approach allows resection in patients with extensive bilateral liver metastases that have responded or remain stable on chemotherapy. In the first stage, metastases in the FLR are removed with a minor resection. After the first surgery, the hepatic regenerative capacity is assessed and PVE should be performed, if the sFLR is insufficient. After adequate regeneration, a second-stage major resection is performed up to 8 weeks after PVE. In a study from MDACC, using this approach, in patients with a median of seven liver metastases, the 3-year overall and disease-free survival rates were 86% and 51%, respectively, after perioperative chemotherapy and two-stage hepatectomy (43).

summary During the last decade, several new chemotherapeutics agents were introduced in the armamentarium for the treatment of colorectal liver metastases. These new drugs were used as adjuvant treatment as well as preoperative treatment before liver resection. The rationale for preoperative chemotherapy is as follows: ●

●

●

To increase resectability in patients initially deemed unresectable, by downsizing the metastases To improve progression-free survival in patients with resectable metastases, when compared to surgery alone To select patients who may not benefit from surgery due to tumor progression while on chemotherapy.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS However, preoperative treatment may increase the incidence of chemotherapy-associated hepatotoxicity, including steatosis, steatohepatitis, and sinusoidal injury. Each injury has been associated with the use of specific agents, such as steatohepatitis in patients who received irinotecan-based chemotherapy and sinusoidal injury in patients who received oxaliplatin-based chemotherapy. Steatohepatitis is associated with increased risk of mortality due to liver failure and represents a relative contraindication to major hepatic resection. Significant sinusoidal injury with fibrosis and regenerative nodular hyperplasia may increase the risk of bleeding from liver resection, but no increased mortality was associated with sinusoidal injury and oxaliplatin. Preoperative chemotherapy should be administrated only in short courses. Several studies suggested limiting the use of chemotherapy to less than 4 months. In patients receiving bevacizumab, the period between the last dose of the drug and surgery should be at least 5 weeks. Before liver surgery, the future liver remnant should be assessed. In patients who have received prolonged chemotherapy, PVE is indicated if the standardized future liver remnant is ≤30%. Preoperative chemotherapy should be coordinated by a multidisciplinary team and should be adjusted according to patient, tumor, and liver characteristics.

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14. Adam R, Aloia T, Levi F, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol 2007; 25: 4593–602. 15. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008; 371: 1007–16. 16. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346: 1221–31. 17. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129: 113–21. 18. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123: 134–40. 19. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313–21. 20. Zeiss J, Merrick HW, Savolaine ER, et al. Fatty liver change as a result of hepatic artery infusion chemotherapy. Am J Clin Oncol 1990; 13: 156–60. 21. Peppercorn PD, Reznek RH, Wilson P, Slevin ML, Gupta RK. Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer. Br J Cancer 1998; 77: 2008–11. 22. Sorensen P, Edal AL, Madsen EL, Fenger C, Poulsen MR, Petersen OF. Reversible hepatic steatosis in patients treated with interferon alfa-2a and 5-fluorouracil. Cancer 1995; 75: 2592–6. 23. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA. Hepatic toxicity associated with fluorouracil plus levamisole adjuvant therapy. J Clin Oncol 1993; 11: 2386–90. 24. Behrns KE, Tsiotos GG, DeSouza NF, et al. Hepatic steatosis as a potential risk factor for major hepatic resection. J Gastrointest Surg 1998; 2: 292–8. 25. Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg 2003; 7: 1034–44. 26. Parikh AA, Gentner B, Wu TT, et al. Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg 2003; 7: 1082–8. 27. McCormack L, Petrowsky H, Jochum W, Furrer K, Clavien PA. Hepatic steatosis is a risk factor for postoperative complications after major hepatectomy: a matched case-control study. Ann Surg 2007; 245: 923–30. 28. Fernandez FG, Ritter J, Goodwin JW, et al. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 2005; 200: 845–53. 29. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004; 15: 460–6. 30. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006; 24: 4983–90. 31. Metreveli RE, Sahm K, Denstman F, Abdel-Misih R, Petrelli NJ. Hepatic resection at a major community-based teaching hospital can result in good outcome. Ann Surg Oncol 2005; 12: 133–7. 32. Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic metastases. Lancet 2008; 371: 963–5. 33. Chun YS, Vauthey JN. Extending the frontiers of resectability in advanced colorectal cancer. Eur J Surg Oncol 2007; 33 Suppl 2: S52–8. 34. D’Angelica M, Kornprat P, Gonen M, et al. Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case-control study. Ann Surg Oncol 2007; 14: 759–65. 35. Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008; 26: 1830–5. 36. Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with

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41. Welsh FK, Tilney HS, Tekkis PP, John TG, Rees M. Safe liver resection following chemotherapy for colorectal metastases is a matter of timing. Br J Cancer 2007; 96: 1037–42. 42. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area and body weight predict total liver volume in Western adults. Liver Transpl 2002; 8: 233–40. 43. Chun YS, Vauthey JN, Ribero D, et al. Systemic chemotherapy and twostage hepatectomy for extensive bilateral colorectal liver metastases: perioperative safety and survival. J Gastrointest Surg 2007; 11: 1498–1504. 44. Reddy SK, Morse MA, Hurwitz HI, et al. Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg 2008; 206: 96–106. 45. Chun YS, Laurent A, Maru D, Vauthey JN. Management of chemotherapyassociated hepatotoxicity in colorectal liver metastases. Lancet Oncol 2009; 278–86.

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19

Thermal ablation of liver metastases Samir Pathak and Graeme J. Poston

introduction Colorectal cancer is a common malignancy and as many as 25% of patients will have liver metastasis (CRLM) at presentation and a further 20% to 30% will develop metachronous disease following colorectal surgery (1). The vast majority of disease-related deaths are due to metastatic disease. In metastatic disease the median length of survival without treatment is approximately between 5 and 12 months (2). Currently hepatic resection is established as the treatment modality of choice for colorectal liver metastases (CRLM) with 5-year survival rates of up to 60% being reported by some groups (3–6). Unfortunately at the time of presentation only 20% to 30% are deemed suitable to resection because of tumor location, number of metastases, other comorbidities, and lack of hepatic reserve (7). Consequently, in recent times there has been considerable interest in the use of oxaliplatin-based neoadjuvant therapy to reduce tumor burden, so increasing the probability of achieving a curative resection and hence improve overall disease-free survival. Even patients who initially had unresectable hepatic disease may respond to chemotherapy and become resectable (8). However, despite a more aggressive approach to surgical resection and the use of combination regimens of highly active chemotherapy drugs, a significant proportion of patients are still not eligible for resection. Additionally, the high rate of recurrence seen in the liver, affecting 53% to 68% of patients requiring repeat resections can only be tolerated by a subset of patients (9). Hence, recently there has been considerable interest in thermoablative techniques and their potential role in the management of CRLM. Ablative technologies involve the delivery of localized treatment via open, laparoscopic, or percutaneous route. Theoretical advantages include less physiological stress, making treatments suitable for patients who may not otherwise be appropriate for formal resection. The potential for either percutaneous or laparoscopic approach offers an alternative for patients unfit or unwilling to undergo major abdominal surgery and general anaesthesia (9–13). Formal resection is guided by vasculobiliary anatomy, with significant amounts of healthy parenchyma being removed along with disease. Targeted ablations minimize the removal of healthy parenchyma, making it useful in patients with borderline parenchymal volume and function. Anatomically difficult lesions may not be amenable to formal resection, but accessible by probe ablation. Ablation can also be performed as an adjunct to surgical resection in patients with bilobar disease, where patients have the majority of their tumor burden formally resected with remnant disease burden being ablated. However, there remains a need for more long-term survival data regarding ablative therapies. There have been no randomized control trials comparing any ablative therapy to resections in patients who would be candidates for either therapy or

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comparing ablative techniques against each other, and only one trial has shown survival superiority of ablation combined with chemotherapy over chemotherapy alone in liver only disease (see later). This chapter aims to detail the mechanism of action of the various ablative therapies available, and also to review the available literature regarding the implementation of these techniques.

limitations of the literature Apart from the European CLOCC Study (EORTC 40004) (see later), there are no published randomized controlled trials (RCTs) comparing the use of radiofrequency ablation (RFA), ethanol ablation, or cryoablation with hepatectomy in the treatment of colorectal liver metastases. Furthermore, there is only one study comparing microwave ablation (MCT) with partial hepatectomy for the treatment of CRLM (14). Therefore the majority of the data reviewed come from single-arm, retrospective, and prospective single-center studies. The results derived from each study must be viewed with caution as the number and ethnicity of patients in each study varied greatly (e.g., studies from Japan vs. Western populations). Possible selection bias and varying end-points between studies also existed. Additionally, it must be borne in mind that the definition of resectability has evolved over the course of time and this resultantly would have led to differing cohorts of patients between studies. Clinical results for distinct patient populations (neuroendocrine metastases, noncolorectal GI metastases, hepatocellular carcinoma, etc.) were often combined. Some articles reported independent tumor outcomes whereby others gave a combined outcome. Furthermore, other baseline characteristics such as extrahepatic disease and the use of neoadjuvant or adjuvant chemotherapy varied greatly between studies. End points were not always reported uniformly. Some considered survival or recurrence from the time of diagnosis, whereas other studies looked at these end points from time of first treatment. We have therefore tried to assess comparative treatment efficacy using 1-, 2-, 3-, 4-, and 5-year survival rates, median survival rates, complication rates, local (hepatic) recurrence, site-specific (at ablation site) recurrence, and overall recurrence. No single study reported all of the above. The heterogeneity of the studies and the absence of long-term data for microwave ablation, in particular, make it difficult to offer an evidence based recommendation for the ablative management of unresectable colorectal hepatic metastases.

cryotherapy Cryoablation of hepatic metastases using insulated probes containing liquid nitrogen/argon have been used for the destruction of CLRM (15). They are placed into each metastasis, whereupon

THERMAL ABLATION OF LIVER METASTASES liquid nitrogen or argon is used to freeze the lesion, using temperatures as low as −30°C. The progress of the enlarging ice ball may be monitored radiologically using MRI/CT or ultrasound scanning (16). Initially this was seen to be advantageous, however subsequently it has been demonstrated that the peripheries of the ice ball may not have reached a sufficiently low temperature to cause cellular death (17). Furthermore, histopathological assessment of lesions produced by cryotherapy has also shown that there is significant amount of tissue adjacent to blood vessels that remains undamaged by the ablation (18). This “heat sink” effect may result in viable tumor remaining in seemingly “treated” lesions, explaining high local recurrence rates. The physiological basis of cryotherapy has been well investigated and is dependent upon the rapid formation of ice crystals during the freezing process. Additionally, cellular hypoxia due to disruption of the surrounding microvascular structures also induces cell destruction and enhances the direct damage resulting from ice ball formation (19). There are no clearly defined indications for the use of cryotherapy but patients with unresectable metastatic disease secondary to either extensive bilobar involvement or difficult anatomical location may benefit. Tumors, which lie in close proximity to major blood vessels such as the inferior vena cava, large portal branches or large hepatic veins, may make cryotherapy difficult due to the “freeze-thaw” effect previously described. Conventionally, a laparotomy was required for the direct application of probes; however probes have now been developed that are small enough to be placed percutaneously. In the studies reviewed, reports of 3- and 5-year survival were sparse, and varied between 30.9% to 44% and 13% to 26%, respectively. Median survival ranged between 22.9 and 94.2 months (Table 19.1). However, the marked heterogeneity of these studies makes direct comparison difficult. Major complication rates (defined as complications requiring the patient to remain in hospital) were high, ranging from 22% to 70%. The major concern with use of cryotherapy is the “cryoshock” phenomenon, where patients develop a systemic response to ablation, consisting of marked thrombocytopenia leading to coagulopathy, pleural effusion, acute respiratory distress syndrome, and myoglobinuria (30–33). The true incidence of cryoshock is difficult to establish, though reports from the literature suggest a mortality of 0% to 8%. A large multicentre survey estimated that it was responsible for 18% of perioperative deaths (31). The high rate of local complications (hemorrhage from a cracked liver, subphrenic abscess, bilomas, and biliary fistulae) and fear of cryoshock has led to this technique falling out of favor as other safer and equally efficient techniques have evolved.

edge cryotherapy Edge cryotherapy employs the application of cryotherapy to the resection margins posthepatectomy in order to extend the margins of resectability. Several studies describe the use of cryotherapy when a histopathologically positive margin is expected. During this procedure, flat cryoprobes are placed against the resection edge of the remnant liver, whereupon remnant liver tissue is frozen to a depth of at least 1 cm (34). Reported 3- and 5-year survival for these patients was 43% to 60% and 26% to 44%, respectively,

with a median survival of 29 to 39 months. Major complication rates were reported as 0.22% to 25%. Again, these outcomes reflect the heterogeneity of these studies. Major hepatic resections have an overall complication rate (major and minor complications) of around 20% (5). The fact that two studies report major complication rate of a similar magnitude (35,36), with survival data in keeping with most major series assessing resection alone, would suggest that edge cryotherapy presents a theoretical advantage for patients deemed “unresectable.”

radiofrequency ablation Radiofrequency ablation (RFA) uses radiofrequency radiation to produce heat locally within the hepatic parenchyma. The radiofrequency current generates ionic agitation, which in turn is translated into heat, resulting in the subsequent breakdown of proteins and cell membranes (43). The main advantage when compared to cryotherapy is that the probes can be placed percutaneously. However, as with all locally ablative techniques, the efficacy of the treatment diminishes with increasing size of the lesion. Hence, manufacturers have designed a variety of electrodes that can be deployed in situ to produce a number of tips. RFA refers to coagulation from all electromagnetic resources with a frequency less than 900 kHz, with the majority functioning within the parameters of 300 to 500 kHz. Initially, problems existed with early radiofrequency designs due to the effects of high temperatures in the tissue surrounding the probe. This is due to tissue impedance secondary to tissue charring. Subsequently, this impedance results in reduced dissipation of current (44,45). This problem has been the major drawback of RFA, though it has been countered somewhat by the use of cooled electrode tips. However, the principle limiting factor of RF ablation remains the size of the achievable ablated tissue. This is because only the tissue immediately adjacent to the tip is heated by ionic agitation. The remainder of the tissue is ablated via heat produced via thermal conduction. This effect is magnified in the presence of large blood vessels, which further reduce heat via a phenomenon known as “the heat sink” effect (19). Both normal liver parenchyma and metastatic liver are water-rich and also have an extensive blood supply (via angiogenesis in the case of metastases). Hence, thermal conduction is facilitated, but as mentioned previously, this is a less efficient means of ablation than ionic agitation. Therefore, current opinion suggests that RFA is more susceptible to the heat sink effect than microwave ablation. Various measures have been used previously to reduce the heat sink effect, such as occlusion of the portal vein and hepatic artery at the time of ablation. Although the ablative area is increased, the risk of bile duct damage and portal vein thrombosis is increased. Because of the relative simplicity of the technique, the fact that it can be performed percutaneously and the comparatively cheap devices employed, RFA is a technique that remains widely practised (32).

review of the literature regarding rfa Previous reviews have suggested that there are no compelling data supporting the use of RFA in patients with viable extrahepatic disease (EHD) (46). EHD is known to be a poor prognostic

181

182 N 44 116 55 172 56 86 30 61 20 49 15

1 3.9 — 4.2 — 4 3 3.38 1.7 5.1 1.4

5 4.4 — 3.6 — — 2 4 2 — —

Size (cm) — 9.5 18 16 — — 0 16 — 0 0

EHD — 82 — 89 — 85 76 87 — — —

1 year

Year

1997 1998 1998 2000 2001 2002 2005 2006

Author

Korpan (35) Dwerryhouse (37) Seifert (38) Finlay (39) Gruenberger (40) Rivoire (36) Seifert (41) Niu (42)

63 26 44 75 86 24 55 124

N — 1 1 2 2 2.9 2.4 4.1

Metastases (n) 3.1 5 5 — 5 4.5 3.5 5

Size (cm) 0 — — 0 0 — 18 15

Extrahepatic disease % — — — — — 92 — 84

1 year survival %

Table 19.2 Summary of Studies Looking at Edge Cryotherapy (Survival and Complications)

Year 1998 1998 2003 2003 2004 2005 2005 2006 2007 2007 2007

Author

Seifert (20) Seifert (21) Seifert (22) Yan (23) Kerkar (24) Brooks (25) Joosten (26) Chen (27) Kornprat (28) Paganini (open) (29) Paganini (29) (lap)

Metastases (n)

Table 19.1 Summary of Studies Looking at Cryotherapy (Survival and Complications)

— — — 50.5 — — — 61

2 years survival %

— 56 — 65 67 — 61 54 — — —

2 years

60 — — — 54.7 58 — 43

3 years survival %

— 32.3 44 41 43 43 — 36 — 30.9

3 years

4 years

— — — — — 37 — 28

4 years survival %

— — — 24 — — — — — — —

44 — — — — — 26 24

5 years survival %

— 13 26 19 22 19 — — — —

5 years

— 29 33 33 — 39 29 29

Median survival (months)

33 26 29 28 30 33 — 26 — 22.9 94.2

Median survival (months)

25 0.27 0.22 — 0.34 21 — —

Major

22% 31% — 28% — — 30% — 30% 26% 70%

Major

— — — — 34% — — —

Minor

— — — — — — 20% 55% 53%

Minor

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

THERMAL ABLATION OF LIVER METASTASES indicator, predicting decreased overall survival and disease-free survival compared to patients without EHD (3,47). The authors remain unconvinced of this conclusion, since several studies consisting of patients with EHD (range 8.7–30%) have demonstrated reasonable median survival (range 18–37 months). Berber et al. (48) evaluated their 10-year experience with RFA in 234 patients who had a variety of neoplastic process occurring within the hepatic parenchyma. Their results showed that 80% of patients had progressive disease, despite aggressive chemotherapy, with the oncological intervention failing approximately 8 months before RFA. The authors also found no significant difference in patients who had EHD at the time of treatment, against those who did not. This observation strengthens our opinion that EHD is not an accurate predictor of outcome in patients with unresectable colorectal liver metastases. Hence, patients should not be denied RFA on this basis alone. There does not appear to be a maximum number of metastases that may be treated via RFA. However, there is a perception that local recurrence and survival rates appear to be negatively correlated with number and size of treated metastases. This review did not identify evidence clearly supporting this hypothesis, although a trend toward it is evident. The reasons for this conclusion are not obvious but it may be that patient factors, such as age, comorbidity, and operator experience have a significant influence. Generally, the highest ablation success rates were achieved in patients with solitary colorectal liver metastases or patients with a few metastases smaller than 3 cm (49–53). As with formal resection, the aim of any tumor eradication therapy is to achieve a clear negative margin. It follows therefore that that the best results are obtainable when the tumor is smaller than the size of coagulative necrosis produced by a single ablation probe, and it is therefore the size of ablation zone that limits the use of RFA. Most ablation devices can produce single ablations of around 4 cm in diameter. As probe delivery is performed by hand, either “blindly” or using two-dimensional imaging techniques (USS, CT), probes may be inadvertently placed away from the geometric centre of a lesion, resulting in a rim of untreated tissue. This opinion may explain higher recurrence rates in lesions larger than 3 cm. Attempts have been made to increase the ablation size and overcome the inherent limit of RFA by developing probes that deploy multiple “tines” around a lesion, as well as adopting techniques that reduce blood flow through parenchyma, another method known to increase lesion size by increasing the area which reaches sufficient temperature by indirect heating (54). The location of metastases within the liver is an important factor in determining the success of RFA. Tumors adjacent to large hepatic vessels are problematic, as larger vessels act as a heat sink, making it more difficult to ablate the tumor. Several studies commented on the increased failure rates in tumors adjacent to major blood vessels (26,55). Ablation near portal vein pedicles is also associated with an increased risk of major bile duct injuries, possibly as a result of de-epithelialization injuries related to heat.

microwave ablation Microwave coagulation (MCT) was initially developed in the early 1980s by Tabuse et al. in order to optimize haemostasis along the plane of dissection during hepatic resection. The microwave

coagulation of tissue surfaces was slower and produced deeper areas of tissue necrosis, compared to normal electrocautery units. This led to it being investigated as a technique for the treatment of unresectable hepatic malignancies (81). Microwave radiation lies between infrared radiation and radiofrequency, with frequencies from 900 to 2450 MHz. Tissue heating is based on the agitation of water molecules, which in turn cause cellular death via coagulation necrosis. Thus it is different from RFA as the frequency of the electromagnetic radiation used is considerably higher. This results in a greater ability to localize the dissipation of energy, though the tissue penetration is reduced (81–83). The microwave generators available for clinical use have an output of between 70 and 90 W. The microwave emitting needle is placed directly into the tumor, usually under radiological guidance. The emitting needle is attached to the microwave generator and when the generator is activated, each area of the tumor is treated for 30 to 60 seconds at 70 to 90 W. The rapid generation of heat using MCT produces 10 to 25 mm zones of coagulative necrosis after only 30 to 60 seconds. The rapid development of coagulative necrosis precludes the further dissipation of heat to surrounding tissues. Thus, microwave offers many of the benefits of RFA, with some substantial theoretical advantages. These benefits include higher intratumoral temperatures, faster ablation times, larger tumor ablation volumes, ability to use simultaneous multiple applicators and less procedural pain (30,32). With RFA, the zone of active tissue heating is limited to a zone of a few millimeters surrounding the active electrode, with the remainder of the ablation zone being created via thermal conduction. However, via a superior convection profile, microwave produces a larger zone of active heating, allowing a more uniform destruction of cells within the target area. RFA is also limited by the impedance with tissue boiling and charring, because water vapor and char act as electrical insulators. Due to the electromagnetic nature of microwaves, microwave ablations appear unaffected by the effect of water vapor and charring. MCT technology allows for open, laparoscopic, and percutaneous routes of delivery. Ablation is performed using a thin antenna that is attached to the microwave generator. In the literature, different protocols for time and power of ablation have been proposed, dependent on the tissue and antenna type (84). Seki et al. (85) treated 15 patients with solitary colorectal liver metastases who declined formal resection using percutaneous microwave ablation. Ten patients were alive at the end of the follow-up period (9–37 months), with a median survival of 24.2 months. This is broadly similar to best chemotherapy, but obviously direct comparisons are difficult between such homogeneous studies. No recurrence was detected in adequately treated lesions, although two patients experienced recurrence due to inadequate treatment at presentation as defined by incomplete destruction on posttreatment imaging. Another Japanese group (14) performed a small randomized control study on 30 patients comparing hepatic resection versus MCT. One, 2- and 3-year survival rates for the microwave group were 71%, 57%, and 14% compared to

183

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 69%, 56%, and 23% for the resection group. The mean survival time was 25 months for the microwave group versus 23 months for the resection group. Statistically, there was no difference in survival between the two groups. A significant proportion of patients in both arms of this study developed hepatic failure without explanation as to why this occurred. Tanaka et al. (88) performed a retrospective analysis of 53 patients who underwent hepatectomy or hepatectomy plus microwave ablation. Their results suggested no difference between the two groups in terms of recurrence or survival. This suggests that ablative therapies may be used to extend the margins of resectability. In a review of 31 patients by Bhardwaj et al. (93), of whom the majority had unresectable colorectal metastases, median survival was 29 months, with a 3-year survival of 40%, and local recurrence was only 2%. Despite the variety of primary and secondary lesions, these figures illustrate the potential for MCT in the treatment of hepatic metastases.

Ultrasound probe

Ultrasound beam Iceball surrounding and encompassing tumor

Probe within liver Ultrasound

Cryoprobe

(A)

(B)

Figure 19.1 Cryoablation (surgical view A) under intra-operative ultrasound control (B).

percutaneous ethanol injection Percutaneous ethanol injection (PEI) involves passing single or multiple fine needles followed by intratumoral injection of pure ethanol, causing cytotoxic cell death mainly via dehydration. The main disadvantage with PEI is that treatment in patients with large metastases has been found to be inadequate due to incomplete alcohol diffusion within the tumor mass. Additionally, the results for PEI in the treatment of CLRM have not been as promising as for primary hepatocellular carcinoma, due mainly to the difference in tumor characteristics (94). HCC is usually hypervascular and may be encapsulated, qualities which will reduce leakage into the surrounding hepatic parenchyma, while ensuring diffusion through the lesion. However, CRLM tend to be dense and infiltrative, making the diffusion of ethanol more unpredictable, resulting in pockets of untreated tumor. For this reason, thermoablative techniques are preferred for CRLM (16). There was a paucity of data regarding use of PEI for the treatment of colorectal liver metastases. Only three series were identified, which looked at the feasibility of PEI as a treatment, as opposed to survival and complication rates. It is unlikely that future research will be channeled in this direction as the tumor characteristics of metastases make them unfavorable for PEI.

the clocc study Finally, at the time of coming to press, Ruers and colleagues presented the final results of the EORTC CLOCC (EORTC 40004) Study at the 2010 ASCO meeting in Chicago (97). This study was conceived as a 400-patient Phase III randomization of patients with up to nine unresectable liver-only metastases to receive either oxaliplatin-based chemotherapy or chemotherapy plus RFA (open, laparoscopic, or percutaneous) with or without concomitant resection of easily resectable lesions. The primary end-point was powered to test for a 38% overall survival benefit in the RFA arm. This was an extremely ambitious project, and recruitment was understandably extremely difficult. After a period of extreme frustration, the trial objective was reduced to a 100-patient

184

Figure 19.2 Radiofrequency ablation.

randomized Phase II, with an actual accrual of 119 patients. However, it remains a unique landmark study, probably never to be repeated, and the only prospective study to address the question of the real survival benefit of thermal ablation therapy for metastatic liver disease. Although there was a significant improvement in 3-year progression free-survival (PFS) of 27.6% for RFA + chemotherapy compared to 10.7% for chemotherapy alone (p = 0.025) (Fig. 19.3), a secondary end point, overall survival (OS) at 30 months (the primary study end point) was no different for RFA + chemotherapy (63.8%) over chemotherapy alone (58.6%) (p = 0.218) (Fig 19.4). It must be remembered that when designed, the study was never powered to demonstrate a significant result for its primary end point with such low numbers, and it is extremely unlikely that any investigators will ever be bold enough to try to repeat such a study. Therefore in the pragmatic real world, we must accept the evidence that we have, which in our opinion suggests a survival benefit for thermal ablation therapies in the treatment of relatively low-volume unresectable liver metastases.

THERMAL ABLATION OF LIVER METASTASES Progression free survival 100 90 80 Overall logrank test: p = 0.025 70 60 50 18.08% 40 30 RF + Chemo

20 10

Chemo (years)

0 0

1

2

3

4

5

6

O 53

N 59

Number of patients at risk: 24 12 5

4

2

1

Treatment CT

44

60

34

8

3

0

RF+\-resection+CT

20

13

7

Figure 19.3 Three year PFS in the CLOCC study comparing RFA + chemotherapy (27.6%) to chemotherapy alone (10.7%) (p = 0.025).

Overall survival

100 90 80 70 60 50 40

RF + Chemo

30 20 Overall logrank test: p = 0.218

10

Chemo (years)

0 0

1

O 39

N 59

31

60

2

4

5

6

Number of patients at risk: 52 43 27

15

5

1

Treatment CT

53

19

7

1

RF+\-resection+CT

44

3

27

7

Figure 19.4 Thirty month OS comparing RFA+chemotherapy (63.8%) to chemotherapy alone (58.6%) (p = 0.218).

185

186

Year

2000 2000 2008 2009 2007 2008 2009 2006 2008 2006 2003 2007 2009 2006 2008 2007 2005 2005 2002 2001 2007 2007 2002

Author

De Baere (56) Elias (57) Park (58) Knudsen (59) Sorensen (60) Lee (61) Hur (62) Lermite (51) Veltri (63) Aloia (64) Oshowo (65) Suppiah (66) Reuter (67) Hildebrand (68) Berber (69) Siperstein (70) Gilliams (53) Berber (71) Iannitti (72) Solbiati (73) Terraz (74) Abitabile (52) Stippel (75)

RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA

Ablative type 54 14 30 36 102 37 25 14 122 30 25 30 66 56 68 235 73 135 52 109 16 47 23

Number 1.8 6.2 1.2 — 3.25 — — 2 1.63 — — 1.9 2.8 3.5 1 2.8 4.1 3.2 2.7 1.6 1.75 3.12 5.57

Metastases (n) 1.3 1.4 2 2.1 2.2 2.25 2.5 2.7 2.9 3 3 3.1 3.2 3.5 3.7 3.9 3.9 4.1 5.2 — — — —

Size (cm) — — No No No — No — 20.5 — 28 — 15 — 38 23 No 30 — — — — 8.7

EHD

Table 19.3 Summary of Studies Looking at RFA (Survival and Complications)

81 — — — 87 — — 90 79 — — 75 — 92 — — 91 — 87 — 84 88 —

1 year — 95 — — 62 — — 54 — — — 45 — 67 — — — — 77 67 68 80 —

2 years — — — 26 46 — 60 54 38 57 52.6 7 — 42 20.6 20.2 28 — 50 33 — 57 —

3 years — — — — 26 — — — — — — 3 — — — — — — — — — — —

4 years — — — 34 — 46.5 25.5 — 22 27 — — 21 — 30 18.4 25 — — — — — —

5 years

— — 36 39 32 40 — — 31.5 — 37 23.2 27 28 20.5 24 overall 38 28.9 — 30 — 39 18

Median survival (months)

— 33.3 — 11 6.9 — 0 11.5 1.1 — 4 — 10 3.4 — — 4 — 7.1 0.9 2.9 13 7

Major

—

— — — — 4 — 0 — 7 — — 5 49.1 — 2.9 — 6 — — 6.4 2.9

Minor

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

2003 2003 2004 2005 2005 2006 2007 2008 2009

Pawlik (76) Scaife (77) Abdalla (3) Elias (78) Joosten (26) Amersi (49) Kornprat (28) Gleisner (79) Nikfarjam (80)

RFA ± resection RFA ± resection RFA ± resection RFA ± resection RFA ± resection RFA ± resection RFA ± resection RFA ± resection RFA ± resection

Ablative type 124 50 158 63 28 74 19 66 23

Number 3 2 — 2.4 3 3.3 5 2 —

1.8 2 — 15 2 3.56 2 2.5 —

size (cm)

Author Seki (85) Shibata (86) Liang (11) Yokoyama (87) Tanaka (88) Iannitti (89) Kuang (90) Ogata (91) Zhang (92) Bhardwaj (93)

Year 1999 2000 2003 2003 2005 2007 2007 2008 2008 2009

Ablative type MCT MCT MCT MCT/RFA MCT MCT MCT MCT/RFA MCT MCT N 15 14 28 12 16 33 11 32 34 24

Metastases (n) 1 4.1 2 2.8 2.2 2.57 1.47 4 — 2.87 Size (cm) 2.1 2.7 3.12 2.4 4.8 3.6 2.75 2.8 — 2 —

No No — No No No — — —

EHD

EHD (%) 0 0 5 — 5 — 0 22 — 0 —

Table 19.5 Summary of Studies Looking at MCT (Survival and Complications)

Year

Author

Metastases (n) — — — 92 93 — — 92 —

1 year

1 year — 71 91.4 — 80 — — — 82.1 40 —

Table 19.4 Summary of Studies looking at RFA ± Resection (Survival and Complications)

2 years — — 59.5 — — — — — — — —

— 66 — 67 75 — — — —

2 years

3 years — 57 46.4 — 51 — — — — — —

— — 43/37 47 — — — 51.2 —

3 years

4 years — — 29 — — — — — — — —

— — 36/22 — — — — — —

4 years

5 years — 14 — — 17 — — 32 — — —

— — — — — — — 28 68

5 years

Median survival (months) 24.2 27 20.5 — 28 — — 43 — 29 —

37.3 — — 36 — 29.7 — 38.1 —

Median survival (months)

Major (%) — 14.0 0.0 — 19.0 16.1 4.0 3.4 — 0.0 2.6

20 22 — 27 11 13 — — 11

Major

— — — 7.8 — 76.3 0 80.1

Minor (%) 6.7 —

— — —

— —

— —

Minor

THERMAL ABLATION OF LIVER METASTASES

187

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 19.6 Summary of Studies Looking at PEI (Survival and Complications) Author

Year

Number

Metastases (n)

Size (cm)

EHD

Kessler (95)

2002

13 (inc HCC)

Unknown

Unknown

Unknown

Giorgio (96)

2003

47

Unknown

Unknown

Unknown

Recurrence rates

Median survival

Major

50% (inc HCC) Unknown

Unknown

8%

25%

Unknown

3%

17.7%

Minor

Table 19.7 Overall Comparison of Studies Reviewed (Cumulative) Ablative technique

Recurrence (Range %)

Survival rates (%)

Local

Overall

1 year

2 years

3 years

4 years

5 years

Major complication rates (%)

Cryotherapy Ethanol MCT RFA

12–39 — 5–13 10–31

78–88 — 50–78 47–86

84 — 73 85

59 — 60 67

37 — 30 36

21 — 29 30

17 — 16 24

29 5 7 6

Median

RFA + resection Edge cryotherapy

5 Year

4 Year

3 Year

2 Year

1 Year 0

10

20

30

40

50

60

70

80

90

100

Figure 19.5 Survival figures for studies reviewed (ablation as adjunct to surgery).

conclusions The ideal ablative therapy should cause complete tumor ablation, yet be parenchyma sparing, reproducible, safe, and be minimally invasive. Current advancements, particularly in RFA and MCT, are promising but the perfect ablative model is still elusive. The literature cannot support the use of percutaneous ethanol injection for the treatment of colorectal metastases, though we accept that it has a role in the management of hepatocellular carcinoma. Similarly, the literature demonstrates that although cryoablation has acceptable survival figures, its ongoing use cannot be advocated given the high rate of local complications (Table 19.7). Ablative therapies offer great potential for lesions that cannot be formally resected. The increasing burden of metastatic colorectal disease means that a growing number of patients will have unresectable metastases and hence will be candidates for ablation. It is important that the ablation causes complete tumor destruction within the treatment zone. Heat sink effect may

188

result in tumor viability even within a seemingly completed ablation. The ability to accurately place the probe is also vital to ensure that the treatment zone encompasses the focus of disease. Currently, most centers use RFA or microwave ablation as treatment of choice. Microwave offers the theoretical advantage of larger ablation volumes, shorter ablation duration, and the ability to perform multiple simultaneous ablations to increase ablation volume as well as more predictable ablation zones around vessels. The lower local recurrence rate found in this review probably reflects the more predictable ablation characteristics on MCT. Conversely the larger body of evidence surrounding RFA is probably a manifestation of its maturity as a technology, rather than an implicit endorsement of its superiority over other technologies. The role of ablative technology in a palliative setting is unclear. However, 3-year survival of between 30% and 37% compares favorably with best supportive chemotherapy (Figs. 19.5 and 19.6). The underlying mechanism behind this remains unclear, though it may be related to decreasing the tumor burden.

THERMAL ABLATION OF LIVER METASTASES Radiofrequency ablation

Median

Microwave ablation Cryotherapy

5 Year

4 Year

3 Year

2 Year

1 Year 0

10

20

30

40

50

60

70

80

90

Survival (%) Figure 19.6 Survival figures for ablative studies reviewed.

Ethanol ablation Radiofrequency ablation Microwave ablation Cryotherapy RFA+resection Edge cryotherapy

0

5

10

15 20 25 Complication rates(%)

30

35

40

Figure 19.7 Complication rates for all studies reviewed.

The safety profiles of RFA and MCT appear similar and in the current climate, both are safe and effective therapies, which should be deployed (Fig 19.7). Further studies are needed to demonstrate long-term outcomes and ongoing research will ensure that ablative technologies continue to evolve rapidly.

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THERMAL ABLATION OF LIVER METASTASES 63. Veltri A, Sacchetto P, Tosetti I, et al. Radiofrequency ablation of colorectal liver metastases: small size favorably predicts technique effectiveness and survival. Cardiovasc Intervent Radiol 2008; 31(5): 948–56. 64. Aloia TA, Vauthey JN, Loyer EM, et al. Solitary colorectal liver metastasis: resection determines outcome. Arch Surg 2006; 141(5): 460–6; discussion 6–7. 65. Oshowo A, Gillams A, Harrison E, Lees WR, Taylor I. Comparison of resection and radiofrequency ablation for treatment of solitary colorectal liver metastases. Br J Surg 2003; 90(10): 1240–3. 66. Suppiah A, White TJ, Roy-Choudhury SH, et al. Long-term results of percutaneous radiofrequency ablation of unresectable colorectal hepatic metastases: final outcomes. Dig Surg 2007; 24(5): 358–60. 67. Reuter NP, Woodall CE, Scoggins CR, McMasters KM, Martin RC. Radiofrequency ablation vs. resection for hepatic colorectal metastasis: therapeutically equivalent? J Gastrointest Surg 2009; 13(3): 486–91. 68. Hildebrand P, Leibecke T, Kleemann M, et al. Influence of operator experience in radiofrequency ablation of malignant liver tumours on treatment outcome. Eur J Surg Oncol 2006; 32(4): 430–4. 69. Berber E, Tsinberg M, Tellioglu G, Simpfendorfer CH, Siperstein AE. Resection versus laparoscopic radiofrequency thermal ablation of solitary colorectal liver metastasis. J Gastrointest Surg 2008; 12(11): 1967–72. 70. Siperstein AE, Berber E, Ballem N, Parikh RT. Survival after radiofrequency ablation of colorectal liver metastases: 10-year experience. Ann Surg 2007; 246(4): 559–65; discussion 65–7. 71. 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(7): 1358–64. 72. Iannitti DA, Dupuy DE, Mayo-Smith WW, Murphy B. Hepatic radiofrequency ablation. Arch Surg 2002; 137(4): 422–6; discussion 7. 73. Solbiati L, Ierace T, Tonolini M, Osti V, Cova L. Radiofrequency thermal ablation of hepatic metastases. Eur J Ultrasound 2001; 13(2): 149–58. 74. Terraz S, Constantin C, Majno PE, et al. Image-guided multipolar radiofrequency ablation of liver tumours: initial clinical results. Eur Radiol 2007; 17(9): 2253–61. 75. Stippel DL, Bohm S, Beckurts KT, Brochhagen HG, Holscher AH. Intraoperative radiofrequency ablation using a 3D navigation tool for treatment of colorectal liver metastases. Onkologie 2002; 25(4): 346–50. 76. Pawlik TM, Izzo F, Cohen DS, Morris JS, Curley SA. Combined resection and radiofrequency ablation for advanced hepatic malignancies: results in 172 patients. Ann Surg Oncol 2003; 10(9): 1059–69. 77. Scaife CL, Curley SA, Izzo F, et al. Feasibility of adjuvant hepatic arterial infusion of chemotherapy after radiofrequency ablation with or without resection in patients with hepatic metastases from colorectal cancer. Ann Surg Oncol 2003; 10(4): 348–54. 78. Elias D, Sideris L, Pocard M, et al. Incidence of unsuspected and treatable metastatic disease associated with operable colorectal liver metastases discovered only at laparotomy (and not treated when performing percutaneous radiofrequency ablation). Ann Surg Oncol 2005; 12(4): 298–302. 79. Gleisner AL, Choti MA, Assumpcao L, et al. Colorectal liver metastases: recurrence and survival following hepatic resection, radiofrequency ablation, and combined resection-radiofrequency ablation. Arch Surg 2008; 143(12): 1204–12.

80. Nikfarjam M, Shereef S, Kimchi ET, et al. Survival outcomes of patients with colorectal liver metastases following hepatic resection or ablation in the era of effective chemotherapy. Ann Surg Oncol 2009; 16(7): 1860–7. 81. Izzo F. Other thermal ablation techniques: microwave and interstitial laser ablation of liver tumors. Ann Surg Oncol 2003; 10(5): 491–7. 82. Wemyss-Holden SA, Dennison AR, Berry DP, Maddern GJ. Local ablation for unresectable liver tumors: is thermal best? J Hepatobiliary Pancreat Surg 2004; 11(2): 97–106. 83. Martin LW, Warren RS. Current management of colorectal liver metastases. Surg Oncol Clin N Am 2000; 9(4): 853–76; discussion 77–8. 84. Carrafiello G, Lagana D, Mangini M, et al. Microwave tumors ablation: principles, clinical applications and review of preliminary experiences. Int J Surg 2008; 6 Suppl 1: S65–9. 85. Seki T, Wakabayashi M, Nakagawa T, et al. Percutaneous microwave coagulation therapy for solitary metastatic liver tumors from colorectal cancer: a pilot clinical study. Am J Gastroenterol 1999; 94(2): 322–7. 86. Shibata T, Murakami T, Ogata N. Percutaneous microwave coagulation therapy for patients with primary and metastatic hepatic tumors during interruption of hepatic blood flow. Cancer. 2000; 88(2): 302–11. 87. Yokoyama T, Egami K, Miyamoto M, et al. Percutaneous and laparoscopic approaches of radiofrequency ablation treatment for liver cancer. J Hepatobiliary Pancreat Surg 2003; 10(6): 425–7. 88. Tanaka K, Shimada H, Nagano Y, Endo I, Sekido H, Togo S. Outcome after hepatic resection versus combined resection and microwave ablation for multiple bilobar colorectal metastases to the liver. Surgery. 2006; 139(2): 263–73. 89. Iannitti DA, Martin RC, Simon CJ, et al. Hepatic tumor ablation with clustered microwave antennae: the US Phase II Trial. HPB (Oxford) 2007; 9(2): 120–4. 90. Kuang M, Lu MD, Xie XY, et al. Liver cancer: increased microwave delivery to ablation zone with cooled-shaft antenna—experimental and clinical studies. Radiology 2007; 242(3): 914–24. 91. Ogata Y, Uchida S, Hisaka T, et al. Intraoperative thermal ablation therapy for small colorectal metastases to the liver. Hepatogastroenterology 2008; 55(82–83): 550–6. 92. Zhang X, Zhou L, Chen B, et al. Microwave ablation with cooled-tip electrode for liver cancer: an analysis of 160 cases. Minim Invasive Ther Allied Technol 2008; 17(5): 303–7. 93. Bhardwaj N, Strickland AD, Ahmad F, et al. Microwave ablation for unresectable hepatic tumours: clinical results using a novel microwave probe and generator. Eur J Surg Oncol 2010; 36(3): 264–8. 94. Bartolozzi C, Lencioni R. Ethanol injection for the treatment of hepatic tumours. Eur Radiol 1996; 6(5): 682–96. 95. Kessler A, Blank A, Merhav H, Orron D, Konikoff F, Oren R, et al. Minimally invasive techniques in the treatment of liver tumors. Isr Med Assoc J 2002; 4(12): 1106–10. 96. Giorgio A, Tarantino L, de Stefano G, et al. Complications after interventional sonography of focal liver lesions: a 22-year single-center experience. J Ultrasound Med 2003; 22(2): 193–205. 97. Ruers T, Punt C, v Coevorden F, et al. Final results of the EORTC Intergroup randomized study 40004 (CLOCC) evaluating the benefit of radiofrequency ablation combined with chemotherapy for unresectable colorectal liver metastases. Proc ASCO 2010; J Clin Oncol 2010; 28 (15): A-3526.

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20 Resection for hepatocellular carcinoma

Rajesh Satchidanand, Stephen W. Fenwick, and Hassan Z. Malik

introduction

staging systems

Hepatocellular carcinoma (HCC) is one of the most common malignancies with more than a million cases reported every year worldwide. It is a common cause of death in the Far East because of high endemecity of hepatitis B virus (HBV) infection. In the West, the rising trend in the incidence of HCC is parallel to the epidemic of Hepatitis C (HCV) virus infection (1). Alcohol excess, genetic hemochromatosis, aflatoxin B1 (2), and primary biliary cirrhosis are other associated risk factors. In the West, the majority of HCC patients have associated cirrhosis of which a significant number is alcohol related. More than a third of these cases present with HCC as the initial presentation in contrast to the Far East where HCC is often diagnosed at an early stage by surveillance of the at-risk population (3). Symptomatic HCC has a poor prognosis with a median survival of 1 to 8 months (4). A multi-disciplinary approach involving the surgeons, hepatologist, clinical oncologist, and radiologist is needed to formulate the best treatment options. Surgical resection offers the best possible treatment outcome but a large proportion of patients are not suitable for such an approach.

A staging system allows for separation of patients into groups and selection of appropriate treatment modality. A number of staging systems are used in HCC using tumor characteristics and underlying liver pathology. The most commonly used method of tumor, nodes, and metastases (TNM) in the American Joint Committee on Cancer–Tumor–Metastases (AJCC), TNM staging dependant on resection and postoperative histology (9). The Okuda Classification includes variables related to the tumor and liver function (10). The Cancer of the Liver Italian Program Investigators staging systems includes ChildTurcotte-Pugh (Child A/B/C) score, tumor morphological characteristics, AFP, and vascular invasion/portal vein thrombosis. The Japan Integrated Staging score uses a combination of Child A/B/C score and TNM staging system. By far, The Barcelona Clinic Liver Cancer (BCLC) using tumor variables and the current available treatment options gives a better prognostic value in early cases (Fig. 20.2) (11).

diagnosis Asymptomatic HCC is diagnosed either as an incidental finding or on routine surveillance of at-risk population. Ultrasound scan (with or without contrast enhancement) with measurement of serum alfa-feto protein (AFP) is routinely used for screening (5,6). Once a suspicion of a focal lesion is raised, further assessment with contrast-enhanced computerized tomography (CECT) and/or magnetic resonance imaging (MRI) with contrast enhancement is needed to confirm the diagnosis of HCC. Tumor biopsy is rarely needed and in fact should be avoided in potentially resectable lesion due to the risk of tumor seeding along the needle track and intra-celomic spread. Furthermore, CECT is a good modality to look for the presence of cirrhosis, ascites, and metastases. A typical HCC shows hyper vascular enhancement with characteristic feature of early uptake of contrast and portal venous washout, an enhanced pseudocapsule, vascular invasion on CECT which gives more than 80% accuracy in diagnosing these lesions (7). MRI is more sensitive in detecting lesions 1 to 2 cm in size. A quarter of intra-hepatic lesions smaller than 10 mm is miss-diagnosed on pre-operative investigations. Diagnosing any lesion ≥2 cm with characteristics CECT/MRI findings is possible with a high degree of accuracy. In lesions 1 to 2 cm without concordance with two radiological investigations, a raised AFP of ≥400 µ/L and one radiological modality with positive features, diagnosis is possible (8). In lesions <10 mm, expectant follow-up with repeat imaging at 3 to 6 months is an appropriate management algorithm (Fig. 20.1).

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treatment A number of treatment options are available for patients with HCC. These include 1. Liver resection (LR) 2. Orthotopic liver transplant (OLT) including deceased/ cadaveric donor liver transplant (DDLT/CLT) and living donor liver transplant (LDLT) 3. Treatment prior to OLT: bridging the gap 4. Less invasive procedure involving chemical or thermal destruction of liver parenchyma 5. Regional or systemic chemotherapy 6. Radiotherapy including external beam irradiation or embolization with radioactive particles Before selecting a treatment option, careful consideration should be given to preoperative staging, underlying condition of the liver and the general fitness of the patient. Staging laparoscopy is a mandatory prior to LR or OLT to rule out extrahepatic disease. Assessing the residual liver function in chronic liver disease is very important before LR, as any major resection in a cirrhotic patient may result in fatal liver failure in the immediate post-operative period. Traditionally, the Child A/B/C scoring system has been used to assess the residual liver function. However, the Model for End-stage Liver Disease (MELD) scoring is used as an alternative in United States. Ascites on CECT, bilirubin of >2 mg/dL, and iodocyanine green retention test (used extensively in the East) (8) at 15 minutes of <30% bodes ill for residual liver function. Clinically relevant portal hypertension with hepatic vein gradient of >10 mm of mercury, esophageal varices, splenomegaly, and a platelet count of <100 × 109/L are accurate predictors of post-operative liver decompensation (12). Patients with Child

RESECTION FOR HEPATOCELLULAR CARCINOMA HCC within Milan criteria

Child-Pugh A

Solitary < 3 cm

Deep location

Solitary 3–5 cm

Peripheral location

Child-Pugh B–C

2–3 nodules < 3 cm

Solitary < 5 cm 2–3 nodules < 3 cm

Deep location Portal hypertension Varices, platelets < 100,000/mm3

Yes

No

Portal vein embolization If right hepatectomy required

RF ablation

Laparoscopic resection

Open resection

Transplantable

Transplantation

Recurrence Not transplantable

RF, TACE, resection, New drugs, supportive care

Figure 20.1 Algorithm for management of transplantable hepatocellular carcinoma used at Henri-Mondor Hospital. Source: From Ref. (29).

A can withstand up to 50% liver resection, but in those with Child B, a future remnant liver value of less than 75% is associated with major complications. LR remains the treatment of choice in early cases of noncirrhotic HCC, in tumors of <5 cm size, or up to three tumor nodules each <3 cm in size. Even though early experience with OLT yielded good results, it was fraught with recurrence (13). Increasing incidence of HCC with scarcity of donor livers available for transplant meant stringent criteria for patient selection. Hence, with the adoption of the more restrictive Conventional Milan Criteria (CMC: 1 lesion <5 cm, 2–3 lesions <3 cm), OLT has resulted in better long-term results (14). With increasing experience, some groups have suggested expanding the boundaries of CMC. One such recommendation is University of California, San Francisco (UCSF), criteria for patients with one lesion ≤6.5 cm or two to three lesions ≤4.5 cm with a total tumor diameter of <8 cm (15).

early stage hcc Patients with one lesion <5 cm in size or two to three lesions <3 cm in size with good residual liver functions are considered as having early stage disease. In these patients LR, OLT or percutaneous ablative therapy with a curative intent yielding high response rate are possible (16). Both LR and OLT have the best outcomes and treatment of choice is dependent on the availability of a donor liver. Tumor progression while waiting for a donor liver may decide the treatment option.

Liver Resection Liver resection in early HCC can be used in three different settings: (a) primary therapy, (b) to obtain material for morphological assessment of the tumor and to select patients who would benefit OLT, and (c) as a bridge therapy for those who are enlisted for OLT.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

HCC Stage 0

Stage A–C

PST 0, child-pugh A, okuda 1

Very early stage (0) single < 2 cm. Carcinoma in situ

Stage D Okuda 3, PST > 2, Child-Pugh C

Okuda 1–2, PST 0–2, Child-Pugh A–B

Early stage (A) Single or 3 nodules < 3 cm, PS 0

Intermediate stage (B) Multinodular, PS 0

Advanced stage (C) Portal invasion, N1, M1, PS 1–2

Terminal stage (D)

3 nodules ≤ 3 cm

Single Portal pressure/bilirubin

Associated diseases

Increased Normal

Resection

No Liver transplantation (CLT/LDLT)

Yes

PEI/RF

Curative treatments

Portal invasion, N1, M1

No

Chemoembolization

Randomized controlled trials

Yes New agents Symptomatic treatment

Figure 20.2 Barcelona Clinic Liver Cancer staging classification and treatment schedule. Stage 0: Patients who have very early HCC are optimal candidates for resection. Stage A: Patients who have early HCC are candidates for radical therapies (resection and ablation, liver transplantation, or percutaneous treatments). Stage B: Patients who have intermediate HCC may benefit from chemoembolization. Stage C: Patients who have advanced HCC may receive new agents in the setting of a randomized, controlled trial. Stage D: Patients who have end stage disease receive symptomatic treatment. Abbreviations: LDLT, living-related donor liver transplantation; PEI, percutaneous ethanol injection; RF, radiofrequency. Source: From Ref. (30).

Primary Resection Therapy LR for HCC has come a long way from early attempts with more than 50% mortality and no 5-year survival. With better understanding of tumor morphology, availability of advanced imaging modalities, patient selection, greater understanding of liver anatomy, improvement in surgical techniques, intraoperative ultrasound scan, and well-trained dedicated liver surgeons has resulted in up to 70% 5-year survival rates comparable to OLT, but a recurrence of 40% to 70% still represents a major cause of death (8,16). LR can be performed as a wedge resection, segmentectomy, or major resection. The extent of the liver resection is dependent on the size of the tumor, whether it is unifocal or multifocal and the presence or absence of cirrhosis in the residual liver. A peripherally located small lesion especially in segment 2 or 3 of liver can be safely resected either laparoscopically or by open resection. But in the presence of cirrhosis, wedge resection or non-anatomical resection in a rigid liver can be difficult and associated with significant blood loss. A hemi hepatectomy can achieve a good tumor clearance with least postoperative complications in lesions measuring 2 to 3 cm. This could be managed either laparoscopically or by handport assisted laparoscopic surgery (17). Deeply seated lesions or large single lesions measuring 3 to 5 cm with no evidence of portal hypertension need major

194

hepatectomy. Preoperative portal vein embolization (PVE) can be used to increase the functional residual volume of liver. Though theoretically this could overcome the problems of postoperative hepatic decompensation, barring few smaller studies, randomized controlled trials have not shown benefit from PVE (18). The ratio of functional residual volume to total liver volume should be more than 25% in non-cirrhotic livers and >40% in cirrhotic livers. In high-volume centers and in the Far East, major hepatectomies are undertaken with minimal postoperative complication rates. Tumor recurrence following primary resection has an incidence of 70%. Recurrence is more common after resection in the cirrhotic liver due to the ongoing process of carcinogenesis. It is more common in multifocal lesions, vascular invasion, and positive resection margin. Salvage OLT can be used for those with recurrence following resection, although patients will still have to fulfil the criteria for transplant. Resection Prior to OLT LR can be used to help select patients for OLT (19). This gives an opportunity to examine not only the surrounding liver but also the specimen for histo-pathological examination. A tumor with adverse morphological features (such as satellite nodules, vascular invasion) could preclude a patient for OLT even though it meets the CMC. Conversely, a large tumor which

RESECTION FOR HEPATOCELLULAR CARCINOMA falls just outside the CMC, but with good prognostic features could be considered for transplant. With more experience in managing this condition, there is constant urge to push the boundaries of CMC. Resection to Bridge the Gap Prior to OLT Tumor progression in patients waiting for OLT is a common problem, especially in aggressive tumors. In centers with a long wait for OLT, traditionally transarterial chemo-embolization (TACE), percutaneous ablation with ethanol injection (PEI), or radiofrequency (RFA) is used. The amount of tumor necrosis cannot be accurately quantified. Moreover, inadequate tumor necrosis can lead to tumor recurrence following OLT. LR can be used instead to bridge the gap prior to OLT (20). LR is better at tumor control than either TACE or RFA while waiting for OLT. This strategy is restricted to Child A and to a lesser extent in Child B and subsequent OLT can be technically challenging. Liver Transplant In patients with early HCC which are unresectable due to underlying chronic liver disease, OLT offers the best possible outcome. This not only removes the tumor but also the underlying causative factor. In carefully selected patients who meet the CMC, 5-year survival rates in excess of 70% can be achieved (11,14). With a paucity of donor liver, especially in the Far East where the incidence of HCC is high, tumor progression leads to dropout from the waiting list. Though it is difficult to ascertain the exact rate of dropout, about 22% on the waiting list for OLT drop out in the first year due to tumor progression (5,21). Tumors with more than two nodules on presentation and those measuring >3 cm have a higher likelihood of drop out from the waiting list. OLT can be used as (a) primary therapy and (b) salvage OLT Primary Therapy Primary OLT without any pre-transplant treatment, in patients with early HCC who meet the CMC within first 6 months of diagnosis, is the ideal treatment. But due to scarcity of available donor liver, this is not always possible. Traditionally, in the West, DDLT is the method of choice. To make the status of patient amenable for OLT while on the waiting list and to prevent drop out various adjuvant therapies can used. Commonly used are TACE, RFA, and to a lesser extent LR. Furthermore, LDLT has been used, more so in the Far East to overcome the lack of donor organs. The survival of the graft in low-volume liver transplant in LDLT is dependent not only on the extent of ischemia–reperfusion injury but also on the presence or absence of portal hypertension in the recipient. Early interest in the West has not been sustained due to adverse publicity following donor mortality risk. Even in the Far East, LR seems to be initial choice of therapy with LDLT being used in case of tumor recurrence. Pushing the boundaries of CMC has resulted in more and more patients falling just outside the accepted norms being referred to the transplant units. The idea of expanded criteria is mooted on the basis of Metro Rail paradigm “the farther you travel, the higher the price” (22).

Salvage OLT In patients who have had LR, PEI, or RFA as the primary treatment survival figures at the end of 5 years is 70% (11,14), 53% (23), and 60% (24), respectively. In those with recurrence, salvage surgery in the form of OLT can be offered. In the Far East, with perpetual shortage of donor liver, LDLT is being used more frequently for salvage OLT. The selection criteria for LDLT are far more liberal than the stringent CMC used for DDLT. Chemical or Thermal Ablation In patients with small tumor located deeply within the liver parenchyma, tumor ablation performed percutaneously or trans-arterially is possible. RFA (24,25) is used routinely not only as a primary therapy but also as a pre-transplant therapy to reduce the dropout rate. The limiting factor is the tumor size and presence of larger vessel close to the tumor with complications occurring in 8% to 23% including abscess formation, biliary injury, and a potential for tumor seeding along the track. PEI (26) is a cheaper alternative with fewer side effects, but the use is limited by tumor size given the fact that best results are seen for tumors <2 cm. Both provide a good cumulative survival benefits.

intermediate and advanced stage hcc Those patients who have larger asymptomatic tumor which does not fall into CMC category, Child B, compensated chronic liver disease and the absence of extra hepatic spread is considered to have intermediate stage HCC. LR though controversial has been used as an initial therapy option in large HCC with comparable outcomes (27). TACE and RFA either exclusively or in combination have been used to downstage HCC with good results (28). This could be used not only as a prognostic indicator for post transplant outcome, but also for selection of patients for OLT. Application of expanded criteria such as UCSF still needs full validation and has been used in relatively few centers. However, some centers do routinely offer primary OLT with acceptable 5-year survival figures. In the Far East, LR is being offered as a first-line therapy with salvage OLT being used for recurrence. Patients with unresectable HCC with vascular invasion and/or extra hepatic spread are considered to have advanced HCC. Treatment for advanced HCC is restricted to TACE, RFA, or radio sphere embolization. TACE has shown significant benefit in unresectable HCC with good response rates. Patients have a transient post-embolization syndrome with pain, fever, and transient raise in liver enzymes. Major complications such as ischemic necrosis of gall bladder, liver abscess, and biliary stricture are rare. Systemic chemotherapy is rarely being used because of poor response rates. Furthermore, in patients with cirrhosis, hypersplenism, worsening of portal hypertension, major variceal bleeding, or bleeding from gastrointestinal tract and onset of encephalopathy are some of the serious complications

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18. Kianmanesh R, Regimbeau JM, Belghiti J. Selective approach to major hepatic resection for hepatocellular carcinoma in chronic liver disease. Surg Oncol Clin N Am 2003; 12(1): 51–63. 19. Belghiti, J, Carr BI, Greig PD, Lencioni R, Poon RT. Treatment before liver transplantation for HCC. Ann Surg Oncol 15(4): 993–1000. 20. Sala M, Fuster J, Llovet JM, et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma. An indication for salvage transplantation. Liver Transpl 2004; 10: 1294–300. 21. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30: 1434–40. 22. Yao FY. Liver transplantation for hepatocellular carcinoma: beyond the Milan. Crit Am J Transplant 2008; 8: 1982–9. 23. Livraghi T, GiorgioA, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients : long term results of percutaneous ethanol injection. Radiology 1995; 197: 101–8. 24. Choi D, Lim HK, Rhim H, et al. Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-institution series. Eur Radiol 2007; 17(3): 684–92. 25. Lencioni R, Pina CD, Bartolozzi C. Percutaneous image-guided radiofrequency ablation in the therapeutic management of hepatocellular carcinoma. Abdom Imaging 2005; 30(4): 401–8. 26. Ebara M, Okabe S, Kita K, et al. Percutaneous ethanol injection for small hepatocellular carcinoma: therapeutic efficacy based on 20-year observation. J Hepatol 2005; 43(3): 458–64. 27. Pandey D, Lee K-H, Wai C-T, Wagholikar G, Tan K-C. Long term outcome and prognostic factors for large hepatocellular carcinoma (10 cm or more) after surgical resection. Ann Surg Oncol 14(10): 2817–23. 28. Cheng BQ, Jia CQ, Liu CT, et al. Chemoembolization combined with radiofrequency ablation for patients with hepatocellular carcinoma larger than 3 cm: a randomized controlled trial. J Am Med Assoc 2008; 299(14): 1669–77 29. Cherqui D, Laurent A, Mocellin N, et al. Liver resection for transplantable hepatocellular carcinoma: long term survival and role of secondary liver transplantation. Ann Surg 2009; 250(5): 738–46. 30. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: 1914.

21

Treatment of laparoscopically discovered gallbladder cancer Jason K. Sicklick, David L. Bartlett, and Yuman Fong

introduction Traditionally a great deal of pessimism has been associated with the treatment of gallbladder cancer (1). There are many reasons for the skepticism associated with this disease entity since its first description in 1778 (2). Foremost is the aggressive nature of this cancer for dissemination. Gallbladder cancer spreads early by direct invasion into the liver, as well as through lymphatics to regional nodes, by peritoneal dissemination to produce carcinomatosis, and by hematogenous means to produce synchronous liver and other distant metastases. As a result, gallbladder cancer often presents at a time when surgical excision is either no longer possible or is technically difficult while alternative therapies including chemotherapy and radiation are generally ineffective. Therefore, it is not surprising that in 1924 Blalock recommended that surgery be avoided for gallbladder cancer if the diagnosis could be made preoperatively (3). In fact, until recently, the 5-year survival in most large series was less than 5%, and the median survival was less than 6 months (4,5). In the modern era, liver resection has become increasingly safe. More recent experience has demonstrated that radical surgery may be a sensible and potentially curative option in the treatment of this disease (6,7). The data have demonstrated that surgical excision is the treatment option of choice for those patients whose gallbladder cancers are confined to the local region of the liver and porta hepatis (8–10). Beginning in late 1980s, when the techniques for laparoscopic cholecystectomy were introduced, a new presentation for gallbladder cancer was conceived. With the advent and popularization of laparoscopic cholecystectomy, increasing number of cases of gallbladder cancer were being discovered laparoscopically. Currently, approximately 750,000 cholecystectomies are performed in the United States annually for presumed calculous biliary disease (11). Since gallbladder cancer is encountered in 1% of cholecystectomies for cholelithiasis (7), a significant number of patients will present with this clinical scenario. Therefore, meticulous inspection of the gallbladder should be mandatory (12). The current chapter will review data addressing the utility of subsequent radical resection for laparoscopically discovered gallbladder cancer. We will begin with a brief general review of gallbladder cancer, which focuses on the natural history and results of surgical treatment. Summarized data on presentation and results of treatment for laparoscopically discovered disease will be discussed, including the differences of discovery by an open rather than laparoscopic operation.

epidemiology Gallbladder cancer is the most common biliary tract malignancy and the fifth most common gastrointestinal malignancy in the United States. In fact, there are approximately 5,000 new

diagnoses each year (13). It has an annual incidence of 1.3 per 100,000 in females and 0.8 per 100,000 in males, with an average incidence of 1.2 cases per 100,000 population per year (14). This cancer is responsible for approximately 2,800 deaths per year. The most obvious associated conditions for gallbladder cancer are gallstone disease and chronic cholecystitis. Between 75% and 98% of all patients with carcinoma of the gallbladder have cholelithiasis (15). Most importantly, gallbladder cancer will be found once in every 100 cases of presumed gallstone disease. The natural history of gallbladder cancer has been defined through many retrospective reviews and large surveillance programs. The overall 5-year survival is consistently less than 5%, with a median survival of 5 to 8 months. Piehler et al. (5) reviewed 5,836 cases in the world’s literature from 1960 to 1978. They reported an overall 5-year survival of 4.1% and a 1-year survival of 11.8%. Only about 25% were resectable for cure, and of those resected for cure, 16.5% survived 5 years. Perpetuo et al. (4) reviewed the M.D. Anderson Cancer Center experience with gallbladder cancer over 36 years and reported a 5-year survival rate of less than 5% and median survival of 5.2 months. Cubertafond et al. (16) reported the results of a French Surgical Association Survey of 724 carcinomas of the gallbladder. They reported a median survival of 3 months, a 5-year survival rate of 5%, and a 1-year survival rate of 14%. They observed no differences among the different surgical procedures adopted, and concluded that no progress had been made in the treatment of gallbladder cancer. A survey of gallbladder cancer in Wessex, United Kingdom, revealed only four patients out of 95 surviving from 8 to 72 months after the time of diagnosis (17). A review of gallbladder cancer from Australia revealed a 12% 5-year survival rate, with all survivors having stage I or II disease. The median survival for patients with stage III or IV disease was only 46 days (18). SEER data from the United States demonstrated similarly unsatisfying results, with only marginal improvement over earlier studies with median overall survival time being 10 months (95% CI 9 to 11 months), as well as 1-year, 2-year, 3-year, and 5-year overall survival rates of 46%, 30%, 23%, and 17%, respectively, in 4,180 patients (19). A multi-institutional review from Japan, on the other hand, reported a 50.7% 5-year survival for 984 patients undergoing radical resection versus 6.2% for 702 patients undergoing more conservative management (20). These results suggest that it may be possible for surgery to have a role in changing the natural history of this tumor. Therefore, it is clear that radical liver resection, or extended liver resection, in gallbladder cancer does have survival benefit in selected cases (7,21,22). Despite this data, it is important to emphasize that there has been only one small randomized, prospective trial on the treatment of gallbladder cancer. Moreover, there are no

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS randomized trials comparing extended resection to conservative management. The routine use of more radical resections, including those of segments IV and V and the common bile duct, despite a negative cystic duct margin, has gained some popularity. There is no randomized data in the literature to show that this is mandatory in patients with Tis, T1, or T2 disease where a negative margin is obtained.

pathology At early stages, gallbladder carcinomas are difficult to grossly differentiate from chronic cholecystitis. As a result, they are often found incidentally upon pathologic section. Even at late stages, when the tumor can obstruct the common bile duct and produce jaundice, gallbladder cancer is often mistaken for benign disease since associated gallstones and Mirizzi’s syndrome are common (23). Therefore, a long-term obstruction of the mid-common bile duct should be considered a gallbladder cancer until proven otherwise. Tumors that arise in the neck and within Hartmann’s pouch may also infiltrate the common hepatic duct, making them clinically and radiographically indistinguishable from hilar cholangiocarcinomas. Approximately 60% of tumors originate in the fundus of the gallbladder, 30% in the body, and 10% in the neck (24). These tumors grow most commonly in a diffusely infiltrative form (25), with a tendency to involve the entire gallbladder, and spread in a subserosal plane, which is the same as the surgical plane used for routine cholecystectomy. If such a tumor is unrecognized at the time of surgery, a simple cholecystectomy will not completely excise the disease and may lead to dissemination of tumor. Although the nodular type of tumor may show early invasion through the gallbladder wall into the liver or adjacent structures, it may be easier to control surgically than the infiltrative type because the margins are better defined. The papillary growth pattern has the best prognosis because even large tumors have only minimal invasion of the gallbladder wall (14). The most common histologic cell type of gallbladder cancers is adenocarcinoma (26). Other rare subtypes of gallbladder cancer include papillary carcinoma, mucinous carcinoma, clear cell carcinoma, signet ring carcinoma, squamous cell carcinoma, small cell (oat cell) carcinomas (27), adenosquamous tumors (28), sarcomas, carcinosarcoma, carcinoid, lymphoma, melanoma, and gastrointestinal stroma tumors (GIST) (29,30).

patterns of spread Gallbladder carcinoma commonly disseminates by four modes: 1. Direct extension and invasion of the liver and adjacent organs 2. Lymphatic spread 3. Shedding and peritoneal dissemination, and 4. Hematogenous spread to distant sites. The gallbladder lies on segments IVb and V of the liver and these segments are involved early in tumors of the fundus and body. Direct extension into the portal structures (i.e., portal vein, hepatic artery, and bile duct) commonly occurs and is a major cause of symptoms. Lymphatic spread is also common and most often involves cystic and pericholedochal nodes.

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Tumor may then pass to lymph nodes posterior to the pancreas, portal vein, and common hepatic artery. Advanced disease may ultimately reach the interaortocaval, celiac axis, and superior mesenteric artery lymph nodes. Gallbladder cancer also has a remarkable propensity to seed and grow within the peritoneal cavity, which may account for its ability to grow along the tracts of needle biopsy sites and laparoscopic port sites. Growth in those sites may be further exacerbated by bile spillage during laparoscopic cholecystectomy (31,32). In fact, another group demonstrated that the incidence of port site/ peritoneal recurrence was higher in patients with gallbladder perforation (3/7, 43%) than in those without (0/21, 0%; p = 0.011) (33). The long-term survival was worse in the seven patients with gallbladder perforation (cumulative 5-year survival of 43%) as opposed to those without perforation (cumulative 5-year survival of 100%; p < 0.001). Hematogenous spread is less common but will present most often as noncontiguous liver metastases, and more rarely as lung or brain metastases. At postmortem examination, Perpetuo et al. (4) reported that 91% of patients had liver metastasis and 82% had intra-abdominal lymph node involvement, 60% had peritoneal spread, 32% had lung metastases, and 5% had brain metastases.

staging The multitude of staging systems (Table 21.1) used for this disease has made it difficult to compare treatment results. Nevin et al. (34) originally classified patients into five stages based primarily on the thickness of invasion, and combined patients with direct liver extension or distant metastases into stage V. Donahue et al. (35) modified the Nevin system to include tumors with contiguous liver invasion as stage III and noncontiguous liver involvement as stage V. Stage IV continued to include lymph node metastases. The Japanese Biliary Surgical Society staging system separated tumors into four stages according to the degree of lymph node metastasis, serosal invasion, peritoneal dissemination, hepatic invasion, and bile duct infiltration. The main weakness of this staging system is that lymph node metastases are considered in the same stage as microinvasion of the liver. Despite these various systems, the most common system for evaluating gallbladder cancer worldwide has been the American Joint Committee on Cancer (AJCC) TNM staging system for gallbladder cancer (26). Unfortunately, the 6th edition of the AJCC staging system underwent radical changes due to a desire to match the staging of other biliary cancers. The staging system was therefore not consistent with data. A recent paper documented the deficiencies of the 6th edition staging system using 10,705 cases of this disease from the National Cancer Database (36). Thus, the new 7th edition staging will revert to a system much more in line with past staging (Table 21.1). According to this system, tumors without perimuscular invasion are considered stage I. Tumors with invasion into the perimuscular connective tissue but without extension beyond the serosa or into the liver are considered stage II. Tumors that perforate the serosa and/or directly invade the liver and/or adjacent structures, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic biliary tree are stage IIIA if

TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER Table 21.1 Summary of Most Commonly Used Staging Systems Stage

AJCC 5th edition (TNM)

I

Mucosal (T1N0M0)

II

Muscular invasion (T2N0M0)

III

Liver invasion <2 cm; lymph node mets (T3N1M0)

IV

(1) Liver invasion >2 cm (T4N0M0, TxN1M0 (2) Distant metastases (TxN2M0, TxNxM1) N2 lymphadenopathy [peripancreatic (head only), periduodenal, perioportal, celiac, superior mesenteric, or paraaortic nodes] [—]

V

AJCC 6th edition (TNM)

Modified Nevin

Japanese

Proposed 7th edition AJCC

IA: Mucosal or muscular invasion (T1N0M0) IB: Perimuscular invasion (T2N0M0) IIA: Perforate the serosa and/ or directly invade the liver and/or adjacent structures (T3N0M0 IIB: Tumors with regional nodal lymph node metastases but no invasion of the main portal vein, hepatic artery, or multiple extrahepatic organs/ structures (T1-3N1M0) Tumor invades the main portal vein, hepatic artery, or multiple extrahepatic organs/ structures. (T4NxM0) (Distant metastases (TxNxM1)

In situ carcinoma

Confined to gallbladder capsule

Mucosal (T1N0M0)

Mucosal or muscular invasion

N1 lymph nodes; minimal liver orbile duct invasion

Muscular invasion (T2N0M0)

Transmural direct liver invasion

N2 lymph nodes; marked liver or bile duct invasion

Lymph node metastasis

Distant metastases

Transmural (T3N0M0), or T-3 with nodal involvement Metastatic disease, or vascular involvement with nodal metastases (T4N1M0)

[—]

Distant metastases

[—]

there is no regional lymph node metastasis. Stage IIIB tumors have nodal metastases but no vascular invasion. Stage IVA includes those patients with vascular invasion, and stage IVB includes patients with distant metastases or those with vascular invasion and nodal metastases.

clinical presentation The clinical presentation of gallbladder cancer is often identical to biliary colic and/or chronic cholecystitis, making it difficult to diagnose preoperatively. It is also difficult to easily distinguish gallbladder cancer from benign gallstone disease from blood tests. Elevated alkaline phosphatase and/or bilirubin levels are found in cases of advanced tumors, but may also be found for patients with gallstones. A CEA greater than 4 ng/ml is 93% specific for the diagnosis of gallbladder cancer, but is only 50% sensitive (37). A serum Ca 19–9 level (38) greater than 20 units/ml has 79.4% sensitivity and 79.2% specificity, but neither test is routine in patients suspected of having benign disease. Vigilance for cancer in examination of preoperative sonograms or CT scans is essential. Any mass or polyp associated with the gallbladder (Fig. 21.1) or the presence of a porcelain gallbladder should raise concerns of a gallbladder cancer.Figure 21.1 It is often difficult to make the diagnosis of gallbladder cancer based upon clinical history as it often presents similarly to

Figure 21.1 CT scan demonstrating a papillary carcinoma of the gallbladder. This patient was subjected to a laparoscopic cholecystectomy in spite of this scan and required a subsequent reoperation for a potentially curative radical resection.

benign calculous disease. In a report of 42 laparoscopically discovered gallbladder cancers, in only two of the cases did the laparoscopic surgeon suspect a cancer prior to the surgical procedure (39). The laparoscopic procedure consisted of 19

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS cases of laparoscopic cholecystectomy, one laparoscopic cholecystectomy with intraoperative cholangiogram, and six laparoscopic biopsies only. There were 16 cases that were converted to open procedures, including 12 open cholecystectomies, three open cholecystectomies with common bile duct exploration, and one cholecystectomy with hepaticojejunostomy. Even at the conclusion of the laparoscopic procedure, in only 20 of the 42 cases (47.6%) was there any suspicion of cancer. This underscores the difficulties in diagnosing gallbladder cancer and the ease with which this aggressive malignancy is confused with benign stone disease. Recent studies (40–42) have evaluated the role of meticulous inspection of gallbladder specimens at the time of laparoscopic cholecystectomy. Akyurek et al. (40) inspected 548 laparoscopic cholecystectomy specimens by making an incision in the gallbladder wall and palpating the mucosa after removing the gallbladder from the abdominal cavity. If an abnormal mucosa was observed or palpated, it was marked and then histopathologic examination was performed. They identified 50 cases to be suspicious and histopathologic examination of frozen sections revealed incidental pathologies in 15 specimens. Moreover, five of these specimens had gallbladder cancers. The sensitivity and specificity of the procedure was 78.9% and 93%, respectively, suggesting that this is a simple method for identifying incidental gallbladder cancers and may allow for a definitive resection to be performed at the time of the initial operation. In another study of 983 cases, 11 cancers were identified. Based upon frozen sections, cancer was diagnosed in 40% of Tis lesions, whereas it was found in 83% of T2 or T3 lesions, which required conversion to a more radical operation (41). A larger cohort of 1452 patients identified four patients with gallbladder cancers and, in all cases, there was either preoperative or intraoperative suspicion (43). Together, these studies would suggest that careful inspection and selective evaluation of suspicious gallbladder lesions using frozen sections should be performed.

traditional methods for such assessment. For small tumors, the pattern of obstruction seen on PTC or ERCP may assist in differentiating gallbladder cancer from other tumors or benign disease (46). In the last decade, MR cholangiopancreatography (MRCP) (Fig. 21.2) has improved to become a suitable, noninvasive substitute for direct cholangiography (47). Historically, clinical suspicion for main portal venous and/or hepatic arterial involvement by tumor usually prompted angiography to definitively demonstrate resectability. Improvements in Doppler ultrasound and in MR angiography provide noninvasive substitutes for such assessment. We will often assess a patient presenting with known gallbladder cancer with a single MR scan (48). Detailed information on liver involvement, biliary extension, vascular proximity and involvement, and nodal disease can all be gleaned from this single noninvasive test. With the quality of current cross-sectional imaging, it is rare that direct cholangiography or angiography is necessary. Recently, a role for fluorodeoxyglucose positron emission tomography in the management of patients with gallbladder cancer has been established. This test is useful in diagnosing nodal, peritoneal, and distant metastases (49). In a series of 31 patients with gallbladder cancer, 7 (23%) had therapy altered by staging with FDG-PET.

surgical management

radiologic workup

A wide range of operations has been advocated for gallbladder cancer from simple cholecystectomy to combined extended hepatectomy, common bile duct resection, and pancreaticoduodenectomy (50). Debate still exists as to the extent of surgery (51). A survey of prominent gastrointestinal surgeons in the United States indicated that 49% recommended lymph node dissection and 64% recommended some form of liver resection for stage T2–4 disease. The cynical attitude toward this disease is reflected by the recommendation of 21% of surgeons to perform only a simple cholecystectomy for nodepositive disease (52). Studying the earliest stages of the disease, incidental Tis or T1A gallbladder cancer discovered in specimens following

Most patients with laparoscopically discovered gallbladder cancer will have had an ultrasound performed for suspected cholelithiasis. Review of this ultrasound may provide information concerning liver involvement by tumor, biliary extension of tumor, and/or vascular involvement. However, it is most often that another cross-sectional imaging test is indicated for further assessment of these sites for disease, as well as to assess for presence of nodal disease. The combination of CT scanning and ultrasonography (44) is the most common combination for initial assessment, although MRI scanning can be substituted for CT (45). If the initial assessment suggests evidence of laboratory or radiologic signs of biliary obstruction, assessment of the extent of biliary involvement by another imaging technique may be necessary. Gallbladder cancer can cause obstructive jaundice by direct invasion of the common hepatic duct, or by compression and involvement of the common hepatic duct by pericholedochal lymph nodes. A high correlation between Mirizzi’s syndrome and gallbladder cancer exists (23). Endoscopic or percutaneous cholangiograms (PTC) are the

Figure 21.2 Magnetic resonance cholangiopancreatography demonstrating extent of gallbladder cancer. Extension of tumor within and obstructing the common bile duct is shown with isolation of the left and right hepatic duct. The portal vein (white arrow) is patient and not involved by tumor.

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TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER laparoscopic cholecystectomy does not warrant further surgery if the cancer is limited to the lamina propria-muscularis layer and if a subsequent staging workup is negative. These patients have a 5-year survival rate ranging from 90% to 100% (53). Data would indicate that a potentially curative approach for gallbladder cancer, except for disease at the earliest stages, would require a liver resection and a lymphadenectomy. In the past, some argued that T2 cancers with negative margins may only require a simple cholecystectomy. More recent data suggests that this is not the case. A study from Memorial Sloan-Kettering Cancer Center (MSKCC) demonstrated that even in T2 gallbladder cancer, extended or radical resection affords improved survival over cholecystectomy alone (54). It is clear from pathologic data that T2, T3, or T4 tumors were all associated with greater than a 50% chance of metastases to the regional lymph nodes (Table 21.2). As liver resections have become increasingly safe, increasing numbers of surgical centers are performing radical resections for this disease and data are consequently accumulating that justifies such an aggressive approach. Unless a patient has clear contraindications to resection, including medical comorbidities or unresectable disease, surgical exploration should be attempted. We will review the data supporting radical resection for gallbladder cancer at various stages of disease. Then a discussion of the justification of such treatment in patients with laparoscopically discovered gallbladder cancer will be presented. The most practical way of thinking about laparoscopically discovered gallbladder cancer is to base therapy upon clinical T stage of disease. Not only is there a close correlation of T stage with prognosis, but patients presenting in this setting will usually have had the gallbladder excised and the extent of Table 21.2 Findings Related to T stage of Disease Stage T2 T3 T4

Total metastases (%)

Peritoneal metastases (%)

Nodal metastases (%)

9 16 16

12 43 68

50 50 66

T2, submucosal invasion; T3, full thickness invasion through gallbladder wall with <2 cm extension into liver; T4, > 2 cm extension into liver. Source: From Ref. (39).

local disease defined pathologically. Knowing the likelihood of further local, nodal, peritoneal disease will allow for rational therapeutic choices. Tumors Confined to the Muscular Propria (T1 Tumors) There are abundant data to indicate that early gallbladder cancer, which has not penetrated through the muscular layer of the gallbladder, is adequately treated by simple cholecystectomy. Tsukada et al. (55) demonstrated that in 15 cases with T1 lesions, there were no cases with lymph node metastasis. Table 21.3 (6,20,21,28,35,56–61) summarizes results of resection for stage I disease. After simple cholecystectomy alone, the 5-year survival was 78% to 100% (59,62). In a report of 56 patients treated with simple cholecystectomy alone, only two patients recurred and subsequently died of their disease. Both had submucosal spread of the tumor to involve the cystic duct margin (21). When patients present after laparoscopic cholecystectomy with a pathologic diagnosis of T1 gallbladder cancer, a careful review of the pathology is imperative. Care must be taken to verify both negative margins including the cystic duct stump and that there are no areas of deeper invasion. If the gallbladder margin is involved by tumor, a liver resection is required. If the cystic duct stump is involved, an excision of the common bile duct, including the junction with the cystic duct, is indicated. No nodal dissection is necessary. Tumor Invading into the Subserosal Layer (Stage II) By definition, T2 tumors do not transgress the serosal plane. However, the recommended management for T2 disease is an extended or radical cholecystectomy to include a liver resection and regional lymph node dissection including periportal, peripancreatic, and celiac nodes. This recommendation is based on the pattern of spread of disease. In the most common infiltrative form of gallbladder cancer (25), the cancer often spreads in a subserosal plane, which is the same as the surgical plane used for routine cholecystectomy. This results in a higher likelihood of positive margins after simple cholecystectomy. In the review by Yamaguchi and Tsuneyoshi (59), patients had tumor extending into the subserosal layer and 11 of these had positive microscopic margins after simple cholecystectomy. Furthermore, the likelihood of metastatic disease to regional

Table 21.3 Actuarial Survival Results Reported In Retrospective Reviews after Resection of Stage I Gallbladder Cancers Author

Year

N

Ouchi et al. (56) Yamaguchi and Enjoji (28) Donohue et al. (35) Gall et al. (57) Ogura et al. (20) Shirai et al. (58) Yamaguchi and Tsuneyashi (59) Shirai et al. (21)

1987 1988 1990 1991 1991 1992 1992 1992

Matsumoto et al. (6) Oertli et al. (60) de Aretxabala et al. (61)

1992 1993 1992

14 11 6 7 366 39 6 56 38 4 6 32

Procedure Not specified Not specified Simple cholecystectomy: 83% Simple cholecystectomy Not specified Simple cholecystectomy Simple cholecystectomy Simple cholecystectomy Extended cholecystectomy Extended cholecystectomy Simple cholecystectomy Simple cholecystectomy: 69%

3-Year survival (%)

5-Year survival (%)

78 100 100 86 87 100 100 100 100 100 100 94

71.4 Not reported 100 86 78 100 100 100 100 100 100 94

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS lymph nodes exceeds 50% (7,39,52). Indeed, it is perhaps this group of T2 lesions which will have the best chance of benefiting from definitive extended re-resection (61). Five-year survival of patients subjected to simple cholecystectomy is 20% to 57% while the survival of patients subjected to radical resection is 70% to 100% (Table 21.4) (63–66). For patients presenting with T2 gallbladder cancer discovered at laparoscopic cholecystectomy, a re-exploration with the intent to perform a liver resection and regional nodal dissection is recommended. During this re-exploration, inflammation from the previous operation will make it difficult to determine the exact extent of disease. Furthermore, all of the laparoscopic port sites should be excised in a full thickness manner. The patients must be informed that final pathology may not demonstrate residual tumor. Advanced Tumors (stages III and IV) Patients with T3 or T4 gallbladder cancer will present after laparoscopic cholecystectomy not only with an obvious pathologically positive margin for tumor, but also with a hepatic mass on cross-sectional imaging. Debate raged in the past regarding justification of radical surgery for such advanced disease. As radical resections have become increasingly safe, reports of long-term survivors after aggressive surgical management are abundant in the literature; Table 21.5 reviews these studies. Onoyama et al. (67) reported a 63.6% 5-year survival for Japanese Biliary Surgical Society stage II and 44.4% 5-year survival for stage III disease after extended cholecystectomy (AJCC 5th edition stage III). They reported a 5-year survival rate of 8.3% for stage IV disease. In addition, they noted a 5-year survival rate of 60% for patients having metastatic disease to N1 nodes. Shirai et al. (21) reported a 45% 5-year survival for patients with node-positive tumors, documenting nine patients surviving over 5 years after radical

resection. Gall et al. (57) reported that four of eight patients undergoing curative resection for AJCC stages III and IV gallbladder carcinoma at the initial operation were alive after 81, 50, 13, and 8 months. Our data from MSKCC revealed a median overall survival for the 435 patient cohort of 10.3 months. The median survival for those presenting with stages Ia–III disease was 12.9 months and 5.8 months for those presenting with stage IV disease (68). We previously reported a 67% actuarial 5-year survival for patients with completely resected stage III and 33% 5-year survival for patients with completely resected stage IV tumors (7, 66) These results represent marked alteration of the natural history of this tumor. These data would indicate that radical surgery for advanced gallbladder cancer may be potentially curative (Table 21.5) (64–66). Patients presenting with T3 and T4 disease after laparoscopic cholecystectomy should have imaging performed to rule out signs of unresectable disease, including noncontiguous liver metastases or signs of carcinomatosis. Barring any contraindications to surgery (i.e., medical contraindications to major abdominal surgery, cirrhosis, or insufficient remnant liver volume to maintain adequate hepatic function), patients should be re-explored for radical resection of tumor, which usually requires a major liver resection and regional lymphadenectomy. Re-resection after Laparoscopic Cholecystectomy Data available for re-resection for gallbladder cancer treated initially with open simple cholecystectomy suggest that, for tumors with a depth of penetration greater or equal to the perimuscular coat (i.e., T2), a radical re-resection is warranted (62). However, the prognosis for patients subjected to two operations for gallbladder cancer is thought to be less favorable than for patients treated with a single procedure. Gall et al. (57) reported a median survival of 42 months for patients

Table 21.4 Actuarial Survival Results Reported in Retrospective Reviews after Resection of Stage II Gallbladder Cancers Author

Year

N

Yamaguchi and Enjoji (28) Donohue et al. (35) Ogura et al. (20) Gall et al. (57) Shirai et al. (58)

1988 1990 1991 1991 1992

Yamaguchi and Tsuneyashi (59) Matsumoto et al. (6) Oertli et al. (60) Cubertafond et al.a (16) Bartlett et al. (7) Paquet (107) Shih (63) Kai (64)

1992 1992 1993 1994 1996 1998 2007 2007

Jensen (65)

2008

D’Angelica (66)

2008

73 12 499 7 35 10 25 9 17 52 8 5 34 9 25 769 196 41

a

Multi-institutional survey. Chole, cholecystectomy.

202

Procedure Not specified 67% Extended chole Not specified 86% Simple chole Simple chole Extended chole Simple chole Extended chole Simple chole 88% Simple chole Extended chole Extended chole Extended chole Simple chole Extended chole Simple chole Extended chole Extended chole

3-year survival (%) 40.1 58 53 86 57 90 36 100 29 20 100 100 49 22 60 40 55 84

5-year survival (%) Not reported 22 37 86 40.5 90 36 100 24 Not reported 88 80 49 22 60 29 42 79

TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER undergoing a curative resection at the first operation versus 12.5 months for those undergoing a curative resection at a second operation. Our experience over a 10-year period demonstrated a median survival of 15.7 months for those discovered incidentally at laparoscopic cholecystectomy (68). More recent data would suggest that there is no difference in outcomes in patients who undergo laparoscopic cholecystectomy for unsuspected gallbladder cancer (69,70). Moreover, there appears to be no difference in survival or recurrence between patients that have undergone initial open or laparoscopic cholecystectomy (71). However, it is clear that obtaining an R0 resection significantly improves survival in patients undergoing re-resection (72,73). To that end, a study from Johns Hopkins Hospital (63) showed that there was no survival difference between patients who were immediately converted to an open resection when identified to have gallbladder cancer intraoperatively (N = 6) versus those patients who had a completed laparoscopic cholecystectomy and were re-explored at a later point after discovery of a gallbladder cancer at histopathological review (N = 33). This study would suggest that gallbladder carcinoma discovered during a laparoscopic cholecystectomy does not require immediate conversion to an open resection and should be referred to a tertiary care center for further exploration. In a recent series of 206 cases of laparosocpically discovered gallbladder cancer, 136 patients were re-explored (68). Thirtyfive of these patients were found to have no cancer on exploration or in the final re-excision specimen, while 101 had residual tumor re-excised. Of note, those without residual disease still

had a 50% chance of eventually dying of cancer. The 5-year survival of the patients with no residual disease was 63% and median survival 72 months. Those completely resected of residual disease had a 5-year survival of 22% and a median survival of 19 months. Those with incompletely resected residual disease had a median survival of 12.7 months, and no patient survived 5 years. Liver Resection Except for the patient with T1 tumors who has a positive cystic duct margin, because of the possibility of residual disease remaining within the gallbladder bed, all other patients undergoing re-exploration for re-resection should have some form of liver resection (i.e., a radical or extended cholecystectomy). Even patients with T2 tumors have a likelihood of residual gallbladder bed disease because the most common plane for simple cholecystectomy is subserosal. Recommendations for liver resection for gallbladder cancer have ranged from a limited wedge excision of 2 cm of liver around the gallbladder bed to routine extended right hepatic lobectomy. We prefer an anatomic segment IVb and V resection when possible, because this anatomic operation allows the greatest chance of tumor clearance while minimizing the amount of functional liver removed. In cases of previous cholecystectomy, such a limited resection may not be possible. Scars from the previous surgery may be difficult to distinguish from tumor and a more radical resection may be necessary to ensure complete eradication of disease. It

Table 21.5 Actuarial Survival Results reported in Retrospective Reviews after Resection of Stage III and IV Gallbladder Cancers 3-Year survival (%)

5-Year survival (%)

III

38

–

12 12 8 12 13

III III III III/IV III/IV

80 44 63 17 16

– 44 63 – 16

1990 1991

17 8

III/IV III/IV

50 50

29 –

Shirai et al. (58) Ogura et al. (20)

1992 1991

20 453

III/IV IV

– 18

45 8

Todoroki et al. (92) Nimura et al. (50) Matsumoto et al. (6)

1991 1991 1992

27 14 27

IV IV IV

7 10 25

– – –

Chijiiwa and Tanaka (102) Onoyama et al. (67) Bartlett et al. (7)

1994 1995 1996

11 14 7

IV IV IV

11 8 25

– 8 25

Kai (64) D’Angelica (66) Jensen (65)

2007 2008 2008

16 63 119

III/IV III/IV III

40 45 18

36 28 9

Author

Year

N

Matsumoto et al. (6)

1992

8

Chijiiwa and Tanaka (102) Onoyama et al. (67) Bartlett et al. (7) Ouchi et al. (56) Nakamura et al. (103)

1994 1995 1996 1987 1989

Donohue et al. (35) Gall et al. (57)

Stage

Comments Majority with common bile duct resection Extended resections only Extended resections only Extended resections only Extended resections only Includes 5 HPD, 10 extended hepatectomy Extended resections only Includes only curative resection at initial surgery All patients have lymph node metastases Multi-institutional series with 25% simple cholecystectomy All patients had IORT All patients underwent HPD Includes 3 HPD, 6 extended hepatectomy, 11 CBD resection Extended resections only Japanese staging Long-term survivors with no lymph node metastases

CBD, common bile duct; HPD, hepatopancreatoduodenectomy; IORT, intraoperative radiation therapy.

203

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS must be emphasized that complete excision of any suspicious areas must be performed since any residual tumor will result in recurrence that is usually rapidly fatal. Often, therefore, a right lobectomy or trisegmentectomy will be necessary. Lymph Node Dissection Studies of lymphatic spread of gallbladder cancer have been published and reviewed (74). Recommendations for lymph node dissection for gallbladder cancer have ranged from excision of the cystic duct node alone to en bloc portal lymphadenectomy with pancreaticoduodenectomy (6). Justification for more radical procedures comes from the propensity for early spread to the superior, anterior, and posterior pancreaticoduodenal nodes. Combined liver and pancreatic resections have high operative mortalities of near 20%, and are not justified by long-term results. Portal lymphadenectomy for tumor penetrating the gallbladder beyond T2 is supported by our findings of positive nodes in over 50% of patients with T2, T3, or T4 gallbladder cancer (39). We also believe that an adequate portal lymphadenectomy requires resection of the common bile duct. Particularly in patients who have just had a cholecystectomy, the portal lymph nodes are often intimately associated with the bile duct. Resection of the common bile duct greatly facilitates nodal clearance. In general, a full Kocher maneuver should be performed. The lymphatic tissue should then be dissected behind the duodenum and pancreas and subsequently swept superiorly. Any interaortocaval nodes or superior mesenteric nodes should be included in the specimen if possible. The common bile duct should be transected as it courses posterior to the duodenum into the pancreas. The portal vein and hepatic artery should be skeletonized and all tissue swept superiorly along with the transected duct. At the confluence of the right and left hepatic ducts, the common bile duct should be divided again (assuming the cystic duct does not enter the right hepatic duct). A Roux-en-Y hepaticojejunostomy should be performed to re-establish biliary– enteric continuity. Laparoscopic Port Sites A number of studies have demonstrated the propensity of tumor to recur in the laparoscopic port sites because gallbladder cancer has a great potential for peritoneal seeding and dissemination (Table 21.6) (75–82). Indeed, our preliminary report of the first ten patients we encountered with laparoscopically discovered gallbladder cancer included two patients in whom the tumor recurrence was found in a port site (79). The incidence of peritoneal metastases is higher than reported in the pre-laparoscopic era. One report found a 32% recurrence rate appearing as a new or enlarging abdominal wall mass on physical examination and/or CT scanning for followup of disease (83). Another study by Paolucci (84) found 174 cases of port site metastasis after laparoscopic cholecystectomy and 12 recurrences in the surgical scar after converted or open cholecystectomy. This report found a 14% incidence of port site metastases at 7 months after laparoscopic cholecystectomy for cancer. Therefore, it has become our standard practice to excise laparoscopic port sites at the re-exploration. During

204

Table 21.6 Recurrence of Tumor in Laparoscopic Port Sites Author Drouard et al. (75) Clair et al. (76) Landen (77) Fligelstone et al. (78) Fong et al. (79) Nduka et al. (80) Nally and Preshaw (81) Kim and Roy (82) Antonakis et al. (42) Cucinotta et al. (108) Hamila et al. (109) Paolucci (84)

N

Port

1 1 1 1 2 1 1 1

Umbilical Umbilical Umbilical Umbilical Umbilical Epigastric Umbilical Umbilical 0 Not specified Not specified Various

3 4 174

that operation, care must be taken to perform a full abdominal inspection to rule out peritoneal disease (85). Whether such excision of port sites is useful requires further investigation, since port recurrence may be just a marker for diffuse peritoneal dissemination of disease. Complications The operations described above are extensive procedures with substantial risks. In particular, the majority of patients undergoing treatment for gallbladder cancer are in their seventh or eighth decade of life and may be at increased risk as a consequence of concomitant medical comorbidites. In a multi-institutional review of 1686 gallbladder cancer resections from Japan, a comparison of morbidity by procedure was made (20). A morbidity of 12.8% was reported for cholecystectomy, 21.9% for extended cholecystectomy, and 48.3% for hepatic lobectomy. The mortality rates were 2.9%, 2.3%, and 17.9%, respectively. There were 150 hepatopancreatoduodenectomies for gallbladder cancer, with a 54% morbidity rate and a 15.3% mortality rate. The morbidity and mortality rates of major liver resections have decreased in later reports, even in the aged population (86). In our report of re-resection for laparoscopically discovered gallbladder cancer, all resected patients were subjected to some form of liver resection and the operative mortality was 5% (39). The most common complications are bile collections, liver failure, intra-abdominal abscess, and respiratory failure. The risk of resection for each patient and for each type of resection needs to be weighed against the chance of benefiting from the procedure based on the stage of disease.

adjuvant therapy Because of the rarity of gallbladder cancer in general, as well as the rarity of completely resected disease, there is only one prospective, randomized trial examining the utility of adjuvant therapy for gallbladder cancer. This trial assessed 5-year overall survival in patients following noncurative resection who received postoperative adjuvant chemotheraoy using mitomycin C and 5-FU. Survival was improved with adjuvant therapy (26% vs. 1%, P = 0.03). (87) However, most data available is derived from retrospective series. Conclusive data do not support the routine use of chemotherapy (88–90).

TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER Data regarding radiation therapy are more substantial, but still far from conclusive (91). Todoroki et al. (92) examined intraoperative radiation therapy after complete resection for stage IV gallbladder cancer. They reported a 10.1% 3-year survival for patients receiving intraoperative radiation therapy versus 0% for surgery alone. Bosset et al. (93) examined postoperative external beam irradiation after complete resection in seven patients. They concluded that it was a safe treatment, and five of the seven patients were still alive at a median follow-up of 11 months. Hanna and Rider (94) reported radiation therapy in 51 patients and reported survival to be significantly longer in patients receiving postoperative radiotherapy compared with those who had surgery alone. In a retrospective review from Finland, the median survival of patients receiving postoperative radiation was 63 months compared with 29 months for patients receiving surgery alone (95). Another small study from the Mayo clinic evaluated 21 patients following curative resection along with adjuvant combined modality therapy with external beam radiation and 5-FU (96). These 21 patients had a 5-year survival rate of 64% versus a historical surgical cohort with a 5-year survival rate of 33% after R0 resection alone. Currently, in patients with node-positive disease, we are recommending radiation therapy. Chemotherapy is only used as a potential radiation-sensitizing agent.

palliative management Palliative therapy should be considered in the context that the median survival for patients presenting with unresectable gallbladder cancer is 2 to 4 months (60,97). The goal of palliation should be relief of pain, jaundice, and bowel obstruction, as well as prolongation of life. These should be done as simply as possible given the aggressive nature of this disease. Biliary bypass for obstruction can be difficult because of advanced disease in the porta hepatis. A segment III bypass is usually necessary if surgical bypass is chosen to relieve jaundice (98,99). However, such bypasses have a 12% 30-day mortality rate (99) In the event of a preoperative diagnosis of advanced, unresectable gallbladder cancer in the jaundiced patient, therefore, a noninvasive radiologic approach to biliary drainage is justified. Systemic chemotherapy (100) and radiation therapy (101) have little effect on these tumors. Patients with unresectable disease and good functional status who desire therapy should be directed to investigational studies to determine whether any novel therapies may be of benefit.

summary Gallbladder cancer is an aggressive disease with a dismal prognosis. It should not, however, be approached with a fatalistic attitude. Appropriate workup and extended resection can result in a cure. Gallbladder cancer will be encountered approximately once every 100 times that a gallbladder is removed for presumed benign gallstone disease. For those patients discovered to have a T1 cancer during pathologic analysis, no further therapy is indicated as long as all the margins, including the cystic duct margin, are negative (56,58). However, T2, T3, or T4 tumors deserve consideration for reexploration (54,61,102–106). Selection for re-resection relies

upon evaluation of the patient’s general medical fitness as well as rigorous radiologic workup to rule out disseminated disease. Evidence of distant nodal (i.e., N2) disease on preoperative workup precludes a curative resection as no long-term survivors have been reported with gross N2 disease. These patients should be treated only as symptoms develop but should not be offered a reoperation for curative intent. Those re-explored for resection should undergo a standard extended cholecystectomy, including an extensive nodal dissection to include the superior pancreaticoduodenal nodes and a skeletonization of the vessels in the porta hepatis. If the nodal dissection is compromised by the presence of the common bile duct, then this should be resected. In addition, a segment IVb and V resection of the liver or extended resection of the liver should be included, as dictated by the location of the tumor as well as surrounding inflammation and scar tissue.

key points Gallbladder cancer will be found in 1 per 100 cholecystectomy specimens (incidence 1.2 cases per 100,000 population per year). ● ●

●

●

75% to 98% association with cholelithiasis. A long obstruction of the mid-common bile duct is gallbladder cancer until proven otherwise. Radiologic investigation of gallbladder cancer: Ultrasound MRCP CT ERCP/PTC if jaundiced Surgical management: Stage I (T1N0M0): Simple cholecystectomy alone Stage II (T2N0M0): Radical cholecystectomy Stage III (T3N0M0) ± hepatic invasion <2 cm: Radical cholecystectomy Stage IV (T4N0M0) ± liver invasion >2 cm – No dissemination: extended hepatectomy – Widespread dissemination: no surgical option

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86. Fong Y, Blumgart LH, Fortner JG, Brennan MF. Pancreatic or liver resection for malignancy is safe and effective for the elderly. Ann Surg 1995;222(4):426–34. 87. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002;95(8):1685–95. 88. Chao TC, Jan YY, Chen MF. Primary carcinoma of the gallbladder associated with anomalous pancreaticobiliary ductal junction. J Clin Gastroenterol 1995;21(4):306–8. 89. Oswalt CE, Cruz AB, Jr. Effectiveness of chemotherapy in addition to surgery in treating carcinoma of the gallbladder. Rev Surg 1977;34(6):436–8. 90. Morrow CE, Sutherland DE, Florack G, Eisenberg MM, Grage TB. Primary gallbladder carcinoma: significance of subserosal lesions and results of aggressive surgical treatment and adjuvant chemotherapy. Surgery 1983;94(4):709–14. 91. Todoroki T. Radiation therapy for primary gallbladder cancer. HepatoGastroenterology 1997;44(17):1229–39. 92. Todoroki T, Iwasaki Y, Orii K, et al. Resection combined with intraoperative radiation therapy (IORT) for stage IV (TNM) gallbladder carcinoma. World J Surg 1991;15(3):357–66. 93. Bosset JF, Mantion G, Gillet M, et al. Primary carcinoma of the gallbladder. Adjuvant postoperative external irradiation. Cancer 1989;64(9):1843–7. 94. Hanna SS, Rider WD. Carcinoma of the gallbladder or extrahepatic bile ducts: the role of radiotherapy. Can Med Assoc J 1978;118(1):59–61. 95. Vaittinen E. Carcinoma of the gall-bladder. A study of 390 cases diagnosed in Finland 1953-1967. Annales Chirurgiae et Gynaecologiae Fenniae - Supplement 1970;168:1–81. 96. Kresl JJ, Schild SE, Henning GT, et al. Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiation Oncol Biol Phys 2002;52(1):167–75. 97. Wanebo HJ, Castle WN, Fechner RE. Is carcinoma of the gallbladder a curable lesion? Ann Surg 1982;195(5):624–31. 98. Bismuth H, Corlett MB. Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet 1975;140:170–6. 99. Kapoor VK, Pradeep R, Haribhakti SP, Sikora SS, Kaushik SP. Early carcinoma of the gallbladder: an elusive disease. J Surg Oncol 1996;62(4):284–7. 100. Taal BG, Audisio RA, Bleiberg H, et al. Phase II trial of mitomycin C (MMC) in advanced gallbladder and biliary tree carcinoma. An EORTC Gastrointestinal Tract Cancer Cooperative Group Study. Ann Oncol 1993;4(7):607–9. 101. Houry S, Schlienger M, Huguier M, et al. Gallbladder carcinoma: role of radiation therapy. Br J Surg 1989;76(5):448–50. 102. Chijiiwa K, Tanaka M. Carcinoma of the gallbladder: an appraisal of surgical resection. Surgery 1994;115(6):751–6. 103. Nakamura S, Sakaguchi S, Suzuki S, Muro H. Aggressive surgery for carcinoma of the gallbladder. Surgery 1989;106(3):467–73. 104. Fong Y, Malhotra S. Gallbladder cancer: recent advances and current guidelines for surgical therapy. Adv Surg 2001;35:1–20. 105. Whalen GF, Bird I, Tanski W, Russell JC, Clive J. Laparoscopic cholecystectomy does not demonstrably decrease survival of patients with serendipitously treated gallbladder cancer. J Am Coll Surgeons 2001;192(2):189–95. 106. Todoroki T, Takahashi H, Koike N, et al. Outcomes of aggressive treatment of stage IV gallbladder cancer and predictors of survival. HepatoGastroenterology 1999;46(28):2114–21. 107. Paquet KJ. Appraisal of surgical resection of gallbladder carcinoma with special reference to hepatic resection. J Hepatobiliary Pancreat Surg 1998;5(2):200–6. 108. Cucinotta E, Lorenzini C, Melita G, Iapichino G, Curro G. Incidental gall bladder carcinoma: does the surgical approach influence the outcome? Aust NZ J Surg 2005;75(9):795–8. 109. Hamila F, Letaief R, Khnissi M, et al. [Port site recurrence after laparoscopic cholecystectomy]. Tunis Med 2006;84(11):697–700.

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22

Liver transplantation for HCC: Asian perspectives Shin Hwang, Sung-Gyu Lee, Vanessa de Villa, and Chung Mao Lo

introduction Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly cancer worldwide (1). HCC is closely associated with chronic liver disease and more than 80% of cases occur in cirrhotic livers (2). Since functional reserve of the liver is often significantly impaired, application of treatment modalities such as liver resection, transarterial chemoembolization, or local ablation therapy is limited. Not only HCC recurrence, but also progressive deterioration of liver function decrease patient survival. Liver transplantation (LT) is the only treatment that offers a chance of cure for the tumor and the underlying liver cirrhosis at the same time, although there is an additional risk of accelerated tumor recurrence from immunosuppression. The outcome of LT for HCC in Western countries is encouraging, but availability of liver grafts still remains the main limitation for LT. Since the incidence of HCC combined with chronic liver diseases is much higher, and organ donation from deceased donors is much fewer in Asian countries compared to Western countries, it is difficult to use Deceased Donor LT (DDLT) as one of the main treatment modalities for HCC in Asia. In fact, organ donation from deceased donors remains below five per million per year in most Asian countries because of various social and cultural reasons (Fig. 22.1) (3). Because of these constraints, Living Donor LT (LDLT) is now the main method of LT in a number of Asian countries, and is an alternative to DDLT in every indication for LT. Numerous technical innovations have been achieved to secure donor safety as well as ensure patient survival. The outcomes of LT for HCC in major Asian LT centers are acceptably favorable and also comparable to those seen in Western countries (3). Patient selection criteria for HCC have also been proposed by several major Asian LT centers based on their own data (4–7).

hepatocellular carcinoma in asia Hepatitis B and C are the most common etiologic agents for HCC (8). Since Hepatitis B Virus (HBV) is more prevalent in most Asian countries, 80% of HCC occurs in areas where HBV infection is endemic, and the geographic distribution of HCC largely follows that of HBV infection (2). Chronic HBV infection is endemic in Asia, where an estimated 300 million individuals are infected by HBV, representing about 75% of the world’s chronic HBV carriers (9). China has the highest ageadjusted incidence of HCC (37.9 per 100,000 in males and 14.2 per 100,000 in females), and accounts for 50% of all cases in the world (1,2). Unlike other Asian countries, prevalence of HBV infection is exceptionally low in Japan, where hepatitis C is more prevalent and similar to that seen in Europe and the United States (8,10). Conventional standard treatments for HCC include surgical resection and non-surgical treatments such as chemoemboli-

208

zation, local ablation, and injection therapy. Surgical resection has been regarded as the treatment of choice for HCC, but it has definite limitations in both tumor resectability and patient safety when hepatic functional reserve is markedly reduced. Although it has been shown that liver resection can be achieved safely in selected patients with cirrhosis (11,12), it is widely accepted that it carries a significant risk of postoperative morbidity, even in patients with Child–Pugh grade A cirrhosis. With reasonable patient selection, liver resection is associated with relatively low operative mortality rates, ranging in recent studies from 0% to 4% (11–13). Long-term survival results after surgical resection, however, are affected by tumor recurrence and progressive deterioration of liver function (14,15). Non-surgical treatments often result in incomplete tumor control and also reveal high recurrence rates when used for advanced HCC lesions. The natural history of untreated and non-surgically treated HCC in Asia is worse than that of similar cases in Western countries. A study from Hong Kong (16) showed that the 1-year and 2-year survival rates of patients with untreated HCC were 7.8% and 0.9%, respectively, whereas a comparable study from Spain (17) showed 54% and 40%, respectively (3).

history of lt in asia LT in Asia started early and yet progressed slowly when compared with Western countries (3). The first liver transplant in Asia was performed in 1964 by Nakayama with a graft from a non-heart beating donor in Chiba, Japan (18). This was only 1 year after Starzl’s first attempt in the world for human LT in Denver, USA (19). It was a highly controversial exploit because organ donation from a deceased person was not accepted in Japanese culture at that time. The second transplant in Asia was performed in 1978 in Shanghai, P.R. China (3,20). In 1984, Chen, in Taiwan, performed the first liver transplant with long-term survival in Asia at a time when there was still no brain death law in that country (21). Legislation regarding brain death was passed in Singapore (22) and Taiwan in 1987, and subsequently in Japan and Korea (23). In Asia, the serious scarcity of deceased donor organ donation and strong demand for LT provided a powerful driving force for the development of LDLT as a practical alternative in replacing DDLT. The first LDLT in Asia was performed by Nagasue of Shimane University, Japan, in 1989 (24), only 1 year after the first attempt of LDLT by Raia in Brazil in 1988 (25). Subsequently Hong Kong, Korea, and Taiwan rapidly initiated pediatric LDLT programs transplanting a left lateral section or a left lobe graft from a parent donor to a child. However, the ultimate need for LDLT was in adult patients. Transplant centers in Asia have repeatedly advanced the frontier of adult-to-adult LDLT. In 1993, Makuuchi in Japan performed the first successful adult LDLT using a left lobe

LIVER TRANSPLANTATION FOR HCC: ASIAN PERSPECTIVES Japan 0.07 1.9 Korea 4.2 Hong Kong 4.7 Singapore 6.6 Taiwan Australia United Kingdom Canada Germany Portugal Italy France Belgium Austria USA Spain 0

5

10 10.7 12.8 14.4 19 20.9 22.2 22.8 24.6 25.2 35.1

10 15 20 25 30 Number of deceased donors per million of population

35

40

Figure 22.1 Comparison of organ donation rates from deceased donors in different countries in the East and West in 2005 (3).

graft (26). The left lobe graft, which usually comprises less than 40% of the whole liver volume, is often too small for an adult recipient. For successful LDLT for adult patients, graft size is the most important factor in determining the outcome of LDLT and is still a controversial concern for selection of the ideal donor. The Kyoto group first reported the use of a right lobe graft for a pediatric recipient as a result of a variance in the donor’s arterial anatomy in 1994 (27). The first case report (28), and subsequently the first series (29) of successful adult LDLT, using a right lobe graft was reported from Hong Kong in 1997. Further technical advances in adult LDLT, including the addition of the caudate lobe to a left lobe graft (30) and the use of right lateral section grafts (31), were reported from Japan. In 1999, authors proposed conservation of the middle hepatic vein trunk to the donor, and the reconstruction of hepatic venous drainage of the right anterior section of the liver graft to avoid congestion injury of both the right lobe liver graft and the donor’s remnant left lobe (32). Middle hepatic vein reconstruction has apparently increased the success rate of the right lobe LDLT in adult patients and widened the safety margin and the pool of living donors. As an attempt to provide adequate graft volume for an adult recipient and minimize the risk of an individual donor, authors also performed implantation of dual grafts from two donors for one recipient in 2000 (33,34). In Asia, where the supply of deceased donor organs remains seriously limited and the demand for LT is persistently increasing, the applicability of LDLT will continue. For successful LDLT, the risk to the donor should be balanced by the greater benefit to the recipient. Every effort must be taken to minimize donor morbidities, making this procedure beneficial to the donor and the recipient (35–38).

selection criteria of hcc and outcome LT offers the opportunity to eliminate both tumor and underlying liver cirrhosis at the same time. From the viewpoints of quality of life and tumor recurrence, any other treatment

modality cannot achieve such a favorable result comparable to that of LT. However, it should be emphasized that HCC recurrence is the most common cause of late patient death after LT (4,39–41). The clinical sequence of post-transplant HCC recurrence is usually much worse than in non-transplant patients since the response to treatment for HCC recurrence after LT is disappointing. To date, the most effective measure to prevent post-transplant HCC recurrence is strict selection of transplant candidates after exclusion of patients with known risk factors for HCC recurrence. Eligibility guidelines for transplantation, such as the Milan and University of California at San Francisco (UCSF) criteria, have been adopted to reduce the post-transplant HCC recurrence and the wasting of donor organs (42,43). The Milan criteria were originally established on the basis of pre-transplant imaging findings but were re-evaluated on the basis of explant liver pathology, whereas the UCSF criteria were based on explant pathology but validated by pre-transplant imaging findings. Each of these two sets of criteria is derived from the experience with DDLT (Table 22.1). Application of these criteria to LDLT has resulted in patient survival outcome, very similar to that following DDLT, as shown in high-volume multi-center cohorts from Japan and Korea (40,41). Moreover, the prognostic powers of the Milan and UCSF criteria were reported to be the same in both DDLT and LDLT (41). When selecting transplant candidates, there is a real risk of discrepancies between the pre-transplant radiological and explant pathologic staging (4,40,41). Candidates for DDLT should be selected after consideration of the extent of HCC at the time of listing, and any further progression of HCC during the waiting period. LDLT, because of its shorter waiting time, is less affected by tumor progression, permitting more flexible selection of transplant candidates than DDLT. A substantial proportion of adult LDLT patients not fulfilling the Milan or UCSF criteria has been found to survive longer than expected after LT (4,40,41,44,45). Therefore, it seems reasonable to attempt further reduction of unnecessary dropouts arising from the strict application of narrow selection criteria.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 22.1 Criteria for Indication of LT in the Setting of Hepatocellular Carcinoma.

Center Asan, Korea (4)

Kyoto, Japan (5)

Tokyo, Japan (6) Hangzhou, P.R. China (7)

Milan, Italy (42)

UCSF, USA (47)

Tumor criteria Diameter ≤5 cm; Number of lesions ≤6; No gross vascular invasion Diameter ≤5 cm; Number of lesions ≤10; PIVKA-II ≤400 mAU/mL Diameter ≤5 cm; Number of lesion ≤5 Total diameter ≤8 cm; or total diameter >8 cm and histopathologic grades I and II, and AFP ≤400 ng/mL Diameter ≤5 cm if single lesion; or Diameter ≤3 cm if multiple lesions and number of lesions ≤3 Diameter ≤6.5 cm if single lesion; or Diameter ≤4.5 cm if 2 lesions with total diameter ≤8 cm

Type of donor

Viral hepatitis

Number of patients

Patient survival rate within criteria

Patient survival rate exceeding criteria

1-year: 94.3%, 3-years: 87.5%, 5-years: 81.6% 5-years: 86.7%

1-year: 71.9%, 3-years: 37.2%, 5-years: 20.7% 5-years: 34.4%

Recurrence-free 3-years: 94% 1-year: 92.8%, 3-years: 70.7%, 5-years: 70.7%

Recurrence-free 3-years: 50% 1-years: 49.9%, 3-years: 27.0%, 5-years: 18.9%

4-years: 85%

4-years: 50%

Recurrence-free 1-year: 98.6%, Recurrence-free 5-years: 96.7%

Recurrence-free 1-year: 80.4%, Recurrence-free 5-years: 59.5%

LDLT: 100%

HBV: 93%, HCV: 7%

221

LDLT: 100%

HBV: 34%, HCV: 53%

125

LDLT: 100%

HCV: 62%

78

Not defined

HBV: 100%

195

DDLT: 100%

HBV: 23%, HCV: 67%

48

DDLT: 93%, LDLT: 7%

HBV: 23%, HCV: 65%

168

Abbreviations: AFP, alpha-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; LDLT, living donor liver transplantation; PIVKA-II, prothrombin induced by vitamin K absence II; UCSF, University of California at San Francisco.

The golden standard to date for selection of HCC patients for DDLT and LDLT are the Milan criteria, while the UCSF criteria are regarded as acceptable alternative guidelines. The UCSF criteria, which expand the maximal tumor size to 6.5 cm for a single HCC lesion, produce survival rates comparable to those of the Milan criteria. However, the study populations in the original studies evaluating these two criteria do not seem to be large enough, introducing the possibility of bias from small numbers of patients with recurrent tumors (42,46). The prognostic power of these criteria appears sufficient, but their discriminatory power for those HCC patients who do not meet these criteria is not sufficiently high (4). Many highvolume LT center series or multi-center studies revealed that long-term patient survival rates look uniformly favorable when extent of HCC met the indication criteria, but the recurrence rates showed great differences among indication criteria (Fig. 22.2). Currently proposed criteria for indication of LT are summarized in Table 22.1 (4–7,42,47). Considering that these proposed expanded criteria also showed favorable outcomes in recent studies (4–7), it is probable that the Milan criteria are becoming outdated. However, the question is which criteria should be the new golden standard instead of the Milan criteria (48). It is reported that hepatitis C is a significant predictor of tumor recurrence and impaired survival after LT in patients with HCC (49), implicating that there may be a benefit in the expansion of the Milan criteria for HCC in the non-hepatitis C population. The clinical sequence of HCC in patients with HBV infection has been reported to be favorable compared to

210

that in patients with hepatitis C virus infection because HBV infection is more effectively controllable than hepatitis C infection after LT (50,51). Uniquely, some major LT centers in Korea and Japan challenged the Milan criteria, accepting a much higher number of nodules (five or more) (4–6,52). On the other hand, a number of major LT centers in the United States and Europe have mainly focused on enhanced criteria regarding the tumor diameter (more than 5 cm) (47,53–55). LT is also indicated for small HCC in Child–Turcotte–Pugh (CTP) class B or C cirrhosis, or CTP class A with portal hypertension (42,56–59). However, the optimal treatment strategy for patients with small single HCC, cirrhosis with preserved liver function, and absence of portal hypertension is not yet established. No prospective randomized study has been reported which compares liver resection and LT for small HCC in cirrhotic patients who could be eligible for both treatment modalities. Authors have reported the results of liver resection in 100 cirrhotic patients with single, less than 3 cm-sized HCC who would have been eligible for primary LT, comparing with a group of 17 patients who underwent LT for HCC with similar tumor stage during diagnosis and preserved liver function (60). These results showed that 37 of 39 HCC recurrences initially occurred in the liver after resection, but only one recurrence occurred in lung after LT. Overall patient survival was not proven to be statistically different, but diseasefree survival was significantly different between the two groups (Fig. 22.3). The influence of these encouraging results of LT for HCC may be reflected on the proportion of liver recipients

LIVER TRANSPLANTATION FOR HCC: ASIAN PERSPECTIVES 1.0

1.0

0.8

0.8

Proportion of recurrence

Proportion of recurrence

Beyond Asan

Beyond UCSF

0.6

0.4 Beyond Milan, within UCSF 0.2

0.6 Beyond Milan, within Asan

0.4

Within Milan

0.2

Within Milan 0.0

0

12

24 36 48 Posttransplant months

0.0

60

(A)

0

12

24 36 48 Posttransplant months

60

(B)

Figure 22.2 Comparison of the hepatocellular carcinoma recurrence curves between the Milan and UCSF criteria (A) and between the Milan and Asan criteria (B) (4). 1.0

1.0 LT

0.9

0.9 0.8 Proportion of survival

Proportion of survival

0.8 0.7 0.6 0.5

Hepatectomy

0.4 0.3

0.6 0.5 Hepatectomy

0.4 0.3 0.2

0.2 P = 0.27

0.1

0.1

0

P = 0.047

0 0

(A)

LT

0.7

20

40

60

80

100

120

140

Postoperative months

0 (B)

20

40

60

80

100

120

140

Postoperative months

Figure 22.3 Comparison of the overall patient survival (A) and recurrence-free survival (B) between the patients who undergone hepatic resection and liver transplantation for hepatocellular carcinoma (HCC) <3 cm-sized, single nodule with Child–Turcotte–Pugh class A cirrhosis (60).

undergoing LT per year in Asia (Fig. 22.4). Hepatic resection is still a good treatment modality for selected patients because of lower cost and no requirement for donor organs. However, if a donor is available, primary LT can be considered as a preferred treatment modality for single small HCC of CTP class A cirrhosis in the presence of portal hypertension, because LT may provide excellent disease-free survival and maintenance of normal quality of life (60).

pretransplant treatment for hcc Pretransplant neoadjuvant therapy has been often attempted to the HCC patients waiting for LT by the way of percutaneous ablation or transarterial chemoembolization (61–63). In patients enrolled for DDLT, pretransplant neoadjuvant therapy is important since the waiting period is usually too long to leave the patient without any treatment, and downstaging of advanced tumors may allow expansion of the current criteria without adversely affecting survival. However, the effect of downstaging is not strongly supported from the data of a considerable number of clinical studies (64–67). In reality, the

response to neoadjuvant therapy may be potentially influenced by the selection effect for tumors with better biological behavior. Such a selection bias also influences post-transplant outcome (68–70). Salvage LT has been performed for recurrent HCC or deterioration of liver function after primary liver resection. From the viewpoint of pre-transplant treatment, prior liver resection has two roles: primary treatment and bridging to LT. Considering the incidence of deceased donors and high proportion of LDLT, many of prior liver resection may be intended for primary curative treatment rather than bridge treatment. There are two important points to be taken into account before performing salvage LT (71). The first is the technical feasibility of LT, especially for LDLT. The surgical condition of patients with recurrent HCC after prior liver resection is not very different to that of patients who underwent non-surgical treatment, except that adhesion and anatomical distortion exist within the abdomen, which could be overcome by technical skill (71). Some authors claim that every combination of prior hepatectomy and living donor graft is feasible for patients

211

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 1,200

Number of operations

1,000 HCC

Non-HCC

800 600 400 200 0 1994

1995

1996

1997

1998

1999 2000 Year

2001

2002

2003

2004

2005

Figure 22.4 Annual proportions of liver transplants for hepatocellular carcinoma (HCC) in Asia (excluding mainland China) (3).

undergoing salvage LDLT. The second is the main indication for salvage LT, in which there is still no consensus on eligibility criteria. Authors also suggest that the survival outcome of salvage LDLT, based on explant tumor staging, was equivalent to that of primary LDLT, and it may be reasonable that primary and salvage LDLT share the same indication criteria for HCC. For salvage LDLT, determination of the timing of LT is of practical importance. There are proposals to perform LDLT as early as the situation permits in order to avoid tumor progression, but it is unclear whether patients who had early HCC recurrence after liver resection are adequate candidates for salvage LT. If early recurrence is associated with a well-advanced tumor or unfavorable pathology, the patient may not benefit from salvage LT because there is a very high probability of post-transplant HCC recurrence. In contrast, if early recurrence is related to incomplete local control of small HCC lesions, the patient may be a candidate for salvage LT. Patients with a longer interval between prior liver resection and salvage LDLT show more favorable survival than those with a shorter interval. A thorough pre-transplant HCC workup should be performed because extra-hepatic recurrence was not uncommon in patients with recurrent HCC after resection (37,72,73). For salvage DDLT, there are two important reports revealing contradictory results. Belghiti and colleagues (74) compared 18 patients who underwent secondary LT following liver resection with 70 undergoing primary LT and assessed postoperative outcomes and long-term survival. They concluded that in selected patients, liver resection prior to LT does not increase morbidity or impair long-term survival following primary LT, and, accordingly, liver resection prior to LT can be integrated into the treatment strategy for HCC. On the other hand, Adam and colleagues (75) compared the results of secondary LT for tumor recurrence following resection of initially transplantable HCC in 17 patients with cirrhosis with those of primary LT in 195 patients. They reported that LT after liver resection was associated with a higher operative mortality, an increased risk of recurrence, and a poorer outcome compared with primary LT.

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treatment for recurrent hcc after lt The clinical sequence of post-transplant HCC recurrence is usually much worse than in non-transplant patients, since the response to treatment for HCC recurrence after LT is disappointing (Fig. 22.5). Strict recurrence surveillance for early timely detection for recurrence is recommended. Thus, annual risk-based adjustment of follow-up intervals should be established. Early detection and aggressive treatment for posttransplant HCC recurrence can result in prolongation of patient survival in a considerable proportion of patients (76,77). Such a survival gain may rationalize vigorous post-transplant surveillance for HCC recurrence. It is reported that organ transplant recipients given mammalian target of rapamycin (mTOR) inhibitor have reduced incidence of recurrent or de novo post-transplant malignancies (78). Kneteman and colleagues (79) performed DDLT on 40 patients using sirolimus-based immunosuppression that minimized exposure to calcineurin inhibitors and steroid. Tumor-free 4-year survival was 81.1% and the tumor recurrence rate was less than 5.3% in 19 recipients with tumors that satisfied the Milan criteria and were 76.8% and 19% for patients with extended criteria tumors. From these results, Wall (80) noted that the results obtained with HCC satisfying the Milan criteria were good, although not essentially different from those obtained by others using standard immunosuppressive therapy (81–83), whereas the results with extended criteria tumors were excellent, strongly suggesting mTOR inhibitor therapy inhibited tumor growth. Elsharkawi and colleagues (84) reported a DDLT case in whom three HCC pulmonary metastases underwent complete regression after conversion from cyclosporine and azathioprine to sirolimus and mycophenolate mofetil and who remained tumor-free 18 months later. The recent demonstration of survival benefits for HCC patients treated with the oral agent sorafenib is encouraging progress in the development of molecularly targeted anticancer agents in HCC (85,86). Several new targeted agents have been developed and are under clinical trial in patients undergoing non-surgical treatment, resection, or LT at present. In

LIVER TRANSPLANTATION FOR HCC: ASIAN PERSPECTIVES

Proportion of survival

1.0

0.8

0.6 DDLT

0.4

0.2 LDLT 0.0

0

12

24

36

Months Figure 22.5 Cumulative survival curves after the first detection of hepatocellular carcinoma recurrence in DDLT and LDLT groups. There is no statistically significant difference between these two groups (41).

contrast to previous cytotoxic agents, most targeted agents do not induce regression of tumors but stabilize disease progression. Sorafenib is the first drug proven to prolong survival in advanced stage patients, but the survival benefit is still relatively short. Therefore, future trials should be conducted regarding the combination of sorafenib with other pre-existing treatment modalities or new targeted agents, especially in the potential role of assisting in a bridge to LT (35,87).

conclusion The high prevalence of HCC and subsequent high incidence of HCC in the situation of very low organ donation rate in Asia lead to making a unique pattern of indication and strategy in the application of LT. HCC has begun to be a main indication of LT, especially in the form of LDLT. Effective promotion of deceased organ donation is essential in every Asian country. Although LDLT has become the main form of LT in Asia, donor safety should always be emphasized. The selection indication of LT for HCC is likely to be expanded further, but it should be prudently adopted after qualified risk–benefit analyses. Application for small HCC in patients with preserved liver function has also been an expanded indication after gradual improvements in peri-operative mortality. As before, new innovative surgical techniques will emerge to solve currently intractable technical problems. Emergence of new effective treatment modalities for HCC recurrence will expand the selection criteria further without compromising disease recurrence rate. The practice of LT in Asia will continue to evolve further, giving more benefits to patients with HCC.

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LIVER TRANSPLANTATION FOR HCC: ASIAN PERSPECTIVES 78. Monaco AP. The role of mTOR inhibitors in the management of posttransplant malignancy. Transplantation 2009; 87: 157–63. 79. Kneteman NM, Oberholzer J, Al Saghier M, et al. Sirolimus based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 2004; 10: 1301–11. 80. Wall WJ. Hepatocellular cancer, transplantation, and sirolimus. Liver Transpl 2004; 10: 1312–4. 81. De Carlis L, Giacomoni A, Pirotta V, et al. Surgical treatment of hepatocellular cancer in the era of hepatic transplantation. J Am Coll Surg 2003; 196: 887–97. 82. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TMN criteria. Liver Transpl 2002; 8: 765–74.

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23

Non-surgical treatment of hepatocellular carcinoma Ghassan K. Abou-Alfa and Karen T. Brown

introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide (1). Added to its worldwide prevalence, there is a continued rising incidence of HCC in the western hemisphere (2). More than 80% of patients present with advanced or unresectable disease, and the recurrence rates after surgical resection is as high as 50% (3). Effective therapies for advanced HCC remain an immediate need. In the field of local therapies for locally advanced disease, extensive work has been done in regard to the feasibility and effectiveness of different ablative modalities, with several issues still in debate. In the more advanced and metastatic disease settings, recent data showed an improvement in survival in advanced HCC with sorafenib. This landmark study not only helped in defining a standard of care for advanced HCC, but also generated several clinical questions among whom to treat, and how to account for the cirrhosis and underlying liver dysfunction. Second line therapies and future clinical trials are prime time discussions.

local regional therapies While surgical treatment remains the best hope for cure in patients with primary HCC cancer, many patients are not candidates for resection or transplantation at the time of presentation. This may be due to the extent or distribution of disease, underlying liver function, or the general medical condition of the patient. Although transplantation is essentially curative, patients spend time on a transplant list awaiting a donor organ. During this period they are at risk for progression. Patients who undergo surgical resection have a relatively high risk of developing recurrent disease in the remaining liver (4). Thus, local regional therapies, including trans-arterial embolization and percutaneous chemical or thermal ablation play a significant role in the care of these patients. Arterial Embolization The basic physiologic principle that makes hepatic intra-arterial therapies for HCC feasible is the dual blood supply to the liver. The portal vein provides over 75% of blood flow to the hepatic parenchyma, and provides the primary trophic blood supply, although in cirrhotic patients with portal hypertension there is a shift toward more dependence upon arterial blood flow. Conversely, studies performed in the early 1950s established that the primary blood supply to liver tumors was from the hepatic artery (5). Thus malignant tumors may be targeted by delivering treatments intra-arterially; theoretically treatments administered in this fashion would have little effect on the hepatic parenchyma and would result in fewer systemic side effects. Intra-arterial infusion therapies are usually carried out using permanently implanted ports or pumps and are

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beyond the scope of this chapter. There are currently three main categories of percutaneously administered intra-arterial therapy: bland embolization, chemo-embolization, and radioembolization. Recently drug-eluting microspheres that can be loaded with chemotherapeutic agents have been used for treating HCC as well. Chemo-embolization and Bland Embolization In last 30 years many papers have been published describing myriad techniques for performing hepatic arterial embolotherapy. Chemotherapeutic agents mixed with lipiodol and injected into the artery supplying the tumor, referred to as Trans-catheter Arterial Chemo-Embolization, or TACE, has been extensively studied and used, despite the lack of convincing pharmacokinetic data favoring this method. Studies clearly demonstrating high and prolonged concentration of chemotherapeutic agents within tumor were performed using mitomycin C, doxorubicin, and aclarubicin dissolved in hydrocarbon solvents and then in lipiodol (6), or using a lipophilic agent (7), methods which are not clinically used. When the chemotherapeutic agent is dissolved in water and then mixed with lipiodol and administered as an emulsion, concentration of drug in the tumor is immediately high, but low at 6 hours, 1 day, and 7 days (3). In a study by Raoul et al. (8) doxorubicin was given to patients intra-arterially either alone as an infusion, or emulsified with lipiodol, or with lipiodol and gelatin sponge. There was no significant difference in total amount of doxorubicin released into the circulating blood, but patients in whom gelatin sponge was used had less release within the first hour of treatment. In a prospective randomized clinical study performed to evaluate the effect of lipiodol when added to intraarterial cis-platinum and doxorubicin, there was no difference in response to treatment between the groups given only intraarterial chemotherapy compared to those who received chemotherapy emulsified with lipiodol (9). Another study evaluated intra-arterial doxorubicin versus doxorubicin with lipiodol, and found no difference in the area under the concentration–time curve, or terminal half life, and no difference in pharmacokinetic profile or systemic toxicity using the same dose schedule but administering the doxorubicin intravenously (10). Pharmacokinetic data supporting the use of intra-arterial chemotherapy, or chemotherapy plus lipiodol administered as an emulsion, as commonly used today, remains debatable. What has been demonstrated, in both pharmacokinetic and clinical studies (7,11), is the benefit derived from the addition of an embolic agent, such as Gelfoam, for chemo-embolization. This has led some authors to postulate that the primary tumoricidal effect of embolotherapy might result from ischemia induced by the embolization rather than the chemotherapy or lipiodol. Two well-known randomized trials of

NON-SURGICAL TREATMENT OF HEPATOCELLULAR CARCINOMA chemo-embolization which provide level 1b evidence have shown an improvement in survival compared to best supportive care (13,14). The study by Llovett et al. randomized patients into three arms: bland embolization, also referred to as hepatic arterial embolization (HAE), TACE, and best supportive care (13). Although demonstrating a convincing survival benefit from TACE, it is unfortunate that the study was stopped before enough patients had been accrued to the HAE arm to permit any statement to be made about bland embolization, in particular with respect to no treatment. When the trial was stopped, there was no significant difference in survival between the bland and chemo-embolization groups, despite the fact that Gelfoam pledgets were used as the embolic agent in the bland group. It is known that more proximal vessel occlusion within the liver leads to almost immediate development of flow distal to the occlusion via collateral vessels, as demonstrated by Michels in 1953 (15). Bland arterial embolization results in ischemic cell death, therefore the goal must be to cause terminal vessel blockade. The Gelfoam pledgets used in this trial result in more proximal vessel occlusion. The fact that there was no significant difference in survival between the chemo-embolization group and the group

(A)

embolized with Gelfoam pledgets alone is thus noteworthy. Bland embolization using small particles known to cause terminal vessel blockade is the primary method of intra-arterial therapy at some institutions, and level llb evidence as supported by the data of Maluccio et al. (16). The results of bland embolization are essentially immediate, and significant tumor necrosis can be demonstrated by imaging within hours of the procedure (Fig. 23.1A–C). This is a particularly useful feature in patients who present with significant tumor burden where further progression may render them untreatable. This is also effective for treating tumor thrombus within the portal vein (Fig. 23.2A and B). Bland particle embolization can provide prompt control of disease. Little is written about the response time line in patients treated with TACE. TACE is not performed to “stasis” and the primary effect is considered to be chemotherapy related. Proponents of this method of treatment often point out that the intent is not to induce necrosis. These facts lead one to suspect that maximum response to treatment might not be immediately seen post-embolization. The bland embolization or chemo-embolization debate has been going on for quite some time now. Proponents of TACE continue to assert that this treatment results in deposition of

(B)

(C)

Figure 23.1 (A) Pre-treatment CT (arterial phase) in patient with multi-focal HCC. (B) Non-treatment CT performed 12 hours after left hepatic and phrenic artery particle (bland) embolization. Note retained contrast material and small “gas bubbles” in treated tumor. (C) Post-treatment CT (arterial phase) demonstrating imaging findings consistent with necrosis of treated tumor corresponding to treated tumor that had retained contrast and “gas bubbles” on immediate postembolization CT scan.

(A)

(B)

Figure 23.2 (A) Pre-treatment CT in patient with large HCC in right liver with tumor thrombus extending into portal vein (B) post-treatment CT 6 weeks after bland embolization demonstrating imaging findings of necrosis of tumor within liver and portal vein.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS high concentrations of chemotherapy within the tumor that stays there for prolonged period of time and, rightly, point out that this method is the only one that has been proven to extend survival in the Llovett and Lo randomized trials mentioned previously (13,14). Excellent results (level IIa evidence) following chemo-embolization have been reported from Japan on 8510 patients treated between 1994 and 2001, with 1-, 3-, and 5-year survival of 82%, 47%, and 26% (17). About 74% of the patients had positive hepatitis C serology. Patients were excluded if they had evidence of nodal disease or distant metastases, and only 4% of patients had more than secondorder portal vein involvement; however, almost half of the patients were Child class B or C. Llovett et al. (13) reported the probability of survival following chemo-embolization in their group of 40 patients, the majority of whom had positive hepatitis C serology, to be 82%, 63%, and 29% at 1, 2, and 3 years, respectively, while Lo et al. reported survivals of 57%, 31%, and 26% at 1, 2, and 3 years, respectively, in their study of 40 patients; 90% of whom were hepatitis B serology positive. The cumulative survival rates at 1, 2, and 3 years in a recent report on triple drug chemo-embolization by Buijs et al. (18) who treated 190 patients were 58%, 39%, and 29%. In this level IIb evidence study 40% of patients were hepatitis C serology positive whereas 21% had positive hepatitis B serology. Finally, in a large series of patients treated with bland embolization, Maluccio et al. (16) reported 1-, 2-, and 3-year survival in 159 patients who were without extra-hepatic disease or portal vein involvement by tumor to be 84%, 66%, and 51%; all of these patients were treated without the addition of chemotherapy or lipiodol to the embolic agent. What seems clear from this data is that arterial embolotherapy is an effective method of treating HCC in an effort to prolong the patient’s survival. This has been proven in randomized studies comparing chemo-embolization to supportive care (13,14). Comparable, or better, survival results can be obtained with bland embolization, as demonstrated by Maluccio et al. (16). Drug-Eluting Microspheres Currently available drug-eluting beads, or DEBs, are preformed microspheres available in diameters ranging from 40 to 1200 µm. These spheres are deformable and made from a macromere derived from Polyvinyl Alcohol (PVA). They are typically loaded with doxorubicin when used to treat HCC, using 150 mg per treatment. The pharmacokinetic profile of the DEBs is significantly different than that which is seen with conventional TACE, with level IIb evidence that the peak drug concentration in the serum is an order of magnitude lower for DEBs and the area under the curve (AUC) is significantly lower as well (19). Objective response by EASL criteria has been reported in 70% to 80% of patients (19–21) and 1- and 2-year survival of 92.5% and 88.9% have been reported in a level IIa study of 27 patients with large or multi-focal tumors (19). Radio-embolization Yttrium 90 is a pure β emitter that can be loaded in glass or resin microspheres and delivered to the tumor intra-arterially. Only the glass microspheres are approved by the Food and

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Drug Administration (FDA) for use in treating HCC. Within the tumor vasculature these microspheres can deliver high dose radiation to the tumor. The microspheres can be delivered selectively to the anatomic segment or segments that contain the tumor or, in the case of multi-focal disease, can be administered in a lobar distribution. Unlike TACE or bland embolization, prior to treatment with 90Y patients must undergo planning angiography to evaluate vascular and tumor anatomy and blood flow dynamics. Non-hepatic branches in the territory to be treated that may result in gastrointestinal blood flow are occluded with coil embolization and finally a technetium 99 macroaggregated albumin scan is performed both to test for the presence of gastrointestinal blood flow and to estimate the percent of injected material that is shunted to the pulmonary vasculature. Radiation dose to the lungs of 30 Gy for a single administration or >50 Gy accumulated in multiple administrations, as well as any detectable GI blood flow not correctable by vessel occlusion precludes treatment with intra-arterial 90Y. Recent level IIb data for 90Y glass microspheres used to treat 140 patients with HCC by Atassi et al. reported a 68% response rate by EASL criteria. Median survival for Okuda stage I or II was 800 days versus 368 days and for Child A or B + C was 800 days versus 258 days (22). Level IIa evidence supports the use of radio-embolization for downstaging HCC to other methods of treatment. In a group of 35 patients who were not transplant candidates, Kulik et al. reported that 66% were downstaged to transplant, resection, or ablation and the median survival for the entire group was 800 days (23). Although 90Y has been shown to be an effective method for treating HCC, grade 3 or 4 liver toxicity is seen in up to 1/3 of low risk patients. Radio-embolization is expensive and more complicated to administer than either bland or chemo-embolization. The possibility that radiation-related hepatic fibrosis superimposed on the patients underlying liver disease may result in compromised hepatic function several years after treatment remains unknown. Percutaneous Chemical or Thermal Ablation Since the 1980s, Percutaneous Ethanol Injection Therapy (PEIT) has been widely used to treat patients with HCC (24–27). There is level IIa evidence that this method is effective, particularly when used to treat small tumors <3 to 5 cm (28). In the late 1990s there was a flurry of interest in using acetic acid injection to treat HCC. Despite encouraging results showing significant decrease in local recurrence and increase in survival after acetic acid injection when compared to ethanol, this agent was never in widespread use (29). Chemical ablation has been used primarily to treat patients with three or fewer tumors less than 3 to 5 cm. Even the smallest lesions injected with ethanol typically required several treatment sessions, although methods of treating even large tumors in one session have been described (30,31). In the late 1990s percutaneous methods of thermal ablation, particularly Radiofrequency Ablation (RFA), became available. In 1999, Livraghi et al. published a study of 86 patients who received either RFA or PEIT “randomized” by the distance the patient lived from the hospital (32). This study, which should be considered either Ib or IIa evidence, concluded that

NON-SURGICAL TREATMENT OF HEPATOCELLULAR CARCINOMA “RF ablation results in a higher rate of complete necrosis and requires fewer treatment sessions than percutaneous ethanol injection. However the complication rate is higher with RF ablation than with PEIT. RF ablation is the treatment of choice for most patients with HCC.” Providing level lb evidence of the effectiveness of RFA, in 2003 Lencioni et al. reported a statistically significant difference in local recurrence-free survival in a randomized trial of 102 patients who underwent either RFA or PEIT, with no significant difference in complication rate (33). Thermal ablation has moved to the forefront of treatment for patients with HCC (34) although PEIT is still used for lesions that are unsuitable for thermal ablation, usually because of their location. The concept of combining radiofrequency ablation with embolization as a means of achieving a more complete ablation, and perhaps shortening treatment time has been explored. Better results might be expected when embolization is performed first, since the embolization procedure devascularizes the tumor, eliminating much of the “heat sink” and potentially improving the efficiency of the deposited energy. In 2000, Rossi et al. showed that HCC tumors 3.5 to 8.5 cm in diameter could be ablated in one or two sessions after occlusion of the tumor blood supply with a balloon or gelatin sponge (35). In 2002, Yamakado et al. performed chemoembolization followed by RFA in 64 patients with tumors as large as 12 cm and reported complete necrosis by imaging of all lesions regardless of size with only two instances of local recurrence (36). In a case–control retrospective study published in 2005 Maluccio et al. provided level III evidence that there was no statistically in survival in a group of 40 patients who underwent surgical resection, when compared to significant difference a group of 33 patients treated with bland embolization followed by either PEIT or RFA in tumors up to 7 cm in size (37). The latest level 1b evidence for the effectiveness of combined therapy emerged in 2008 when Cheng et al. a published a randomized-controlled trial of TACE–RFA, TACE alone or RFA alone in 291 patients with HCC larger than 3 cm (38). This paper reported statistically significant improved overall survival in patients treated with TACE–RFA compared to either method alone. The significance persisted when patients were stratified into those with one tumor or more than one tumor. Combining embolization with an ablative method seems to make sense when treating HCC. Performing the embolization prior to the ablation has the advantage of accurately defining number and size of tumors as well as making the tumors much more conspicuous for targeting with CT when the ablation is performed within 24 to 48 hours.

systemic therapies Historical Background Chemotherapy has been studied extensively in HCC. Despite reported responses ranging between 10% and 20%, no study has shown an impact on survival. Doxorubicin has been studied extensively and there is still no agreement about its use in advanced HCC, with response rates ranging between 0% (39) and 79% (40). Despite the poor or debatable outcome of most of these trials, doxorubicin became the default standard for

treatment, and a control arm for several comparative trials testing either other single agents or combination regimens (41). PIAF (cisPlatin, Interferon, Adriamycin, and 5-Fluorouracil) Given the disappointing results of single agent doxorubicin and other single agent therapies, combination regimens have also been investigated. A combination of cisplatin, interferon, doxorubicin, and 5-fluorouracil (PIAF) has demonstrated promising activity in a phase II study. This regimen yielded a response rate of 26% and a median survival of 9 months (42). Of note, 13 patients (26%) who had a partial response, 9 underwent surgery, and 4 (9%) were found to have had a complete pathologic response to chemotherapy. These data were encouraging enough to consider evaluating PIAF versus doxorubicin as part of a large randomized phase III study that failed to show any survival advantage for PIAF (43). More importantly, the data of the phase II study of PIAF raised the possibility of using the combination in the neoadjuvant setting. This approach would be recommended in that specific setting of medically fit patients with good liver function in whom tumor cytoreduction is necessary to permit respectability (Level of evidence IIa, category C). Anti-angiogenic Therapies HCC is a highly vascular solid tumor, and a vascular endothelial growth factor (VEGF) has been shown to promote HCC development and metastasis in preclinical models (44). Sorafenib is a novel molecular targeted agents that inhibits both pro-angiogenic (VEGFR-1, -2, -3; PDGFR-β) and tumorigenic (RET, Flt-3, c-Kit) receptor tyrosine kinases (RTKs). Sorafenib also inhibits the serine or threonine kinase Raf-1 in vitro (45). A phase II trial of sorafenib evaluating response in patients with advanced HCC showed 33.6% of patients to have stable disease (≥16 weeks) commensurate with a median time-to-progression (TTP) of 4.2 months and the median overall survival of all patients was 9.2 months (46). The reported stable disease was commensurate with an interesting observation of central tumor necrosis was found in many patients in the study (Fig. 23.3). A sub-analysis evaluating the correlation between tumor necrosis and response was performed (47). The ratio of tumor necrosis and volume (N/T) was significantly associated with response, with responders having greater increase in the ratio between necrosis and tumor volume relative to baseline, as compared to nonresponders (p = 0.02), This data stresses the need for radiologic techniques other than RECIST to evaluate HCC response such as dynamic imaging. For practical reasons, it is recommended that patients on soarfenib be followed with triphasic CT scans or MRI and any decision to continue or stop therapy should be based on a multiple factors including patient clinical evaluation, imaging studies, and serum markers (where applicable). (Level of evidence III, category C). This phase II study led to the development of a large doubleblinded, randomized phase III trial evaluating single agent sorafenib versus placebo in patients with advanced HCC and no more than Child–Pugh A cirrhosis (48). The trial demonstrated an improvement in survival of 10.7 months in the

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Figure 23.3 Baseline and serial follow-up scans demonstrate tumor necrosis in a hepatocellular carcinoma patient.

sorafenib group versus 7.9 months in the placebo group (p < 0.001, HR = 0.69). The study led to the approval of sorafenib by the FDA for the treatment of unresectable HCC (49) and thus sorafenib became the standard of care in this setting (Level of evidence Ib, category A). The drug-related grade 3–4 toxicity profile included diarrhea (8%) and hand foot syndrome (8%). Despite the infrequency of bleeding events (<1%), one should still use caution in this regard considering the anti-angiogenic nature of sorafenib. Treating Patients with Advanced Cirrhosis The exciting results of the phase III study apply mainly to patients with Child–Pugh A score, similar to the population evaluated in the study. The safety and efficacy of sorafenib in patients with Child–Pugh B or C cirrhosis is still however being evaluated. In the phase II study evaluating sorafenib in HCC (50), 28% of patients had Child–Pugh B cirrhosis. In 28 patients from which pharmacokinetic samples were obtained, AUC (0–8) (mg h/L) was comparable between the Child–Pugh A (25.4) and Child–Pugh B (30.3) patients. Cmax (mg/L) were 4.9 and 6 for Child–Pugh A and B patients, respectively, with similar drug-related side effects profiles. However, Child–Pugh B patients had worsening of their liver function at a more frequent rate. A transient increase of serum bilirubin was reported in 40% of the patients with Child–Pugh B compared to 18% of Child–Pugh A patients. It is unclear and tough if this elevation in bilirubin is drug related or disease progression. Sorafenib acts as a substrate for UGT1A1, and the study did not collect direct bilirubin measurements, so it remains unclear if this total bilirubin may also be due to an inhibitory effect of UGT1A1 and decreased bilirubin glucuronidation. Another study evaluating sorafenib in patients with liver dysfunction may help in giving certain guidance on the use of sorafenib in patients with liver cirrhosis (51). The most commonly reported Drug-Limiting Toxicity (DLT) among patients with elevated bilirubin at baseline was further elevation of bilirubin. In the lack of any further data, one may consider the recommended doses of sorafenib reported in this study: 400 mg PO twice per day for bilirubin up to 1.5 x upper limit

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of normal (ULN); 200 mg PO twice per day (or 400 mg PO daily) for bilirubin 1.5 to 3 × ULN; and to avoid sorafenib for bilirubin above 3 × ULN (Level of evidence IIa, category C). Nonetheless the safety of sorafenib in patients with HCC and advanced cirrhosis needs to be further studied. Future Developments In the advanced disease setting, the next step will be to evaluate other novel therapies or combinations of different agents looking for further improvement in survival. Bevacizumab, another potent anti-angiogenic agent, has been studied extensively in patients with advanced HCC (52,53). In one of the two studies of 28 patients, 4 had to discontinue therapy because of serious adverse events, including 1 transient ischemic attack and 3 serious esophageal bleeding events, which led to a modification of the study to identify and manage esophageal varices prior to enrollment (54). Bevacizumab has also been studied in combination with chemotherapy (55–57) and other biologic agents. The most promising bevacizumab doublet data are in combination with erlotinib (58). Patients with HCC and CLIP ≥ 3 were treated with bevacizumab and erlotinib. Based on the intent-to-treat analysis, 7 of 34 patients had radiographic responses and 27 (79.4%) had stability of disease for as long as 8 weeks. Median progression-free survival (PFS) was 9 months and median overall survival (OS) 19 months. Grade 3 and 4 fatigue and hypertension were each reported in 15% of the cases and similar grade gastrointestinal bleeds were reported in 9% of the cases. The positive outcome of this study supports the biologic relevance of this combination of anti-angiogenic therapy and tyrosine kinase inhibitor in HCC and should be explored further. Sunitinib, another multi-targeted tyrosine kinase inhibitor, has also been tested in HCC (59). Of 26 patients treated with sunitinib at 37.5 mg daily dose, 10 (38.5%) showed stability of disease, with a median PFS of 4.1 months. Another study showed similarly promising results at the dose of 50 mg, with median TTP of 21 weeks and median OS of 45 weeks (60). Sorafenib has been evaluated in combination with doxorubicin as part of a randomized double-blinded phase II

NON-SURGICAL TREATMENT OF HEPATOCELLULAR CARCINOMA study of doxorubicin plus sorafenib compared to doxorubicin plus placebo in chemotherapy-naïve HCC patients (61). The primary endpoint, median time to progression, was 9 months for the doxorubicin plus sorafenib arm and 5 months for the doxorubicin plus placebo arm. An exploratory comparison of OS between the two arms showed a significant difference of 13.7 months in favor of doxorubicin plus sorafenib versus 6.5 months for doxorubicin plus placebo (p = 0.0049, HR = 0.45). The toxicity profile was similar between the two arms of the study and with toxicities commonly seen with single agent doxorubicin and sorafenib. Grade 3–4 toxicities included fatigue (15%) and neutropenia (50%) in both arms. Sorafenib-related toxicity included grade 3–4 diarrhea (11%) and grade 3–4 hand–foot syndrome (9%) in the combination arm. There was more left ventricular dysfunction in the doxorubicin plus sorafenib arm, having been reported in 19% of the cases (all grades) with 2% grade 3–4. The questionable synergy between sorafenib and doxorubicin will be best answered in the currently underway large randomized trial evaluating the combination versus sorafenib alone. Other clinical scenarios where sorafenib has the potential of being evaluated are surgical adjuvant setting, peri-trans-arterial chemo-embolization of embolization, and pre-transplant. In a study aimed at defining angiogenic activity in tumors subjected to Trans-Arterial Embolization (TAE) by evaluating the Tumor Microvessel Density (MVD) in an animal model (62), it was found that tumors treated with TAE showed varying degrees of central necrosis with residual viable tumor cells in the periphery. Tumor MVD in animals treated with TAE was significantly higher than that in the control group (23.6 vs. 17.5; p = 0.001). The animals treated with TAE showed a statistically significant increase in VEGF levels compared with the control group. The use of an anti-angiogenic therapy like sorafenib seems plausible to curb this angiogenic drive. A study evaluating sorafenib in the adjuvant setting is underway. Post-TACE is also underway. In an attempt to reduce on the dropout rate on transplant lists (63), a stabilizing agent like sorafenib seems plausible. However, the potential bleeding concern from an anti-angiogenic agent remains an issue that needs to be studied further.

conclusion HCC remains prevalent worldwide and is showing a steady rise in incidence in the western hemisphere. A high number of patients are in need for either local or systemic therapies. When disease is limited to the liver, a local-regional method of treatment such as embolization or ablation should be the initial treatment. In some cases, combining these methods of treatment or using them sequentially is appropriate. Sorafenib is the first systemic treatment to demonstrate a survival advantage in a large, randomized, controlled phase III study and is now approved by the FDA for patients with unresectable HCC. Future studies are to look into improving the outcome with sorafenib further by combining with other systemic therapies or local therapies. Other uses of systemic therapies, that is, adjuvant therapy, are also under investigation.

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24 Resection of intrahepatic cholangiocarcinoma

Junichi Arita, Norihiro Kokudo, and Masatoshi Makuuchi

Intrahepatic cholangiocarcinoma (ICC) is a rare (1,2) and poorly understood biliary malignancy that is increasing in incidence and therefore, in importance. The literature concerning this disease is mostly limited to retrospective reviews of patients from specialized hepatobiliary centers; moreover, only a few case series have included 50 or more patients (3–6). Surgical resection has offered the only chance of cure in patients since the earliest era (7). However, no consensus or guidelines have been established on the optimum procedure in accordance with the stage of the disease. This article is a review of the current knowledge on intrahepatic cholangiocarcinoma, especially from the viewpoint of experienced liver surgeons who treat it.

terminology and classification The term “cholangiocarcinoma” originally referred to primary tumors of the intrahepatic bile ducts, but not extrahepatic bile ducts (8); however, in its current usage, it includes intrahepatic, perihilar, and distal extrahepatic tumors of the bile ducts (9,10). Therefore, use of the sole word “cholangiocarcinoma” as a disease category is confusing and not recommended. ICC is a carcinoma arising from the mucosa of the intrahepatic bile ducts. The separation between “intrahepatic” and “extrahepatic” bile ducts occurs at the second-order branches of the biliary tree according to the Japanese classification (11), and extrahepatic bile ducts includes the hilar and common bile duct. ICC accounts for approximately 10% of all carcinomas arising from the biliary system (12). In addition to the above-mentioned confusion, “peripheral cholangiocarcinoma” and “cholangiocellular carcinoma” are used almost synonymously with ICC. Attempts have been made to morphologically classify ICC. The most popular classification, advocated by the Liver Cancer Study Group of Japan, is the mass-forming type, periductalinfiltrating type, and intraductal-growth type (11) (Fig. 24.1). The mass-forming type of ICC (MF-ICC) is a localized nodular tumor in the liver parenchyma, with a distinct border and primarily grows expansively, although it sometimes shows hilar invasion (3,13). The periductal-infiltrating type of ICC invades the connective tissue within Glisson’s sheath in an infiltrative rather than expansive fashion. The intraductalgrowth type of ICC (IG-ICC) is characterized by papillary or nodular growth within the lumen of the bile ducts. Some of these tumors exhibit superficial mucosal spread with minimal changes on radiological images, while others may occlude the intrahepatic bile duct to induce macroscopic bile duct dilatation (13). Among the three morphologic types, MF-ICC is the most prevalent, so that much of the description in the following sections refers to this type of the tumor. Originally, MF-ICC was thought to be a distinct category with a poorer prognosis compared with the other types (3,14). However, it has been elucidated that IG-ICC is associated with

a better prognosis than the other types (15–20). The reason for the better prognosis of the latter type of ICC is that this type can be detected in the early stages based on positive radiologic signs or by the detection of liver dysfunction because of biliary obstruction. IG-ICC is often diagnosed before tumor extension beyond the bile ducts and patients with this type of ICC present with smaller tumor sizes than patients with the other types of ICC (20).

epidemiology and risk factors Over 80% of patients with ICC are reported from the developing countries of Asia and Africa, and moreover half are from China (21). ICC accounts for only 1% of all liver malignancies in the United States (22), whereas the reported proportion from Japan is much higher at around 4% (23). The incidence and mortality have been reported to be increasing in most countries where wide disease surveillance has been undertaken (24,25). Several risk factors for ICC have been suggested, however, in most patients with ICC, no such risk factors can be identified (26). Conditions pre-disposing to ICC include infestation with parasitic liver flukes, such as Opisthorchis viverrini and Clonorchis sinensis (27,28); exposure to Thorotrast (29); hepatitis C virus infection (30–33); smoking (27,33); and HIV infection (32). Some common diseases co-existing with ICC have been reported, including primary sclerosing cholangitis and associated ulcerative colitis (26,34), choledochal cyst, Caroli’s syndrome (35), congenital hepatic fibrosis, alcoholic liver disease, and diabetes mellitus (32,33). There are three reports from the United States and Denmark of the results of surveys of large populations conducted to determine the risk factors of ICC (32,33,36). Common risk factors identified in at least two of these were cholangitis, gallbladder stones, choledocholithiasis, alcoholic liver disease, non-specific cirrhosis, hepatitis C virus infection, diabetes mellitus, inflammatory bowel disease, and smoking (32,33,36). Interestingly, although correlation with hepatitis C virus infection has often been reported, involvement of hepatitis B virus infection has never been reported.

pre-operative diagnosis Because previous surveys of ICC have failed to define highrisk groups (37), unlike the case for hepatocellular carcinoma, early detection of ICC patients remains difficult. Moreover, absence of early symptoms in most patients with ICC leads to delays in diagnosis. Some of the possible symptoms associated with ICC include abdominal pain, anemia, and weight loss (38). In contrast to patients with extrahepatic bile duct carcinoma, only 0% to 28% of patients with ICC present with obstructive jaundice (5,6,38). There are no definite tumor markers for ICC, although carcinoembryonic antigen (CEA) and carbohydrate antigen

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

(A)

(B)

(C) Figure 24.1 Morphologic classification of intrahepatic cholangiocarcinoma according to Liver Cancer Study Group of Japan. (A) Mass-forming type. (B) Periductalinfiltrating type. (C) Intraductal-growth type. Source : From Ref. 11.

19–9 (CA19–9) are frequently elevated and so used for both helping to confirm the diagnosis and post-operative monitoring for tumor recurrence. The sensitivity and specificity of CA19–9 for the diagnosis of ICC have been reported to be in the range of 70% to over 90% in patients with primary sclerosing cholangitis, using various cut-off points (39–42), although a much lower sensitivity (53%) was reported in a population without primary sclerosing cholangitis (43). Low sensitivities for the diagnosis of ICC have also been reported for other serum markers that are sometimes used to identify extrahepatic bile duct carcinoma, for example, the serum levels of liver transaminases, alkaline phosphatase, and total bilirubin (5). Because ICCs are essentially adenocarcinomas, they often exhibit imaging findings similar to those of metastatic liver tumors from carcinomas of the gastrointestinal tract. Typically, the tumors are partially spherical in shape, with an irregular surface, and are almost hypovascular, with peripheral enhancement on contrast-enhanced CT, MRI, and ultrasound (44–46). Gastroscopy, colonoscopy, CT with optional positron emission tomography (PET) of the thorax and abdomen should be done to differentiate ICCs from metastatic tumors originating from the gastrointestinal tract. Percutaneous tumor biopsy is not recommended if surgery is considered, because it may cause tumor seeding and complicate the surgical procedure (47). The diagnostic ability of newer imaging modalities, including FDG-PET, for ICC still remains under debate. One study reported high SUV values in all of the 10 cases examined (48), and another reported that the diagnostic accuracy of PET for lymph node metastasis from this type of tumor was 86%; figures that were higher than those reported for CT or MRI; also, higher SUV values were reported to be correlated with a poorer prognosis (49).

surgical strategy As with hepatocellular carcinoma, the counterpart of ICC as a primary liver cancer, the only treatment that may offer a

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chance of long survival in patients with ICC is surgery. In the natural history of unresected ICC, the median survival after diagnosis is less than 1 year (50,51) and most patients present at an advanced stage when they are no longer suitable candidates for curative resection. A study from the United States reported that complete tumor resection was possible in only 29 of 44 patients who were considered for curative resection (5). The prognosis after palliative resection is poor, with median reported survivals of between 2 and 3 months (50,51). No consensus has been established with regard to the criteria for surgery, because of the small number of patients in each reported series. However, based on the literature, it would seem that surgery should be offered to all patients with potentially resectable ICC, regardless of tumor stage. Some have claimed that positive lymph node metastasis detected on examination of frozen sections at laparotomy is a contraindication for tumor resection (3), whereas two reports have recommended surgery for patients with lymph node metastasis, given a solitary hepatic lesion (52) or less than two lymph node metastases (53). Surgery affords no survival benefit in patients with ICC with any extent of distant metastasis (15). Although multiple hepatic lesions have been shown to be correlated with a poor prognosis (6,54–56), the indication for surgery in relation to the number of tumors remains unclear at present. There is also no established consensus with regard to the optimal surgical procedure for patients with ICC. A positive surgical margin has been shown to be associated with a poor prognosis (3,5,6,54,55) and tumor invasion along Glisson’s sheath is often observed (57,58), therefore extended anatomical hepatic resections would seem to be a more rational surgical procedure as compared with non-anatomical limited hepatic resections. However, the superiority of such a procedure has not yet been demonstrated. A recent study reported that under certain conditions, tumor resection with a minimal surgical margin may be reasonable (59). In patients with ICC

RESECTION OF INTRAHEPATIC CHOLANGIOCARCINOMA 100 90

Survival rate (%)

80 70 60 50 40 N0 1,028

30 20

N1 495

10 0

0

12

24

36

48

60 72 84 Survival period (month)

96

108

120

132

144

Figure 24.2 Impact of lymph node metastasis on the overall survival rate of patients with ICC who underwent tumor resection. N0 indicates patients without lymph node metastasis and N1 indicates those with lymph node metastasis. Source : From Ref. 11.

Table 24.1 Outcome After Liver Resection for Intrahepatic Cholangiocarcinoma in Literature First author

Year

Country

n

Kawarada (68) Cherqui (47) Schlinkert (66) Yamamoto (31) Pichlmayr (63) Nakeeb (9) Jan (67) Casavilla (54) Madariaga (55) Chen (38) Valverde (65) Inoue (3) Okabayashi (4) Weber (56) DeOliveira (5) Shimada (59) Paik (6)

1990 1995 1992 1992 1995 1996 1996 1997 1998 1999 1999 2000 2001 2001 2001 2007 2008

Japan France USA Japan Germany USA China USA USA Taiwan France Japan Japan USA USA Japan Korea

11 14 6 10 32 9 41 34 34 138 30 52 60 33 44 47 97

with apparent invasion of the major portal pedicles or major hepatic veins, major hepatic resection should be considered. The decision on the appropriate surgical procedure must be made with reference to the functional liver reserve; an algorithm suggested by Makuuchi and colleagues (60) has been widely adopted for this purpose. Pre-operative portal vein embolization should be considered when the optimal surgical procedure is impossible based on the functional liver reserve (61). Some reports have recommended extrahepatic bile duct resection for MF-ICC, because the majority of this type of ICC shows biliary invasion (14,57,62). The reported incidence, from studies including at least 30 patients, of lymph node metastasis in surgically treated patients with ICC is as high as 18% to 40% (3,54,55,63–65). Patients with lymph node metastasis have a poor prognosis; a

1-year survival, % – – 59.3 – – 53.7 64 67 33 86 63 68 – – – 74.9

3-year survival, %

5-year survival, %

34 – – 44.4 – – 36.6 34 40 17 22 36 35 – – 45 51.8

34 – 33 44.4 – 44 26.8 26 35 14 – 36 29 – 40 40 31.1

Median survival, mo – 14 – – 12.8 22 12 – 19 – 28 – – 37.4 23 – –

nation-wide surveillance conducted in Japan (n = 495) revealed 1-, 3-, and 5-year survival rates of 52.4%, 23.1%, and 15.6%, respectively (Fig. 24.2) (23). The prognostic benefit of lymph node dissection remains controversial. Some authors have demonstrated its usefulness in cases where the tumor is solitary (52,53) and when a limited number of lymph nodes are metastatic (53). On the other hand, Shimada and colleagues (16) contradicted the survival benefit of lymph node dissection, because it was often seen in patients treated without lymph node dissection that recurrent lymph node metastasis occurred not at the hilar site but at distant sites.

prognosis after surgery The prognosis after surgery in patients with ICC is slightly worse than that seen in patients with hepatocellular carcinoma.

225

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 100 90

Survival rate (%)

80 70 60 50 40 30

3,499

20 10 0

0

12

24

36

48

60 72 84 Survival period (month)

96

108

120

132

144

Figure 24.3 Overall survival rates of all patients with ICC who underwent tumor resection. Source : From Ref. 11.

Table 24.2 Prognostic Factors After Surgery for Intrahepatic Cholangiocarcinoma First author

Year

n

Lymph node

Vascular invasion

Positive margin

Tumor size

Multiple tumors

Bilobar disease

Nakeeb (9) Jan (67) Chou (69) Casavilla (54) Madariaga (55) Valverde (65) Inoue (3) Weber (56) DeOliveira (5) Paik (6)

1996 1996 1997 1997 1998 1999 2000 2001 2001 2008

9 41 27 54 34 30 52 33 44 97

– – U U, M U, M U U, M – U U

– U – U U – U, M U, M – –

U U, M – U, M – – U, M U U, M U, M

– – – – U – – – – U

– – – U, M U, M U – U – U, M

– – U U – – – – –

Others – Lymphatic invasion – TNM stage – – Left lobe – – Morphologic type

U, significant by univariate analysis for overall survival; M, significant by multivariate analysis for overall survival.

According to a nation-wide survey conducted in Japan, the 1-, 3-, and 5-year survival rates in 1626 patients who underwent tumor resection for ICC were 70.5%, 43.8%, and 32.7%, respectively (Fig. 24.3) (23). The results of surgical treatment for ICC, most cases of which are accounted for by MF-ICC, are summarized in (Table 24.1 (3–6,9,31,38,47,54–56,59,63,65– 68). Median survival time ranged from 12 to 37 months, and the 5-year survival rate ranged from 14% to 44%; the wide range was probably caused by the small number of patients included in the studies. According to some studies, the pre-operative mortality rates ranged between 2% and 5%. The most common site of recurrence was the liver, followed in frequency by lungs, bones, peritoneum, adrenal glands, and kidneys (54,56). The prognostic factors in patients undergoing surgery for ICC proposed in the literature are listed in (Table 24.2 (3,5,6,9,54– 56,65,67,69). The indicators of poorer prognosis proposed in these multiple reports include positive lymph node metastasis, positive surgical margin, multiple hepatic lesions, presence of vascular invasion, and a large tumor size. While a large tumor size and bilobar tumor location were identified as prognostic factors by univariate analysis in a number of studies, these could

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not be confirmed as prognostic factors by multivariate analysis. Despite these suggested prognostic factors, the contraindications to surgery have not yet been fully elucidated.

adjuvant therapy Because the prognosis after tumor resection alone is far from satisfaction, adjuvant therapy may be considered in some patients. There have been only a few reports of long-term survival with such therapy among patients with ICC (70,71). Moreover, there have been no reported randomized prospective trials of adjuvant therapy in these patients, although the CRUK BILCAP study of surgery versus surgery plus adjuvant gemcitabine continues to recruit in the United Kingdom. There have also been only a few anecdotal reports of chemotherapy for patients with recurrent or unresectable ICC, using 5-FU, cisplatin, epirubicin, gemcitabine, capecitabine, and cetuximab (72–76). Further therapeutic trials are therefore warranted using recently developed treatment modalities or those that are developed in the future, including radiotherapy, immunotherapy, and chemotherapy with or without molecule-targeted drugs.

RESECTION OF INTRAHEPATIC CHOLANGIOCARCINOMA

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Transplantation for hilar cholangiocarcinoma Julie K. Heimbach, Charles B. Rosen, and David M. Nagorney

background Cholangiocarcinoma (CCA) is a malignancy arising from the bile duct epithelium which has a very poor prognosis. The incidence in the United States is approximately 1.2 in 100,000, though it is far higher in Eastern Europe and Asia, and it appears to be increasing worldwide (1–3). Although CCA can occur anywhere along the intra- or extra-hepatic bile ducts, the most common location is at the hilar region, involving the confluence of the right and left ducts (60%) (4,5). While most patients develop CCA de novo, risk factors for the development of CCA relate to chronic inflammation of the biliary tree. In Western countries CCA is most often associated with Primary Sclerosing Cholangitis (PSC), though other risk factors include choledochal cysts, hepaticolithiasis, and parasitic infections including Clonorchis sinensis and Opisthorchis viverrini. The prevalence of CCA in patients with PSC is 5% to 15% (6). Establishing a timely diagnosis of hilar CCA is challenging. The tumor is a desmoplastic lesion which typically grows along the bile duct rather than in a radial diameter which limits early detection by cross-sectional imaging. Endoscopic brushing and biopsy are often negative even in of the presence well-established disease, and the tropism for bile producing growth in a longitudinal fashion often leads to the lack of a mass lesion, even in the face of biliary obstruction (7). Eventually, tumor growth becomes independent of bile and mass lesions develop, which are demonstrable by cross sectional imaging. Direct cholangiography (endoscopic retrograde cholangiography and percutaneous transhepatic cholangiogram) best characterizes the site, extent, and configuration of ductal CCA. However, the use of imaging modalities, including high-resolution CT and MRI, are also important for the diagnosis of CCA by providing additional information regarding adjacent structures which differentiate CCA from benign counterparts. While contrast-enhanced MRI and magnetic resonance cholangio-pancreatography have improved the diagnostic sensitivity and specificity of imaging, due to the biologic principles of the tumor, early diagnosis remains a significant problem (8–10). A promising technique in obtaining a tissue diagnosis may be the use of Spyglass cholangioscopy, which allows biopsy if bile duct lesions under direct endoscopic visualization. Although this technique may prove to be useful for diagnostic purposes, it will not enhance accuracy of pre-operative tumor staging (11). Thus far, no molecular markers in bile have proven reliable in establishing a more timely diagnosis. The serum marker CA 19–9 has not been shown to be accurate enough for screening. However, for patients with PSC and a malignant appearing stricture, serum CA 19–9 >130 U/mL has a sensitivity of 79% and a specificity of 98% (12). Conventional cytology has a sensitivity of only 20% to 40%, though the specificity is 100% (13). The limitation of conventional cytology is the paucicellular nature of a

desmoplastic tumor which leads to the inability to obtain an adequate number of cells to make a definitive diagnosis. Fluorescent in situ hybridization (FISH) is a cytologic technique which allows for the detection of aneuploidy in epithelial cells. In particular, FISH polysomy (two or more chromosomes duplicated) identifies another 20% of patients with CCA missed by conventional cytology while maintaining a specificity of 100% (13). Despite the use of advances cytologic techniques, the ability to make a timely and accurate diagnosis remains sub-optimal. The primary therapy for hilar CCA is surgical resection. There is no effective systemic therapy, though radiation may provide palliation and in exceptional cases, prolonged survival. Outcomes for resection of CCA are limited by the inability to obtain an accurate early diagnosis as many patients present with unresectable lesions. An R0 resection is possible in 70% to 80% of attempted resections and in most series, 5-year survival is approximately 25% to 30% (14–19). Recent resectional approaches for CCA have included techniques such as pre-operative portal vein embolization to induce hypertrophy in the anticipated-remaining hepatic remnant for prevention of liver failure and techniques of vascular reconstruction to expand the potential for R0 resectability. Yokoyama et al. have described an extensive experience with pre-operative portal vein embolization (PVE) in 240 patients, in which selective arterial embolization has been used to improve response to PVE (20). Though the authors report a decrease in operative mortality from 21.9% to most recently (after 2001) 1.6% following PVE, they do not describe the impact of PVE on long-term survival following resection for CCA. A large series from Johns Hopkins also published in 2008 review the outcomes of 564 patients with CCA (50% hilar CCA) and reports on predictors of improved outcome following resection (21). Favorable prognostic factors included patients resected in a more recent time period (after 1995), negative margins, well-differentiated tumors, and negative lymph nodes. For patients with hilar CCA, the median survival was 30 months with 30% 5-year survival. Three other recent single-center series have been reported in the last year and all report similar survival outcomes of 30% to 40% at 5 years and included the use of extended hepatic resection with portal vein reconstruction (22–24). When analysis is restricted to only to those patients with negative resection margins with or without portal vein reconstruction, a 5-year survival of 45% was reported by Hemming et al. (24). Similar improved outcomes with advanced techniques have also been reported by Neuhas et al. (25). All of these data are single-center non-randomized reports with outcomes compared to historical controls.

neoadjuvant chemoradiotherapy followed by liver transplantation Liver transplantation (OLT) was initially proposed as the ideal solution to the problem of achieving a complete resection.

229

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Complete hepatectomy followed by transplantation addressed all relevant margins of resection—hepatic, vascular, and ductal—and provided equivalent, if not more complete regional lymphadenectomy. Unfortunately, early experience with OLT was dismal, as recipients demonstrated a high recurrence rate and very poor survival (26–33). Moreover, the initial application of OLT for CCA did not discriminate between intra-hepatic and extra-hepatic origin. Currently OLT alone is contra-indicated in patients with CCA However, based on the observation that radiation provided effective palliation, and in some cases prolonged survival, a neoadjuvant protocol combining External Beam Radiotherapy (EBRT) and brachytherapy with 5-FU and oral capecitabine followed by OLT was started at the Mayo Clinic in 1993 (34). At the same time, a similar protocol was started in Nebraska employing higher dose of brachytherapy without EBRT (35). The Mayo Clinic protocol is restricted to patients with unresectable, non-metastatic hilar CCA. Diagnosis is established by a positive endoscopic biopsy or brushings, in the presence of a mass lesion (<3 cm in radial diameter), polysomy at multiple chromosomes by FISH and CA 19–9 >100, in the presence of a radiographically malignant stricture. Patients with resectable disease undergo resection, but those with bilobar segmental ductal extension which precludes R0 resection; patients with bilobar hilar vascular encasement or those with underlying PSC are considered for the protocol. Patients are staged by cross-sectional imaging and endoscopic ultra-sound prior to enrollment, and are excluded if they have evidence of metastatic disease, have undergone prior attempted resection with violation of the tumor plane or percutaneous (or transluminal biopsy) of the primary lesion or have medical contra-indications precluding OLT. Enrolled patients receive EBRT administered with a target dose of 4500 cGY in 30 fractions delivered over a 3-week period, with 5-FU given in 500 mg/m2 daily bolus for 3 days at the initiation of EBRT (see Fig. 25.1). Two to three weeks after completion of EBRT, a transluminal boost of radiation is delivered using transcatheter iridum192 seeds with target dose of 2000 to 3000 cGy. Patients remain on oral capecitabine

while awaiting transplantation. Prior to undergoing transplantation, which is performed either with a deceased donor or living donor allograft, patients undergo formal operative staging (either open or more recently, using hand-assisted laparoscopy) with routine sampling of common hepatic artery and peri-choledochal lymph nodes in addition to biopsy of any other suspicious nodules. Our initial experience with neoadjuvant chemoradiotherapy followed by transplantation was encouraging (36,37) and was followed by a comparison of all 38 patients undergoing OLT for unresectable hilar CCA from 1993 to 2002 versus all patients who underwent resection of hilar CCA at the same institution during the same time period (14). A comparison between liver transplantation with neoadjuvant therapy and resection is imperfect because the OLT protocol was restricted to patients with unresectable disease. Nevertheless, transplantation provided superior outcomes, with 82% 5-year survival versus 21% 5-year survival after resection. In this study, a survival benefit for transplantation versus resection was seen both in patients with PSC and in those with de novo CCA. Our most recent published survival data from December of 2006 includes 65 patients with a mean follow-up of 32 months. Patient survival was 91% at 1 year and 76% at 5 years (38). To date, 167 patients have enrolled in this protocol. There have been 111 patients who have undergone OLT with 1- and 5-year survival of 96% and 72%, respectively (see Figs. 25.2 and 25.3). Though patient survival following the combined protocol for treatment of hilar CCA is similar to other indications for liver transplantation, the toxicity of the neoadjuvant therapy is significant. Common complications include cholangitis, liver abscess, duodenal ulceration, malnutrition, liver decompensation, and disease progression (14,36–38). Approximately 20% of patients have evidence of metastatic disease at operative staging and are therefore not eligible for OLT (see Fig. 25.2). Additionally, despite the aggressive pre-treatment protocol, 11 of 65 (17%) in the most recent published analysis still developed disease recurrence following liver transplantation (38). A retrospective analysis of these 11 patients who developed disease recurrence determined that older patients, those with

Hilar cholangiocarcinoma Mayo clinic protocol Selected patients with unresectable hilar cholangiocarcinoma (began in 1993) Neoadjuvant radiation and chemotherapy External beam radiotherapy with bolus 5-FU Brachytherapy with protracted capcitabine

Staging operation to rule-out metastases or local extension of tumor precluding complete resection of tumor

Orthotopic liver transplantation Figure 25.1 Combined chemoradiotherapy followed by liver transplantation protocol for patients with unresectable hilar CCA.

230

Cholangiocarcinoma treatment protocol results (September 1, 2008)

167 patients Irradiation + 5-FU

12 deaths/disease progression 2 transplanted elsewhere 10 receiving neoadjuvant therapy

143 staging operation

27 (19%) staged positive 2 awaiting transplantation 2 transplanted elsewhere 1 death

111 liver transplantation

75 decease donor 35 living donor 1 domino donor

Figure 25.2 Results of a combined chemoradiotherapy followed by liver transplantation protocol for hilar CCA.

TRANSPLANTATION FOR HILAR CHOLANGIOCARCINOMA larger tumors, a prior cholecystectomy, and those with an increased CA 19–9 at transplant (though not at enrollment) to be at an increased risk of recurrence, with a median time to recurrence of 22 months. Those with unfavorable tumor characteristics, such as residual tumor >2 cm in the explanted liver and perineural invasion were also at an increased risk of recurrence. In this series, three patients developed local-regional recurrence while eight had distant metastasis. Recently, Becker et al. analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database for patients with CCA who underwent transplant from 1987 to 2005 (39). There were 280 patients who had a diagnosis of CCA either at listing, at discharge, or both, though it is not known whether the patients received neoadjuvant therapy, pre-transplant staging, or any standardized inclusion criteria. Survival for patients who underwent OLT from 1994 to 2005 with a listing diagnosis of CCA (n = 102) experienced a 5-year actuarial survival of 68%. Given these patients underwent OLT in an era when CCA was a known contra-indication to OLT, it is presumed that most of these patients received neoadjuvant therapy, though this assumption is uncertain. Those transplanted in the same era without a pretransplant diagnosis of CCA (presumably incidental CCA and therefore without neoadjuvant therapy, n = 77) remained with a 5-year survival of 20%, which is similar to the historically poor survival associated with OLT for CCA. The conclusion of this multi-center analysis is that transplant for early stage hilar CCA (unresectable or arising in the setting of PSC) is beneficial based on the survival rate of 68% for those with a known diagnosis of CCA, though the study is hindered by the lack of essential details, such as the use of neoadjuvant therapies. With the potential for broader application of the combined neoadjuvant chemo-radiotherapy and OLT protocol, attention must be focused on the recognition and management of anticipated complications following this aggressive treatment. In addition to pre-operative morbidity such as cholangitis and duodenal ulceration, intra-operative challenges attributable to the neoadjuvant therapy include severe inflammatory changes and dense fibrosis leading to difficulty in identifying and Patient survival after transplantation 1993–2008 96 ± 2% n = 111

100

83 ± 4%

90

72 ± 6%

80 70 60 50 40 30 20 10 0 0

1

2 3 Years after transplantation

4

5

Figure 25.3 Kaplan–Meier analysis of survival for patients undergoing transplantation after completion of neoadjuvant therapy at Mayo Clinic.

separating hilar structures. Late effects of tissue injury from radiation therapy, which may be broadly considered a result of fibrosis and chronic ischemic injury, are also of concern. A recent retrospective analysis of 68 patients who underwent neoadjuvant chemoradiotherapy followed by OLT showed increased incidence of late vascular strictures (arterial and portal vein) when compared to controls undergoing OLT for other indications (40). The late vascular complication rate was 40%, though patient and graft survival did not differ between the groups. In most patients, these complications were manageable with a percutaneous endovascular approach. The key findings from this analysis are that arterial interposition grafts should be used to replace the irradiated native artery in all cases of deceased donor transplantation. Additionally, late strictures of the portal vein (and non-replaced arteries as in the case of a living donor transplant) should be anticipated and may be amenable to endovascular interventions.

organ allocation The findings from the Mayo Clinic and Nebraska protocols as well as the historical data for OLT without adjuvant therapy were carefully considered by the Model for End Stage Liver Disease (MELD) Exception Study Group, which was assembled to consider standardization of diagnoses which commonly led to MELD exception scores (41). The conclusion of this group was to recommend national standardization of MELD score exceptions for patients with early stage, unresectable hilar CCA provided they are enrolled in an approved protocol which includes neoadjuvant therapy, and standard inclusion (i.e., diagnostic), and exclusion criteria. The group proposed an allocation policy applied nationally similar to that currently granted for HCC, which is based on a 10% risk of mortality subject to readjustment every three months. Currently, organ allocation in the United States for hilar CCA, as well as other diagnoses which require MELD exception, varies considerably by each region. It is possible that a national policy for MELD exceptions for common diagnoses may be considered in the future.

conclusions Excellent outcomes can be achieved with neoadjuvant chemoradiotherapy followed by OLT for selected patients with early stage hilar CCA. Obtaining a timely diagnosis remains a key challenge regardless of whether resection or transplantation is being considered. As with hepatocellular carcinoma, it is necessary to determine the risk for disease progression following neoadjuvant therapy for patients awaiting transplantation. Given the severe donor organ shortage, continued analysis of outcomes in order to identify patients not likely to gain benefit from this aggressive protocol is necessary. In light of the results achievable with the combined neoadjuvant chemoradiotherapy protocol, however, a standardized approach to organ allocation which is applied nationally, as for HCC, is necessary and will hopefully be forthcoming. Finally, with application of the protocol across multiple centers, the key principles, such as multi-disciplinary approach, pre-transplant staging to ensure inclusion of only those without metastasis, replacement of irradiated vessels when possible as well as monitoring for postoperative vascular complications, must be highlighted.

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key points 1. The diagnosis of hilar CCA remains a challenge (level II evidence). 2. Based on non-randomized analysis (level II evidence), neoadjuvant chemoradiotherapy followed by liver transplantation for patients with early stage unresectable hilar CCA offers excellent survival. 3. Percutaneous, open, or transgastric biopsy of the primary tumor should not be performed due to the risk of tumor seeding into the peritoneal cavity (level II). 4. Radiation injury may lead to hepatic artery thrombosis and late vascular strictures. Native hepatic arteries should be replaced by arterial conduits in deceased donor transplantation to reduce early thrombosis. Late strictures may be amenable to endovascular treatment (level III). 5. Toxicity of the neoadjuvant therapy is significant, and a multi-disciplinary approach including commitment from radiology, radiation oncology, medical oncology, hepatology, and hepatobiliary/ transplantation surgery is necessary.

references 1. Shaib Y, el-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004; 24: 115–25. 2. Sripa B, Pairojkul C. Cholangiocarcinoma: lessons from Thailand. Curr Opin Gastro 2008; 24: 349–56. 3. Maggs JR, Chapman RW. An update on primary sclerosing cholangitis. Curr Opin Gastro 2008, 24: 377–83. 4. Bismuth H, Castaing D. Hepatobiliary malignancy. London: Edward Arnold, 1994. 5. De Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999; 341: 1368–79. 6. Knan Sa, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002; 51 (Suppl 6): VI 1–9. 7. Gores GJ, Nagorney DM, Rosen CB. Cholangiocarcinoma: is transplantation an option? For whom? J Hepatol 2007; 47: 454–75. 8. Manfredi R, Barbaro B, Masselli G, et al. Magnetic resonance imaging of cholangiocarcinoma. Semin Liv Dis 2004; 24(2): 155–64. 9. Braga HJ, Imam K, Bluemke DA. MR imaging of intrahepatic cholangiocarcinoma: use of ferumoxides for lesion localization and extension. AJR 2001; 177: 111–14. 10. Yeh TS, Jan YY, Tseng JH, et al. Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreaticographic findings. Am J Gastro 2000; 95: 432–40. 11. Chen YK, Pleaskow DK. SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorder: a clinical feasibility study. Gastrointest Endosc 2007; 65(6): 832–41. 12. Levy C, Lymp J, Angulo P, et al. The value of serum Ca 19-9 in predicting cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig Dis Sci 2005; 50: 1734–40. 13. Moreno Luna LE, Kipp B, Halling et al. Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology 2006; 131: 1064–72. 14. Rea D, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005; 3: 451–61. 15. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224: 463–73; discussion 473–5.

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16. Pichlmayr R, Weimann A, Klempnauer J, et al. Surgical treatment in proximal bile duct cancer. A single-center experience. Ann Surg 1996; 224: 628–38. 17. Kosuge T, Yamamoto J, Shimada K, et al. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 1999; 230: 663–71. 18. Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for cholangiocarcinoma. Arch Surg 2001; 234: 270–6. 19. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001; 234: 507–17; discussion 517–9. 20. Yokoyama Y, Nagina M, Nishio H, et al. Recent advances in the treatment of hilar cholangiocarcinoma: portal vein embolization. J Hepatobiliary Pancreat Surg 2007; 14: 447–54. 21. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007; 5: 755–62. 22. Miyazaki M, Kato A, Ito H, et al. Combined vascular resection in operative resection for hilar cholangiocarcinoma: does it work or not? Surgery 2007: 5: 581–8. 23. Hasegawa S, Ikai I, Fujii H, et al. Surgical resection of hilar cholangiocarcinoma: analysis of survival and postoperative complications. World J Surg 2007; 31: 1256–63. 24. Hemming AW, Kim RD, Mekeel KL, et al. Portal vein resection for hilar cholangiocarcinoma. Am Surg 2006; 72: 599–605. 25. Neuhaus P, Joans S. Surgery for hilar cholangiocarcinoma—the German experience. J Hepatobiliary Pancreat Surg 2000; 7(2):142–7. 26. Goldstein RM, Stone M, Tillery GW, et al. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg 1993; 166: 768–71; discussion 771–2. 27. Jonas S, Kling N, Guckelberger O, et al. Orthotopic liver transplantation after extended bile duct resection as treatment of hilar cholangiocarcinoma. First long-terms results. Transpl Int 1998; 11 (Suppl 1): S206–8. 28. Loinaz C, Abradelo M, Gomez R, et al. Liver transplantation and incidental primary liver tumors. Transplant Proc 1998; 30: 3301–2. 29. Iwatsuki S, Todo S, Marsh JW, et al. Treatment of hilar cholangiocarcinoma (Klatskin Tumors) with hepatic resection or transplantation. J Am Coll Surg 1998;187: 358–64. 30. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000; 69: 1633–7. 31. Shimoda M, Farmer DG, Colquhoun SD, et al. Liver transplantation for cholangiocellular carcinoma: analysis of a single-center experience and review of the literature. Liver Transpl 2001; 12: 1023–33. 32. Robles R, Figueras J, Turrion VA, et al. Liver transplantation for hilar cholangiocarcinoma: Spanish experience. Transpl Proceedings 2003; 35: 1821–2. 33. Ghali P, Marotta PJ, Yoshida EM, et al. Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transpl 2005; 11: 1412–6. 34. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl 2000; 6: 309–16. 35. Sudan D, DeRoover A, Chinnakotia S, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transpl 2002; 2: 774–9. 36. Hasson Z, Gores GJ, Rosen CB, et al. Preliminary experience with liver transplantation in selected patients with unresectable hilar cholangiocarcinoma. Surg Oncol Clin N Am 2002; 11: 909–21. 37. Heimbach JK, Gores GJ, Haddock MG, et al. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis 2004; 24(2): 201–7. 38. Heimbach JK, Gores GJ, Haddock MG, et al. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006; 12: 1703–7. 39. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2008; 12(1): 117–22. 40. Mantel HTJ, Rosen CB, Heimbach JK, et al. Vascular complications after orthotopic liver transplantation after neoadjuvant therapy for hilar cholangiocarcinoma. Liver Transpl 2007; 12: 1372–81. 41. Gores GJ, Gish RG, Sudan D, et al. MELD Exception Study Group. Model for end-stage liver disease (MELD) exception for cholangiocarcinoma or biliary dysplasia. Liver Transpl 2006; 12: S95–7.

26 Rare vascular liver tumors

Jan P. Lerut, Eliano Bonaccorsi-Riani, Giuseppe Orlando, Vincent Karam, René Adam, and the ELITA–ELTR Registry a

introduction Vascular hepatic tumors form a continuum going from the completely benign hemangioma (HA) to the very aggressive hemangiosarcoma (HAS). Sometimes due to their difficult differential diagnosis and the rarity of the more malignant varieties, and also to the limited worldwide experience with liver resection and transplantation (LT) for these tumors, these vascular lesions are often neglected or misdiagnosed and their therapeutic management algorithm is unclear. The rarity of malignant vascular liver lesions is well demonstrated by the data of the European Liver Transplant Registry (ELTR). During the period January 1988 to June 2007, 12% (8278) of all European LT were performed because of hepatobiliary tumors, but of these, only 125 (0.1%) were done because of malignant vascular diseases. In this chapter hepatic epithelioid hemangioendothelioma (HEHE), infantile hemangioendothelioma (HIHE), and hemangiosarcoma (HAS) will be discussed, based on a recent literature review and of the experience gathered by the audited ELITA–ELTR during the period 1988 to 2004 (1). The information obtained from both sources allows a more clear insight into diagnosis and treatment of these rare liver diseases. For the sake of completeness, benign Nodular Regenerative Hyperplasia (NRH) is also included in this chapter because of its vascular etiopathogenesis. Hemangioma and lymphangioma are discussed in a separate chapter dealing with benign liver tumors.

hepatic epithelioid hemangioendothelioma ₍hehe₎ HEHE is a rare (<1 per million population), low-grade malignancy which has a malignant behavior potential between HA and HAS (2). This vascular tumor was first recognized in 1982 by Weiss and Enzinger in soft tissues, later on in the head and neck region, then in bones and finally in many other organs, such as lungs and bronchi. Liver involvement occurs most often as a primary tumor. HEHE is more frequent in young adult women; with a peak incidence during the fourth decade. This tumor has been rarely reported in children less than 15 years old. No definitive etiological factor has been clearly identified (2). Macroscopically, HEHE appears as multifocal fibrous masses (Fig. 26.1A and B). Microscopically, HEHE is characterized by pleiomorphic cells, both of medium and of large size, that are epithelioid in appearance and that spread within sinusoids and small veins at the periphery of the lesion, whereas the center is fibrous and studded with elongated tumor cells, sometimes

with intracellular vascular lumens containing red blood cells (Fig. 26.2A and B). In contrast to HAS, the hepatic acinar landmarks are better preserved. HEHE originates from endothelial cells which explains positive immunohistochemistry (IHC) for factor VIII-related antigen and for the endothelial markers CD31 and CD34. Ultrastructural examination also shows characteristic features of endothelial cells, such as a basal lamina, pinocytic vesicles, and Weibel–Palade bodies (2–4). The clinical manifestations of HEHE are unspecific, varying from totally asymptomatic to hepatic failure (Table 26.1). The malignant potential of HEHE often remains unclear in each individual patient. Based on the analysis of the ELITA–ELTR study, the most frequent symptoms are non-specific upper abdominal or epigastric discomfort or pain, weakness, general malaise, and jaundice. About 20% of patients are asymptomatic and 10% present with pulmonary symptoms (Table 26.1). Hepato-splenomegaly (50%) and weight loss (20%) are the most frequent clinical signs; portal hypertension may be caused by tumor compression or venous infiltration (3–6). Anicteric cholestasis and cytolytic activity are frequently present (60% and 40%, respectively). Serum tumor markers are normal in the absence of accompanying liver disease. Radiological investigation identifies two different patterns of HEHE: the early peripheral and nodular, usually bilobar type (peripheral pattern), and the later confluent type (diffuse pattern) with eventual invasion of the greater vessels (Fig. 26.3A). Focal calcifications are present in 20% of tumors. Angiography reveals only moderate vascularization with displacement of marginal vessels (Fig. 26.3B and C). Scintigraphic and FDG–PET imaging plays an important role in the staging of the disease, especially in view of later LT and also in view of the early detection of recurrent disease (7–8). Complete assessment of these patients is mandatory to exclude other, especially thoracic, disease localization. In doubtful cases thorascopic lung and/or pleural biopsy should be performed in order to exclude the often frequent thoracic involvement. Definitive diagnosis, frequently based on a high degree of suspicion, can be made by associating radiological and clinical features, such as occurrence in a young adult (usually female), the contrast between numerous intrahepatic (often calcified) tumors, the overall condition of the patient, and finally the longstanding clinical history. The diagnosis can only be confirmed by pathological examination of appropriate, surgically obtained biopsy material. The treatment algorithm of HEHE was till recently far from standardization. The literature review, including 13 very small

a

The European Liver Transplant Registry is a service of the European Liver and Intestinal Transplant Association (ELITA); see www.eltr.org.

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(A)

(B)

Figure 26.1 Intraoperative view of 7.6 kg heavy HEHE responsible for IVC syndrome and supine dyspnea (A). Characteristic gross appearance of a HEHE hepatectomy specimen showing multiple fibrous masses with zoning phenomenon (B).

(A)

(B)

Figure 26.2 Histological features of HEHE at the periphery (A) and in the center (B) of the lesion. Source: C. Sempoux, Dept. of Pathology.

Table 26.1 Clinical presentation of HEHE in the ELITA–ELTR series Age Gender Symptoms Upper abdominal pain/ discomfort Weakness/fatigue Asymptomatic Anorexia Nausea Dyspnea Signs Hepatomegaly Weight loss Jaundice Ascites Hemangioma Portal hypertension Hepatopulmonary syndrome

234

39 ± 15 years (range 0.4–65) – 2 children 43 F and 16 M 59% 20% 19% 15% 14% 10% 49% 20% 10% 9% 9% 7% 2%

(≥5 pts) series and three reviews, lacks detailed data analysis, and most importantly, long-term follow-up. The published experience does not allow comparison of results of untreated and of surgically and medically treated patients. The place of LT has especially been questioned in view of well-documented spontaneous resolution, long-term survival, the high incidence of extra-hepatic disease (up to 45%) (Table 26.2), the lack of predictive clinical or histological criteria, and finally the high incidence (up to 33%) of, sometimes even very late, recurrent allograft disease (6). The largest institutional series, coming from Pittsburgh and containing 16 patients, showed that LT offers 5-year overall and disease-free survival rates of 71% and 60%, respectively (9). The Mehrabi review indicates that the treatment of choice of HEHE is total hepatic resection (3). In this literature review, the 5-year survival rates of LT, partial liver resection (reported in only very few patients), local or systemic chemo- and radiotherapy (CHTH) and treatment abstention were 55%, 75%, 30%, and 0%, respectively. Partial liver resection is not a logical treatment because HEHE is nearly always a multinodular and bilobar disease. Indeed the examination of the total hepatectomy specimens analyzed in the ELITA–ELTR study showed

RARE VASCULAR LIVER TUMORS

(A)

(B)

(C)

Figure 26.3 CT-scan of HEHE showing the initial peripheral nodular (A) and the later confluent patterns of the disease (B). Angiography confirming the avascular nature and vascular displacement (C).

Table 26.2 Histological presentation of HEHE in the ELITA–ELTR series Bilobar involvement Number nodules >15 Microvascular involvement Macrovascular involvement Hilar lymph node positivity

Extrahepatic localization Lung Mediastinum Peritoneum Spleen Femoral vein Brain and bone Omentum

96% 86% 44.4% 9.4% 33% (18/54p) 4/18 pts (22%) patients only positive on IHC 4/10 pts with extrahepatic EHE localization were lymph node positive 17% (10 pts) 4 1 1 1 1 1

bilobar disease in 96% of cases; 86% of the specimen contained more than 15 tumor nodules (Table 26.2). Moreover, several reports documented disease recurrence, or LT because of recurrent HEHE after partial resection; fortunately, pre-transplant liver surgery doesn’t seem to impair survival after LT (6). The assessment of non-surgical treatments, such as radiotherapy, local tumor destruction, hormonotherapy, systemic or locoregional CHTH, trans-arterial embolization, and chemoembolization, is even more difficult because of the lack of uniform treatment modalities and of long-term follow-up (3). The ELITA–ELTR study is the largest worldwide, detailed long-term study in relation to HEHE (1). This study collected 59 European patients from 32 centers. The follow-up from diagnosis is 104 ± 72 months (median of 93 months) and from LT 83 ± 55 months (median of 79 months). The study validated the place of LT in the treatment of this disease and 5 and 10 years post-transplant survival rates are 83% and 74%, respectively, with 5 and 10 years recurrence-free survival rates of 82% and 64%, respectively (Fig. 26.4A and B). This study confirms that medical and/or surgical pre-LT treatment (present in 30% of pts), invasion of regional lymph node (present in 33% of pts) and of (limited) extrahepatic disease (present in 17% of pts) are not formal contraindications to LT. Combined micro- and macrovascular invasion (present in

49% of pts) is the only parameter which significantly influences outcome after LT. Mitotic index and cellular pleiomorphism are other major histological prognostic criteria reflecting more aggressive tumor behavior (10). Their influence on patient survival could not be analyzed in the ELITA– ELTR study due to the impossibility of obtaining central pathology recording. The recently published UNOS data reporting 128 patients with a median follow-up of 24 months go in the same direction; 1- and 5-year patient survival rates were 80% and 64%, respectively (11). Recurrent disease after (partial and total) hepatectomy should be treated aggressively as prolonged, sometimes even disease-free, survival can be achieved (1,3). The role of re-LT in the treatment of recurrent allograft disease is unclear as only one single case has been reported (5). It is conceivable that in view of the high incidences of extrahepatic disease localization, and of recurrence in- and outside the allograft (22% in the ELITA–ELTR study) (Table 26.3), a more radical approach combining total hepatectomy and antiangiogenic therapy, such as use of VEGF-antibodies, α-interferon and rapamycin could be of value in the treatment of HEHE (1,12). Rapamycin is of particular interest in this context as this drug is nowadays frequently used not only as a renal sparing but also as an anti-tumoral immunosuppressive drug in liver transplant recipients. Such an approach, combined with a better study of the molecular and genetic markers based on tumor biology, will be of great assistance in further improving outcome, monitoring efficacy of emerging neo- and adjuvant treatments and in recognizing the aggressive subtypes of HEHE (3,5,13–15).

hepatic infantile hemangioendothelioma ₍hihe₎ HIHE, the most common mesenchymal tumor of the liver in infants (<3 years), is always diagnosed nearly during the first 6 months of life. The tumor is also more frequent in females and presents with (a)symptomatic hepato-splenomegaly, failure to thrive, congestive cardiac failure (15%) due to intratumoral arteriovenous shunting, cutaneous hemangiomas (20–40%), consumptive coagulopathy due to Kasabac–Merritt syndrome, and medically resistant hypothyroidism (2,16). In the majority of the cases, HIHE appears to be a histological benign tumor that may regress spontaneously in 5% to 10% of cases; however its outcome is usually much poorer because of its severe complications (2,16–18).

235

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS HIHE can occur either as a single tumor (Fig. 26.5A) or it can be multifocal and diffuse (Fig. 26.5B). The lesions are soft, spongy, red-tan nodules, sometimes more firm and greywhite or brown with areas of necrosis and hemorrhage. Histology identifies two types of HIHE. Type 1 the most frequent is made of intercommunicating small vascular channels lined by a single layer of regular endothelial cells (Fig. 26.5C). There may be areas of cavernous changes and extramedullary hematopoiesis is often found. Type 2 HIHE, a more pleiomorphic HIHE with nuclear atypia, multi-layering, and papillary projections (Fig. 26.5D), is now considered as a form of HAS. IHC examination is of importance in relation to the differentiation of HIHE from hepatic vascular malformations associated

with capillary proliferation; immunoreactivity for GLUT-1 can be of help for the diagnosis of HIHE (19). The difficulty with these tumors lies in the fact that HIHE may harbor foci of HAS. Data from the ELITA–ELTR showed that children with HIHE present with a rapid deterioration of their condition or presenting with acute liver failure and/or Budd–Chiari syndrome, indeed also presented with (foci of) HAS (see further). HEHE can be differentiated from HIHE as both have different, age-related, clinical, and pathological features. The natural history of HIHE is variable, but up to two thirds of symptomatic patients die of tumor complications, for example, cardiac failure. Treatment modalities of HIHE vary from medical

Patient survival after liver transplantation for epithelioid hemangioendothelioma: 59 patients 100 90 80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

6

7

8

9

Survival % 2 yrs 1 yr 86% 93%

3 yrs 85%

4 yrs 83%

5 yrs 83%

6 yrs 80%

7 yrs 75%

8 yrs 72%

9 yrs 72%

10 yrs 72%

Number of exposed patients Total 1 yrs 2 yrs 3 yrs 59 55 51 46

4 yrs 41

5 yrs 36

6 yrs 31

7 yrs 26

8 yrs 18

9 yrs 14

10

10 yrs 13

Disease free survival after liver transplantation for epithelioid hemangioendothelioma: 52 patients 100 90 80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

6

7

8

9

Survival % 1 yr 2 yrs 90% 87%

3 yrs 85%

4 yrs 85%

5 yrs 82%

6 yrs 79%

7 yrs 76%

8 yrs 68%

9 yrs 64%

10 yrs 64%

Number of exposed patients Total 1 yr 2 yrs 3 yrs 52 47 45 40

4 yrs 36

5 yrs 31

6 yrs 27

7 yrs 23

8 yrs 16

9 yrs 11

10

10 yrs 11

Figure 26.4 Overall patient survival of HEHE after liver transplantation in the ELITA-ELTR study (A). Recurrent-free survival in the same patient cohort of 59 patients (B).

236

RARE VASCULAR LIVER TUMORS anti-angiogenic therapies using or combining high dose steroids, interferon, CHTH or radiotherapy, other interventional radiological or surgical therapies (2,16–18). Recently the Boston group presented a clearly defined algorithm for the treatment of this paediatric condition. Partial hepatectomy is indicated if lesions are confined to one liver lobe; diffuse HIHE disease, resistant to steroid therapy, should be treated using LT (20).

hepatic hemangiosarcoma ₍has₎ Although relatively rare, HAS is the most common primary sarcoma occurring in the liver. It may account for up to 2% of

Table 26.3 Recurrence of HEHE after liver transplantation in the ELITA–ELTR series Tumor recurrence in 14 (23.7%) patients: 5 patients still alive Delay posttransplantation Lung

45 ± 35 mo 5

Liver

5

Liver and omentum Liver and bone Not precised

1 1 2

49 mo (range 6–98) AWD 59 (ChTh), 84 (Res) mo DWD 23,41,73 mo AWD 112 mo (Res, RF, ChTh) 211 and 212 mo DWD 15,73 (Res, ChTh), 79 mo (Burkitt) DWD 9 mo DWD 4 mo (ChTh) DWD 19, 20 mo

all primary liver tumors. Peak age of incidence is in the sixth and seventh decades of life, with a male to female ratio of 3/1. HAS has rarely been reported in children and, if so, is regarded as a distinct entity (2,21). HAS has received much recent attention because of its frequent association with several environmental carcinogens, such as thorotrast, vinyl chloride, monomer, radium, pesticides, external radiation, cyclophosphamide, arsenical compounds, use of androgenic/anabolic steroids and iron overload, such as seen in hemochromatosis (2). A clear etiological cause of HAS is however not found in 70% of patients. The diagnosis, especially of diffuse HAS, can be extremely difficult. Liver biopsy has been reported as dangerous and non-diagnostic (22). Macroscopically, the HAS appears as illdefined spongic hemorrhagic nodule(s) that involve(s) the whole liver. HAS can present four different types of growth patterns: multiple nodular, large dominant mass, mixed patterns of multiple nodules and dominant mass, and more rarely diffusely infiltrating macro-nodular tumor (Fig. 26.6). At the time of diagnosis, extra-hepatic metastases are present in 20% to 40% of patients; the most common sites of metastases are lung, spleen, bone, and adrenals (2,21). The most characteristic histological pattern of HAS is a sinusoidal and tectorial growth of malignant endothelial spindle cells on the surface of liver cell plates leading to their atrophy, and associated with formation of larger vascular channels and cavernous spaces with papillary projections into their lumen (Fig. 26.7A–C). Tumoral cells have bizarre and

(A)

(B)

(C)

(D)

Figure 26.5 Macro- and microscopic features of HIHE. The lesion can be either solitary (A) or multiple (B). Type 1 HIHE is made of multiple vascular channels with a single layer of regular endothelial cells (C) whereas in type 2 HIHE more atypia are observed (D). Source: S. Gosseye, Dept. of Pathology.

237

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS hyperchromatic nuclei with numerous mitoses and they exhibit IHC positivity for endothelial markers (Factor VIII, CD31, and CD 34). HAS differs from HEHE by the fact that it has more atypical cells and it is much more destructive with obliteration of the normal liver (21). Histological diagnosis on adequate tissue sampling is of utmost importance in order to avoid futile, especially surgical interventions. Although the diagnosis of HAS is nowadays easier following the introduction of nuclear magnetic imaging, the diagnosis still frequently remains difficult. This difficulty is exemplified in the ELITA–ELTR study collecting 22 patients of whom 6 were children. Correct pre-LT histological diagnosis of HAS was only made in one-third of 16 biopsied patients, and half of 22 patients were transplanted because of HIHE or HEHE. At the time of LT, 15% of patients already had distant metastases All four HAS presenting as acute Budd–Chiari syndrome were seen in children with a supposed diagnosis of HIHE (Table 26.4). Pathologic examination of the hepatectomy specimen showed massive and diffuse bilobar involvement in all cases. Biochemical abnormalities in HAS are non-specific; serum alkaline phosphatase is elevated in 70% of patients and tumor markers are negative in the absence of accompanying liver disease. In the early stages HAS may present with hepatosplenomegaly, ascites, jaundice, signs of portal hypertension, weight loss, and muscle wasting; later on, pain, peripheral

edema, acute Budd–Chiari syndrome, acute abdomen due to tumor rupture, and thrombocytopenia may follow. In contrast to HEHE, evolution of these patients is much more rapid and worse. All patients in the ELITA–ELTR study died due to tumor recurrence after a median of 6 months (Fig. 26.8). Similarly, very poor results were reported recently by the Cincinnati transplant tumor registry in six patients and by the Memorial Sloan-Kettering group in five patients (23,24). Embryonal sarcoma is the only liver sarcoma that can nowadays be treated successfully by (partial or more seldom necessary) hepatectomy (23). Both European and American experiences confirm that HAS is an absolute contra-indication to LT. In cases of difficult differential diagnosis between HIHE/HEHE and HAS, it is wise to respect a waiting period of 6 months on the transplant list in order to avoid wasting scarce organ resources. Indeed the aggressive evolution of the liver tumor during this time span will allow the establishment of the correct diagnosis. The outcome for patients with HAS will only be improved by the development of a more effective interdisciplinary oncological approach (24).

Table 26.4 Indication for LT in 22 HAS patients of the ELITA–ELTR series 35.3 ± 22.6 years Children 4.4 years (1–12)

Age

14 males and 8 females Six children <15 years

Gender Invalidating tumor (9 HEHE–6 HAS) Unclear diagnosis of liver failure (22%) Cryptogenic cirrhosis Focal nodular hyperplasia Hemochromatosis Subacute failure Budd–Chiari syndromea Solitary hepatocellular cancer Budd–Chiari syndrome,b HEHE HAS HAS a

15 5 1 1 1 1 1 1 3 2 1 1

Budd–Chiari syndrome: 18%. All children.

b

Figure 26.6 CT-scan of HAS showing a diffuse nodular infiltration of the liver.

(A)

(B)

(C)

Figure 26.7 HAS. Macroscopy showing a diffuse spongy tumoral mass (A); microscopy showing the development of cavitary space (B) because of the sinusoidal progressive growing of tumoral cells destroying the liver cell plates (C). Source: J. Rahier, Dept. of Pathology.

238

RARE VASCULAR LIVER TUMORS

nodular regenerative hyperplasia ₍nrh₎ NRH of the liver is a rare condition that is most often presents with the stigmata of portal hypertension and its sequelae (25). Its prevalence is estimated between 0.70% and 2.6% in autopsy series. NRH is the major cause of non-cirrhotic portal hypertension. Current theories favor a primary vasculopathy with alterations in blood flow as the causative agent. It is supposed that the presence of a portal venopathy (occlusion or terminal portal venules) with or without accompanying hepatic arterial disorders causes diffuse microvascular transformation, finally leading to NRH. Vasculopathy results in ischemia leading to atrophy with compensatory hyperplasia in adjacent unaffected areas. When a critical proportion of the portal venules is affected, portal hypertension ensues. NRH is characterized by the formation of usually small, up to 1 cm, non-fibrotic parenchymal nodules. This absence of fibrosis allows the establishment of the differential diagnosis with micronodular cirrhosis. Histologically, the regenerative nodules are composed by large hyperplastic hepatocytes which compress the adjacent liver cell plates that then become atrophic (Fig. 26.9A), a feature nicely underlined by reticulin stain (Fig. 26.9B). Hemodynamic

Survival function 1.0

Cum survival

0.8 0.6

investigation shows pre-sinusoidal portal hypertension in association with a patent portal vein. Various systemic diseases are known to occur in association with NRH, such as primary biliary cirrhosis, Budd–Chiari syndrome, hemorraghic hereditary teleangiectasia or Rendu– Osler–Weber disease, lympho- and myeloproliferative disorders, collagen-vascular diseases, congenital and acquired hepatic macrovascular abnormalities, as well as exposure to toxins, such as azathioprine and some chemotherapeutic agents. Familial cases of NRH occurring without underlying or associated systemic disease have been described (26). These forms have a poor clinical course and are often associated with progressive renal failure. In relation to LT, it should be noted that recurrent allograft NRH has been reported, that NRH has been reported as a complication of chronic immunosuppression using azathioprine, leading even to re-LT, and NRH has been described in the context of living donor liver transplantation using smallfor-size grafts. Also, NRH and obliterative portal venopathy have been documented in recipients transplanted for biliary tract disease complicated with severe non-cirrhotic portal hypertension (27–29). Six patients with NRH have been reported to the ELTR. Four had favorable outcomes; two died in 20 and 42 months, respectively, post-transplantation due to cardiac failure. Three patients had to be treated prior to transplantation because of bleeding esophageal varices; three presented with cholestatic cirrhosis. One patient had a previous kidney transplant. Four larger series and some case reports describing successful LT for this condition have been reported in literature (26,30).

conclusion

0.4 0.2 0.0 0

5

10 15 Postoperative months

20

25

Figure 26.8 Overall patient survival of HAS after liver transplantation in the ELITA–ELTR study.

(A)

Due to their scarcity, difficulties in diagnosis, as well as lack of consensus around treatment of vascular tumors of the liver, there is no universally accepted standard of care for these patients. The recent review of the literature and of the audited European Liver Transplant Registry data have permitted some clarification of the therapeutic algorithms for these lesions. One should always have a high degree of suspicion in relation to these lesions which may have an extremely divergent clinical

(B)

Figure 26.9 Microscopic features of NRH on a HE section (A) and reticulin stain (B). Source: C. Sempoux, Dept. of Pathology.

239

SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS course. Aggressive diagnostic work-up, using adequate tissue sampling is mandatory especially in order to differentiate the potentially curable HEHE or HIHE from the incurable HAS. HEHE should be treated aggressively by LT. Indeed these lesions represent an excellent indication for LT allowing longterm (disease-free) survival even in the presence of (limited) extrahepatic disease localization at the time of transplantation. Combining LT and anti-angiogenic drugs during the post-transplant follow-up could be of interest to further improve the outcomes. HIHE has a highly variable disease outcome ranging from spontaneous disease regressions to fatal outcomes. Diffuse HIHE resistant to steroid therapy should be treated using LT. The appearance of acute liver failure and/or Budd–Chiari syndrome may be an indicator toward the development of HAS. The outlook for HAS remains extremely dismal to whatever therapy is applied. In HAS, LT is absolutely contra-indicated due to the very rapid and aggressive disease recurrence. In case of unclear diagnosis, futile liver transplantation can be avoided placing the patient on the waiting list for a minimum period of 6 months. This time span confers two advantages; first, it does not interfere with the outcome of liver transplantation in case of HIHE or HEHE, and second, it allows observation of the natural, always fatal, evolution of HAS. Severe, symptomatic, non-cirrhotic portal hypertension caused by nodular regenerative hyperplasia can also be cured by liver transplantation if the therapeutic armamentarium fails to control its severe complications.

appendix Recommended grading of categories of evidence Ia: Ib: IIa: IIb: III:

IV:

evidence from meta-analysis of randomized controlled trials evidence from at least one randomized controlled trial evidence from at least one controlled study without randomization evidence from at least one other type of quasiexperimental study evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and case–control studies evidence from expert committee reports or opinions and/or clinical experience of respected authorities

Recommended strengths of management recommendation A. directly based on category I evidence B. directly based on category II evidence or extrapolated recommendation from category I evidence C. directly based on category III evidence or extrapolated recommendation from category I or II evidence D. directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence

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references 1. Lerut JP, Orlando G, Adam R, et al. The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: report of the European liver transplant registry. Ann Surg 2007; 246: 949–57. 2. Ishak K, Goodman Z, Stocker J. Tumors of the liver and intrahepatic bile ducts. Atlas of Tumor Pathology. Third series, fascicle 31 edn. Washington: Armed Forces Institute of Pathology, 1999: 282–307. 3. Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer 2006; 107: 2108–21. 4. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999; 85: 562–82. 5. Demetris AJ, Minervini M, Raikow RB, et al. Hepatic epithelioid haemangioendothelioma – biological questions based on pattern of recurrence in an allograft and tumor immunophenotype. Am J Surg Pathol 1997; 21: 263–70. 6. Lerut JP, Orlando G, Sempoux C, et al. Hepatic haemangioendothelioma in adults: excellent outcome following liver transplantation. Transpl Int 2004; 17: 202–07. 7. Nguyen BD. Epithelioid haemangioendothelioma of the liver with F-18 FDG PET imaging. Clin Nucl Med 2004; 29: 828–30. 8. Lin E, Agoff N. Recurrent hepatic epithelioid hemangioendothelioma: detection by FDG PET/CT. Clin Nucl Med. 2007; 32: 949–51. 9. Madariaga JR, Marino IR, Karavia DD, et al. Long-term results after liver transplantation for primary hepatic epithelioid haemangioendothelioma. Ann Surg Oncol 1995; 2: 483–87. 10. Kelleher MB, Iwatsuki S, Sheahan Dg. Epitheloid haemangioendothelioma of the liver. Clinicopathological correlation of 10 cases treated by orthotopic liver transplantation. Am J Surg Pathol 1988; 89: 999–1008. 11. Rodriguez JA, Becker NS, O’Mahony CA, Goss JA, Aloia TA. Long-term outcomes following liver transplantation for hepatic hemangioendothelioma: the UNOS experience from 1987 to 2005. J Gastrointest Surg 2008; 12: 110–6. 12. Kayler LK, Merion RM, Arenas JD, et al. Epithelioid hemangioendothelioma of the liver disseminated to the peritoneum treated with liver transplantation and interferon alpha-2B. Transplantation 2002; 74: 128–30. 13. Theurillat JP, Vavricka SR, Went P, et al. Morphologic changes and altered gene expression in an epithelioid hemangioendothelioma during a tenyear course of disease. Pathol Res Pract 2003; 199: 165–70. 14. Calabrò L, Di Giacomo AM, Altomonte M, et al. Primary hepatic epithelioid hemangioendothelioma progressively responsive to interferonalpha: is there room for novel anti-angiogenetic treatments? J Exp Clin Cancer Res 2007; 26: 145–50. 15. Miller MA, Sandler AD. Elevated plasma vascular endothelial growth factor levels in 2 patients with hemangioendothelioma. J Pediatr Surg 2005; 40: 17–9. 16. Lopez-Terrada DL, Finegold MJ. Liver tumors. In: Walker AW, Durie PR, Hamilton JR, Walker-Smith JA, Watkins J, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management, 5th edn. St. Louis: CV Mosby, 2008: 911–26. 17. Selby DM, Stocker J Th, Waclawiw MA, et al. Infantile hemangioendothelioma of the liver. Hepatology 1994; 20: 39–45. 18. Daller JA, Bueno J, Gutierrez J, et al. Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 1999; 34: 98–106. 19. Mo JQ, Dimashkieh HH, Bove KE. GLUT1 endothelial reactivity distinguishes hepatic infantile hemangioma from congenital hepatic vascular malformation with associated capillary proliferation. Hum Pathol 2004; 35: 200–9. 20. Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg 2007; 42: 62–8. 21. Maluf D, Cotterell A, Clark B, et al. Hepatic angiosarcoma and liver transplantation: case report and literature review. Transplant Proc 2005; 37: 2195–99. 22. Saleh HA, Tao LC. Hepatic angiosarcoma:aspiration biopsy cytology and immunocytochemical contribution. Diagn Cytopathol 1998; 18: 208–11. 23. Husted TL, Neff G, Thomas MJ, Gross TG, et al. Liver transplantation for primary or metastatic sarcoma to the liver. Am J Transplant 2006; 6: 392–7. 24. Weitz J, Klimstra DS, Cymes K, et al. Management of primary liver sarcomas. Cancer 2007; 109: 1391–6.

RARE VASCULAR LIVER TUMORS 25. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver. A report of 64 cases among 2500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990; 11: 787–97. 26. Dumortier J, Boillot O, Chevallier M, et al. Familial occurrence of nodular regenerative hyperplasia of the liver: a report on three families. Gut 1999; 45: 289–94. 27. Breen DP, Marinaki AM, Arenas M, et al. Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation. Liver Transpl 2005; 11: 826–33.

28. Gane E, Portmann B, Saxena R, et al. Nodular regenerative hyperplasia of the liver graft after liver transplantation. Hepatology 1994; 20: 88–94. 29. Demetris AJ, Kelly DM, Eghtesad B, et al. Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or smallfor-size syndrome. Am J Surg Pathol 2006; 30: 986–93. 30. Krasinskas AM, Eghtesad B, Kamath PS, et al. Liver transplantation for severe intrahepatic noncirrhotic portal hypertension. Liver Transpl 2005; 11: 627–34.

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27

Management of recurrent pyogenic cholangitis W. Y. Lau and C. K. Leow

introduction While practicing in Hong Kong in 1930, Digby drew attention to a condition which was subsequently known as recurrent pyogenic cholangitis by reporting on eight cases of “common duct stones of liver origin” (1). The term Recurrent Pyogenic Cholangitis (RPC) was used by Cook et al. in 1954 when they reported their experience with the condition in a series of 90 patients (2). The synonyms associated with this condition include Asiatic cholangiohepatitis, oriental cholangiohepatitis, Hong Kong Disease (3), Chinese biliary obstruction syndrome (4), and primary cholangitis (5). This condition is commonly seen in Chinese living in Canton and Hong Kong but is not restricted to the Chinese in the Orient since it also occurs in Chinese immigrants in Malaysia, Singapore, North America, and Australia (6–8). RPC is also common in Japanese in Japan and Taiwanese in Taiwan. Although rare, RPC has also been reported to afflict occidentals (9,10).

pathogenesis In RPC the gallstones found within the biliary system are calcium bilirubinate stones or pigmented calcium stones. Calcium bilirubinate stones are prevalent in Asia and are very rare in Europe and the United States. In addition to the presence of these friable concretions of various shapes and sizes within the biliary tree, the bile is often muddy in consistency and contains numerous fine particles of calcium bilirubinate. Biochemical analysis of these stones revealed a bilirubin content of 40.2% to 57.1% and a cholesterol content of 2.9% to 25.6%. This differs greatly from cholesterol stones, which are common in Europe and the United States, which contain >96% of cholesterol in pure cholesterol stone, and >71.3% in mixed cholesterol stone but the bilirubin content is only 0.02% to 5.0% (11). The peculiarity of the formation of calcium bilirubinate stones in RPC has been ascribed to the high incidence of bile being infected with Escherichia coli (E. coli). In man, the major portion of bilirubin is excreted in bile as bilirubin glucuronide. In the presence of β-glucuronidase, bilirubin glucuronide is hydrolyzed into free bilirubin and glucuronic acid. Normally, calcium is secreted into bile and when it combines with the carboxyl radical of free bilirubin, insoluble calcium bilirubinate is formed. Normal bile is free of β-glucuronidase activity, whereas bile infected with E. coli has intense β-glucuronidase activity. Bile calcium content increases in the presence of biliary tract inflammation and this coupled with the increased hydrolysis of bilirubin glucuronide by the β-glucuronidase from E. coli gives rise to the multiple stones formation classically seen in RPC (11). There are two types of pigmented stones, black, and brown. The infected type seen in RPC is the brown pigment stone. The postulated port of entry for the micro-organisms of bowel origin is via the portal vein from an attack of enteric

242

infection. In the acute stage of RPC, Ong reported that 39.5% of the studied cases had a positive portal blood culture, while the positive supraduodenal lymph node culture rate was 38.1% (12). The rate of infected bile in patients with pigmented stone compared to those with cholesterol stone is correspondingly much higher in the former. In comparing patients with pigmented stones against those with cholesterol stones, Maki demonstrated that 88.3% of the bile in patients with pigmented stone was infected and E. coli was isolated from all cases. This compared to 43.5% in patients with cholesterol stone and of these only 70% of cases had E. coli isolated (13). However, bacteria excreted into the bile within a non-obstructed biliary system will not usually give rise to infection and an attack of cholangitis. Thus obstruction by parasites, such as Clonorchis sinensis (Fig. 27.1) and Ascaris lumbricoides can initiate the sequence of events which eventually lead to the formation of intrahepatic pigment stones (2). Furthermore, the egg or carcass of the parasite can act as a nidus for the deposition of calcium bilirubinate (13). However, only a proportion of patients with RPC have positive ova in stools indicating parasitic infestation, while in some patients the remains of parasites can be identified within the stones recovered (12,13). Clonorchis infection does not occur in the Sarawak state of West Malaysia due to the absence of the snail, Bithynia, which is the first intermediate host in the life cycle of Clonorchis sinensis (12). Yet RPC is common among the Chinese and the indigenous race, the Dyaks. Thus parasitic infestation is only one of the etiological factors for RPC. Maki suggested that the migration of roundworms through the ampulla of Vater leads to papillitis and secondary dyskinesia of the Common Bile Duct (CBD). This leads to increased intrahepatic ductal pressure, dilatation of the CBD and poor drainage of the biliary system (13). A poorly draining biliary system contributing to the formation of intrahepatic stones and colonization of the bile by bacteria was experimentally shown in rabbits by Ong in 1962. Rabbits who had the CBD constricted by a linen thread prior to a single intraportal injection of an E. coli suspension developed ductal dilatation and stone formation in the CBD and intrahepatic ducts. On culture, the bile from the gallbladder and bile ducts was positive for E. coli (12). In the mid 1950s in Japan, the proportion of pigmented to cholesterol stones found in professionals was almost equal. However, almost 90% of the gallstones found in farmers were of pigmented calcium stone. As the farmers were economically less well off, they could only afford a diet which was deficient in fat and protein. It was postulated that the deficient diet may be a factor for the development of pigmented stone (13). Matsushiro et al. have demonstrated that a diet low in protein and fat leads to lower levels of glucaro-1:4-lactone, a powerful inhibitor of β-glucuronidase, in bile (14). The reduced level of glucaro-1:4-lactone in bile thus permits increased hydrolysis

MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS

(A)

(B)

Figure 27.1 (A) Magnified view of Clonorchis sinensis (×12.5). (B) Numerous Clonorchis removed from the CBD of one patient.

of bilirubin glucuronide to free bilirubin and glucuronic acid by the bacterial β-glucuronidase present in infected bile. The free bilirubin then conjugates with calcium in the bile to form the typical calcium bilirubinate stones of RPC. In Hong Kong, RPC is no longer seen in the younger generation born and bred in modern-day Hong Kong. Young patients, in their 30s, who present to our institution with RPC are invariably immigrants from China. We suspect that the much better social and economic conditions of modern-day Hong Kong have played a role in eradicating the condition (15). The reduced incidence of gastroenteritis, the inabilility of the enteric organism, which gained entry via the portal blood, to establish itself within the liver parenchyma due to better host defense from an improved high protein, low carbohydrate diet and possibly the fact that less Chinese herbal medicine is being consumed by the modern generation of youngsters may all have contributed to the demise of this condition.

pathology Macroscopically, due to the repeated attacks of biliary sepsis, it is common to find adhesions between the liver surface and the surrounding parietal peritoneum, especially the diaphragmatic surface, at operation. The liver surface is scarred and prominent dilated ducts may be obvious. The affected lobe of the liver, usually the left, is normally atrophic with compensatory hypertrophy of the remaining lobe. On palpation, the stones within the dilated biliary ducts are easily palpable. Occasionally, the underlying lobe can be so destroyed by the repeated attacks of cholangiohepatitis that what remains is a cavernous biliary sac with minimal surrounding liver parenchyma (Fig. 27.2). Within the sac is a soup of biliary mud and

stones. The brown pigment stones are soft stones which crumble when squeezed between fingers or forceps. The size variation goes from fine grains to stones of 4 to 5cm in diameter. The stones are irregular, can take up the shape of the biliary duct or become faceted when the stones are packed (Fig. 27.3). Apart from the stones, the bile duct is filled with biliary mud. This is a broth of mucus, altered bile products, microcalculi, desquamated epithelium, parasites, and pus. The pathological hallmark of RPC is the steadily progressive, recurrent cholangiohepatitis with periportal fibrosis. Histologically, in the early acute stage of an attack of cholangiohepatitis, it is similar to that of bacterial cholangitis associated with cholecystitis and calculus obstruction seen in the Western world (16), while the histological picture of the acute, chronic, and advanced stage of the disease is not dissimilar to that seen in sclerosing cholangitis (17). In the early lesions the lumen of the small biliary ducts is filled with pus, with rapid extension into the surrounding tissue. There is marked dissociation of the liver cells by polymorphonuclear infiltration of the sinusoids together with Kupffer cell hyperplasia. In the lobules around the affected duct there is a varying degree of cellular necrosis. Resolution of the underlying inflammation leads to dense round-cell infiltration, which is then replaced by fibrous tissue. In the larger intrahepatic ducts, the duct wall becomes inflamed, ulcerated, and destroyed together with the formation of cholangitic abscesses. Resolution results in intense fibrosis which accounts for the undue prominence of the duct wall seen on sectioning a liver affected by RPC. During the acute episode, these larger ducts can become irregular in caliber and short segments of relative stricture can occur at intervals along the duct. The duct proximal to the stenosis dilates.

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Figure 27.2 A totally destroyed left liver lobe consisting of a cavernous biliary sac with negligible liver parenchymal tissue (f = falciform ligament).

Recurrent attacks of infection and resolution lead to permanent damage of the duct wall and the ducts remain dilated. The relative stricture then becomes a true localized stricture. These strictures are most frequently encountered at the site of ductal confluence. One of the main concerns of these inflammatory strictures is malignant transformation into cholangiocarcinoma. Ohta et al., from their autopsy studies, suggested that repeated inflammatory damage to the ductal epithelium from the attacks of cholangitis can lead to atypical epithelial hyperplasia, dysplasia, and eventually cholangiocarcinoma (18). The left lobe of the liver is preferentially affected. The exact reason for this is unknown. One possible explanation may be the selective distribution of portal blood within the liver. Two studies suggested that the left lobe of the liver receives blood from the colon and the left lobe will be the first port of call for enteric organisms such as E. coli which have entered the portal venous system (19,20). Colonization of the bile with E. coli will lead to the production of β-glucuronidase in the biliary system. Another explanation is that the more oblique course of the left hepatic duct results in poorer drainage of the left ductal system as compared to the right hepatic duct, thus leading to increased incidence of stone formation. If stones are found in the right hepatic duct, almost invariably stones are found in the left duct. In one study of 115 patients with hepatolithiasis, the ratio of stones found in the left and right hepatic ducts was 6:1 (5). The stones form in the dilated ducts proximal to the stricture site. These strictures can be multiple and bilobar in distribution and commonly occur at the origin of the right and left hepatic ducts. Stones within the common bile duct are usually lodged at the supraduodenal portion of the duct or at the ampulla. At ERCP, a patulous ampulla of Vater (probably a result of repeated passage of stones) is not an uncommon finding in patients with RPC. The bile in patients with hepatolithiasis is usually infected with enteric organisms. The two most common organisms isolated are E. coli and Klebsiella species. The overall positive bile culture rate has been reported to be as high as 87% and the incidence of positive culture in patients requiring surgical

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Figure 27.3 Large number of pigment stones removed from one patient with RPC.

intervention and those which settled on conservative measures is similar (90% vs. 85%) (21). The gallbladders in these patients are usually thin-walled, large, and distended. The majority of them do not contain gallstones. While the incidence of CBD stones and biliary mud varied from 60% to 90%, the incidence of associated gallstones in the gallbladder was only 15% to 40% (4,7). Macroscopically, the gallbladder looks normal but histological examination invariably shows features compatible with low-grade chronic cholecystitis. Along the gastrohepatic omentum gross lymphadenitis with enlarged lymph nodes is commonly encountered.

clinical presentation Patients with RPC tend to be younger (third and fourth decade) than those affected by cholesterol stone disease, which is much more prevalent in older women, in the Western world. Although the condition does not have particular sex prevalence, those afflicted are almost invariably from the lower socio-economic classes. The usual presentation consists of the classical Charcot’s triad of abdominal pain, fever (with or without chills and rigors), and jaundice which signifies an attack of cholangitis. The patient may not notice the jaundice but a history of tea-colored urine is usual. The jaundice is usually not severe since cholangitis secondary to a completely obstructed biliary system will rapidly progress to acute suppurative obstructive cholangitis with septicemia. In addition to the triad of symptoms, these patients also develop mental confusion and shock, which is referred to as Reynaud’s pentad. The epigastric or right upper quadrant pain is usually described as a constant and gnawing or cutting (12) pain, which may radiate to the back. Vomiting is not a constant feature. Patients have spiking fever, not unlike that seen with an underlying abscess or collection, which normally resolves rapidly when the conservative treatment has been effective. On examination, the patient looks unwell and restless with a tinge of jaundice. The associated jaundice is typically mild and clinically can be just discernible. Abdominal examination may reveal the telltale signs of surgical scars from previous

MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS operations. Tenderness with varying degree of guarding is noted in the epigastrium or right upper quadrant. A tender hepatomegaly may be present. Marked tenderness may imply the presence of an underlying abscess. Deterioration in the abdominal signs (increasing and generalized tenderness) and/ or the development of worsening hemodynamic parameters (persistent hypotension, tachycardia, poor urine output despite adequate resuscitation) argues for emergency surgical intervention to decompress the biliary system. Those patients who present or develop shock have a flushed facie, warm periphery, bounding peripheral pulse, and hypotension. The massive vasodilatation and reduced cardiac contractility secondary to the endotoxemia adequately explain the state of shock.

investigations Both the hematological and biochemical tests do not differentiate patients with RPC from those with other causes of biliary obstruction and infection. Full blood count will reveal an underlying leucocytosis with neutrophilia and mild thrombocytopenia in some patients. A number of patients will also have a concomitant mild derangement of the clotting profile with a prolonged prothrombin time. The deranged liver function test is compatible with an obstructive picture with a moderately raised level of bilirubin and a high serum alkaline phosphatase level. The level of γ-glutamyltranspeptidase is elevated. The slightly elevated alanine transaminase level in some patients is a reflection of the parenchymal damage secondary to the underlying infection within the biliary system. Other than showing the presence of pneumobilia, in some cases a plain abdominal radiograph is not helpful. The calcium bilirubinate stones are radiolucent because of the low calcium and high bilirubin content. The least expensive and most helpful investigation is ultrasonography (USG). It can demonstrate the presence of stones within the dilated intrahepatic and common bile ducts, the presence or absence of an underlying liver abscess and occasionally the presence of a solid liver mass secondary to malignancy complicating a benign stricture. Also it can reveal the presence or absence of gallstone(s) within the gallbladder. Intra- and extrahepatic ductal stones are present in the majority of patients, but cholelithiasis is much less common and is seen in the minority cases. Although intrahepatic stones normally cast sonic shadows on USG, the presence of air within the bile ducts (either spontaneously or secondary to previous biliary drainage procedures) can give rise to highly reflective echoes with posterior shadows, thus confusing and misleading the radiologist in diagnosing the presence of stones within the bile ducts. In about 3% of RPC, pneumobilia is present (22). In some cases the amorphous and small stones can form a cast of the biliary tree and, under such circumstances, highly reflective echoes and posterior acoustic shadowing on USG may be absent. It may then be difficult to identify dilated bile ducts and the ducts can appear as soft tissue masses on USG (7). USG images and its interpretations are operator dependent. Computed tomography (CT) removes this bias and can provide images of the dilated intra- and extrahepatic ducts, even if they are filled with sludge or pus. On CT scanning these

filling defects are of higher attenuation than bile, but have a lower attenuation than contrast-enhanced liver parenchyma (23). Although uncommon, the amorphous stones which completely fill the ducts, and which are isodense with the hepatic parenchyma could be missed on CT. Unlike USG, there is no difficulty in distinguishing pneumobilia from stones on CT and visualization of the extrahepatic ducts is not limited by overlying bowel gas. USG and CT do not provide sufficient details of the ductal anatomy. Cholangiography, in the form of Endoscopic Retrograde Cholangiopancreatography (ERCP) and/or Percutaneous Transhepatic Cholangiography (PTC), is essential for the detail delineation of the entire biliary tract. Older methods of delineating the biliary tracts, such as oral cholecystography and intravenous cholangiography are no longer used because they provide suboptimal visualization of the ductal system. In addition to the potential complication of allergic reaction to the contrast injected, there is no place for intravenous cholangiography in the presence of biliary obstruction or cholangitis. Our first line of investigation is ERCP since it is both diagnostic and therapeutic. The typical cholangiogram will show dilated extrahepatic ducts in more than half the cases. The intrahepatic ducts have the classical “truncated tree” pattern where the “tree” has been trimmed back to its “main branches”. The terminal end of these “branches” is tapered, resembling an arrow or a spear head (Fig. 27.4). It is more common to see a dilated left ductal system containing calculi than an affected right system. There may be an accompanying relative or true stricture distal to the dilated ducts. When a stone or stricture prevents the filling of the intrahepatic ducts, or when it is technically impossible to perform an ERCP due to previous biliary–enteric bypass surgery, PTC under USG guidance is performed. As a result of the stones and stricture(s), the biliary anatomy can be very complicated. Once an obstructed biliary duct is punctured during PTC, the obstructed system must be drained to avoid cholangitis and/or bile leak. Underfilling during cholangiography can lead to missed segmental ducts. More importantly, the paucity of intrahepatic ducts shown on cholangiograms should prompt the surgeon to count the number of segmental ducts present in order not to miss the diagnosis of undrained segment(s). Cholangiography complements USG and CT and their findings should be considered as a whole and not in isolation. We have shown that Magnetic Resonance (MR) cholangiography is comparable to ERCP in diagnosing choledocholithiasis (24). Apart from being non-invasive, MR cholangiography can delineate biliary strictures which may be difficult to show or missed on ERCP due to technical reasons (Fig. 27.5). In a recent study by Park et al. MR cholangiography has been shown to be better than ERCP/PTC (25). Occasionally, a radioisotope scan is performed to demonstrate the presence of undrained or hypo-functioning liver segments. The radiographic features of certain conditions can simulate RPC. Sclerosing cholangitis can lead to biliary tract strictures. However, these are usually more peripherally located and there is a lack of the marked proximal dilatation and stones seen in RPC. Although the common bile duct is massively dilated in choledochal cysts, in most cases, there is an abrupt transition

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS merely help to define the extent and severity of the underlying disease and guide the management plan.

acute management

Figure 27.4 Typical truncated biliary tree appearance together with the arrow or spear head sign (arrow) on ERCP. A large stone(s) in the left duct.

Figure 27.5 MR Cholangiogram demonstrating a stricture (arrow) at the confluence of the right and left hepatic ducts.

to normal or slightly dilated proximal ducts (26). Patients with Caroli disease (cavernous ectasia of the biliary tract) have dilated intrahepatic ducts and calculi but the extrahepatic ducts are disproportionately small (27). The condition is often associated with renal cystic disease (28) which, on CT, helps to distinguish it from RPC. In almost all cases, given the clinical and investigation findings, the diagnosis of RPC is seldom in doubt. The investigations

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RPC patients have repeated attacks of acute cholangitis which would settle on conservative measures in the majority of cases. The need for urgent therapeutic interventional procedures only applies to a minority of cases, such as those with signs of peritonitis secondary to perforated gangrenous gallbladder, ruptured liver abscess, or those with septicemic shock despite conservative measures. The role of definitive procedures for most patients who settled on conservative measures depends on the frequency and severity of each attack, presence of biliary strictures (which may be malignant) and the presence of any existing co-morbid medical conditions. The initial approach to any acute attack is to control the underlying infection with the commencement of intravenous fluid infusion, antibiotic treatment after blood culture, prescription of adequate analgesia and keeping the patient nil per oral. Our standard first line antibiotic regimen is cefuroxime. Metronidazole is sometimes prescribed to cover the anaerobe Bacteroides fragilis, which is present in a minor proportion of patients who have had previous biliary tract surgery and/or complicated anatomy due to stones and strictures. An urgent ultrasound scan of the liver is performed to identify the extent of lithiasis within the biliary tree, the presence of a liver mass which can be an abscess or an underlying cholangiocarcinoma. Those patients who fail to respond or have evidence of a severe attack of cholangitis with or without shock undergo an urgent ERCP. The smallest amount of contrast feasible is used during ERCP as increased biliary pressure from excessive contrast injection will result in cholangio-venous reflux, which can lead to septicemia. No attempt is made to perform a full cholangiogram or to remove all calculi from the biliary system. In the procedure, the system is decompressed with a nasobiliary drain. Only when the patient’s condition has improved and stabilized would a check cholangiogram with endoscopic removal of stones be performed. If part of the biliary tree cannot be decompressed adequately because of an obstructing distal stone or stricture, then endoscopic drainage alone may not be adequate and successful. As such, percutaneous transhepatic biliary drainage of the obstructed biliary ducts will be of use. However, these drainage tubes are small and can be easily blocked by the tenacious biliary mud. If a liver abscess is present, the abscess is drained percutaneously under ultrasound guidance. The patient is monitored closely after admission for signs of deterioration. Those responding to the conservative treatment will have a reduction in abdominal pain, a fall in temperature toward normal and the disappearance of tachycardia over the first 24 to 48 hours. If there is no obvious improvement after 48 hours, the possibility of undrained biliary system or individual liver segments due to impacted stones or underlying strictures must be considered and the need for urgent surgical intervention entertained. At any time during conservative management, the presence of increasing abdominal pain coupled with shock and peritoneal signs mandate urgent surgical treatment.

MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS Those patients who are present in shock must be actively resuscitated. Those who respond quickly can be treated conservatively, while those who fail must undergo therapeutic intervention. It is unclear why conservative measures work for some but not others. In a series of 88 RPC patients presenting with acute cholangitis, 17% required therapeutic intervention for septicemic shock. A pulse rate greater than 100/min and a platelet count of more than 150 × 109/l within 24 hours of presentation were the only two independent factors that predicted the need for therapeutic intervention (21). The sole aim of an urgent therapeutic intervention during an acute attack is to decompress the obstructed biliary system. Non-operative interventional procedures using the endoscopic or percutaneous routes are preferred to open surgical route (29). Occasionally, open surgery is required to deal with peritonitis as a result of gangrenous cholecystitis or ruptured liver abscess. The most expedient means to decompress the CBD is insertion of a large T-tube. No attempt is made to perform definitive surgery. When the usually enlarged and thickwalled CBD is opened, thick-infected biliary mud and bile will be gushed out. The biliary mud and friable bilirubinate stones are scooped out. Following a gentle saline flush of the CBD, a bougie is passed down the CBD into the duodenum to check for patency of the lower end of the CBD. The way an impacted stone in the lower end, which cannot be removed during CBD exploration, is dealt with depends on whether there is a concomitant attack of pancreatitis. In the absence of acute pancreatitis, the stone can be dealt with percutaneously via the T-tube tract when the acute episode is over. In the presence of acute pancreatitis, a transduodenal sphincteroplasty is performed to remove the stone. An alternative is the use of electrohydraulic lithotripsy to fragment the impacted stone, thus avoiding a transduodenal sphincteroplasty (30). The patency of the right and left hepatic ducts is checked to ensure there is free flow of bile into the CHD and CBD. Any strictures found are dilated with graduated sounds to release the infected bile and mud dammed up behind the stricture(s). Gentle irrigation of the hepatic ducts with saline is performed. Irrigation or flushing at high pressure via a syringe must be resisted as this can initiate or aggravate a septicemic state. When bile flow from both hepatic ducts is established, a large bore T-tube is placed, the choledochotomy closed with catgut and the operation is terminated. The T-tube not only decompresses the system but also affords a percutaneous route for endoscopic intervention when the patient has recovered. Large palpable liver abscesses are drained intraoperatively. Multiple small abscesses will respond to appropriate antibiotics after the biliary system is decompressed. A cholecystectomy is performed only when it is grossly distended or there is evidence of cystic duct obstruction, empyema or gangrene of the gallbladder. During the emergency CBD exploration, an otherwise non-inflamed gallbladder, with or without stone(s) in situ, is left behind because of the added risk of performing a cholecystectomy in an ill patient.

definitive management The definitive management of RPC is to use a multidisciplinary approach (31), aiming to remove all biliary stones, to

establish adequate drainage to the biliary system, and to resect non-functioning liver segments which harbor bacteria and serve as foci of infection. If properly performed, definitive interventional procedures decrease the episodes and severity of future attacks of cholangitis. In some patients cure is possible.

minimal access approach Once the acute episode has settled, more definitive treatment via the endoscope or under radiological guidance can be performed. Those treated initially by nasobiliary drainage have a check cholangiogram to delineate the extent of lithiasis and the existence of ductal stricture(s). Stones within the CBD and CHD can be removed with a dormia basket and large stones can be crushed with the mechanical lithotripter or fragmented by laser prior to their removal. For those RPC patients with stones confined to the CBD, endoscopic sphincterotomy with stone extraction only is safe and effective. The medium-term result of endoscopic sphincterotomy is comparable to surgical sphincteroplasty. In 118 patients who underwent endoscopic treatment, 95.8% remained symptom-free after a median follow-up of 2.3 years (8), compared to 83.4% who had a good outcome after surgical sphincteroplasty at a mean follow-up of 7.3 years (32). In the absence of ductal strictures, small intrahepatic calculi not retrieved by ERCP can be shattered by Extracorporeal Shock Wave Lithotripsy (ESWL) and the fragments allowed to fall into the bowel through a widely patent sphincteroplasty. Intrahepatic calculi within dilated biliary ducts usually lie proximal to a site of relative or true stricture. The stricture can be dilated sufficiently to allow complete removal of the stones endoscopically (Fig. 27.6). When the stricture is confined to one lobe of the liver which is atrophic, and the contralateral liver lobe is normal or relatively unaffected, hepatic resection should be performed unless the patient is medically unfit to undergo liver resection. In the presence of multiple strictures, a more conservative approach with repeated dilatation can be successful in achieving stone clearance and control of disease. Balloon dilatation of intrahepatic biliary strictures prior to stone removal has been reported to be highly successful. The immediate overall success rate of complete stone clearance with balloon dilatation in 57 patients was 94.5% (33). Long segmental strictures which are likely to restenose can be successfully stented. The main complications of dilatation therapy include septicemia, hemobilia, mild diarrhea, and restenosis. The cumulative probability of stricture recurrence after dilatation is 4% at 2 years and 8% at 3 years (33). The true long-term patency rate following dilatation alone is still unknown since benign strictures surgically treated can recur 10 or more years later, as partial obstructions can remain completely asymptomatic for long periods. Apart from the problem of restricturing, it is difficult to rule out the presence of a malignant stricture with certainty. In patients with a Percutaneous Transhepatic Biliary Drainage (PTBD) catheter in situ, the tract can be dilated to allow dormia basket stone retrieval under fluoroscopic screening or to allow passage of a flexible twin channel choledochoscope. Under direct vision the stone(s) can be fragmented using the

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(A)

(B)

(C) Figure 27.6 (A) ERCP demonstrating the presence of stones proximal to a relative stricture (arrow) in the left hepatic duct, (B) the stricture is dilated with a balloon prior to stone retrieval, and (C) the dilated left duct is cleared of stones.

electrohydraulic lithotripter and the fragments removed with a basket. Intrahepatic strictures can be dilated or stented. Instillation of stone dissolving agents directly into the affected biliary duct has been advocated by some, but we do not practise this approach as it is often painful, time-consuming, ineffective, and can lead to ascending cholangitis and sepsis. In patients where the initial endoscopic approach has failed, the established percutaneous route can be combined with endoscopy subsequently to achieve stone clearance or stricture dilatation. In those patients who received acute surgical intervention and T-tube decompression of the biliary system, the tract is allowed to mature. After 6 weeks, any stones present can be removed through the tract with a choledochoscope or under radiological control.

definitive surgery Since RPC can and does affect the biliary tract at different sites with varying degrees of severity, the aim of the surgery is to provide adequate biliary drainage for bile and debris. This encompasses stone extraction, stricturoplasty or excision of

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stricture, resecting non-functioning liver segments and creating a bilio–enteric bypass with a permanent percutaneous access loop to the biliary tract to allow subsequent access to the biliary system for stone extraction and dilatation of stricture(s). Before embarking on definitive surgery, it is mandatory to have a complete knowledge of the location of calculi and stricture(s), and the uni- or bilobar extent of disease with or without concomitant liver atrophy. In the presence of predominantly extrahepatic disease, simple exploration of the common bile duct with intraoperative choledochoscopy will suffice. In the absence of extrahepatic ductal stricture, the incisions used for the exploration of the CBD and hepatic ducts will depend on the location of the stones (Fig. 27.7A–D). We routinely remove the gallbladder in these patients since, histologically, it shows underlying evidence of low grade inflammation. Furthermore, if the sphincter of Oddi has been previously destroyed, the gallbladder will permanently be in a collapsed state. The placement of a large T-tube following the exploration will allow post-operative imaging of the biliary tracts and any residual stones found can

MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS

(A)

(B)

(C)

(D)

Figure 27.7 (A) Longitudinal incision for the exploration of CBD only, (B) separate incisions for exploration of the CBD and the hepatic ducts, (C) incision for the combined exploration of the CBD and one of the hepatic ducts (left side is shown), (D) horizontal incision over the hepaticojejunostomy (---- = incision).

be easily removed under radiological control or with a flexible choledochoscope. When there is stenosis of the ampulla of Vater or distal CBD, or impacted stone(s) in the lower CBD, a transduodenal sphincteroplasty is performed. In patients who have had multiple operations on the CBD, the standard approach can be difficult. Under such circumstances, Ong et al. have described an extraperitoneal approach to the duodenum, which is located by its anterior position to the right kidney. A transduodenal sphincteroplasty is performed and the CBD is explored from below (34,35). However, this approach is seldom necessary as the result of endoscopic sphincterotomy has been shown to be comparable (8). In the presence of extra- and intrahepatic calculi, stone extraction can be difficult if they are impacted, situated behind relative or true ductal strictures or, present within angulated ducts, such as the right posterior or left medial segmental ducts. Although direct hepatotomy can be performed to remove the stones, it can be very bloody if the stones are deepseated. Following the removal of all the stones within the CBD and CHD, after a choledochoscopic examination to rule out any strictures in the right and left hepatic ducts, the right and left ducts are flushed with saline. The right and left lobes of the liver are gently massaged in-between the flushing. This maneuvre normally helps to discharge more biliary mud and small

stones from the intrahepatic ducts. Once the effluent is relatively clear, a repeat choledochoscopy is performed. Any residual stones can be retrieved with a dormia basket. Segmental ductal stricture is dilated prior to stone retrieval. Any impacted or large stones can be shattered with the electrohydraulic lithotripter introduced through the working channel of the flexible choledochoscope. It is not always possible to clear the intrahepatic ducts of stones completely. Once the large stones and strictures are dealt with, small stones or fragments can be left to “fall out”, provided an adequate biliary drainage procedure has been performed. The thick, dilated CBD/CHD with an inelastic wall behaves more like a cavernous sac which does not drain adequately, even in the presence of a sphinteroplasty. Although it is reasonable to perform a supraduodenal choledochoduodenostomy as a biliary drainage procedure, this has the disadvantage that patients may develop “sump syndrome”, developing symptoms of pain and fever, which is thought to be a result of debris being lodged in the diseased distal CBD. While the sump syndrome can be treated by performing an endoscopic sphincterotomy, supraduodenal choledochoduodenostomy is contra-indicated in the presence of a proximal biliary tract stricture or when the CBD is not wide enough. Under such circumstances, we routinely perform an end-to-side hepaticojejunostomy with a retrocolic Roux-en-Y loop. This provides a widely patent anastomosis for biliary drainage and for small stones to fall freely into the loop of bowel. Furthermore, the closed end of the Roux loop can provide a permanent access route to the biliary tract. With the hepaticojejunostomy it is crucial that the access loop is short and has a straight course from the anterolateral abdominal wall to the anastomosis. A poorly constructed jejunal loop with redundant length makes subsequent choledochoscopy and access to the intrahepatic ducts difficult. The access loop can either be placed intraperitoneally, to be accessed percutaneously under ultrasound guidance, or it can be placed under the skin as a hepaticocutaneous jejunostomy. We prefer to leave the loop intraperitoneally. In those cases where immediate access to the biliary tract is not necessary, the end of the loop is tacked to the peritoneal surface of the anterolateral abdominal wall with catgut. The staples from the GIA stapler used to transect the jejunum during Roux loop formation or the ligaclips placed around the blind end of the loop at the end of the operation allow the interventional radiologist subsequently to identify and access the loop percutaneously. Once the loop is punctured, the tract can be gradually dilated to admit a twin channel choledochoscope for endoscopic manipulation (15). For those cases where access to the biliary tract is required soon after the operation, a 24 Fr catheter is introduced through the anterolateral abdominal wall into the access loop at the end of the operation. The tract is allowed to mature for 4 to 6 weeks before instrumentation. Hepaticocutaneous jejunostomy has been used by others (36). Although the biliary tract can be accessed sooner through the cutaneous stoma compared to our technique, the cutaneous stoma is not without its complication. Fifteen percent of patients with hepaticocutaneous jejunostomy, performed either with the cutaneous stoma formed at the initial operation

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS or subsequently created from its subcutaneous site, did experience complications. These complications include wound infection of the closed stoma wound, development of cutaneous fistula after stoma closure, difficulty in reconstructing the stoma for subsequent use and development of parajejunostomy hernia. Repeated therapeutic intervention of the biliary tract is inevitable due to the chronic relapsing nature of the condition. The formation of a hepaticojejunostomy with an access loop is a satisfactory and adequate way to manage further attacks of stones, strictures and cholangitic attacks. On a median follow-up time of 27 months, symptoms recurred only in 12 patients (29%). Only one patient required a reoperation for stricture while the others were adequately treated through the access jejunal loop (36). RPC predisposes to the formation of inflammatory, noniatrogenic strictures in the biliary tract. Strictures in the subsegmental and peripheral ducts are difficult to treat. Fortunately, obstruction of these minor ducts does not produce jaundice and the cholangitic attacks may pass unnoticed and the infection subsides without any intervention. However, strictures in the major bile ducts do lead to unrelenting cholangitis, stones and liver abscess formation, septicemic episodes, and death. Over a 10-year period, we treated 57 patients with major bile duct strictures (37). Forty-four of the 60 strictures involved the left hepatic duct (23) or the left lateral segmental ducts (21). Strictures in the CBD or CHD can be treated by the formation of a choledochojejunostomy or a hepaticojejunostomy. Stricture involving the confluence of the hepatic ducts can be treated by hepatotomy and Y–V plasty, but the procedure is technically difficult and bleeding, bile leakage and restenosis are potential serious complications (5,38). We have stopped performing Y–V plasty for such strictures due to our poor results. Instead, we treat such strictures by performing bilateral hepaticojejunostomy. In a relatively normal left lobe of the liver with a left duct stricture at its origin, a left duct approach as described by Hepp and Couinaud (39) for a side-to-side anastomosis between the left duct and a Roux loop can be performed without the need for a left hepatectomy. The biliary drainage procedures performed for these inflammatory strictures are occasionally combined with liver resection, or liver resection alone is performed to deal with these strictures. Before embarking on hepatic resection, the severity of symptoms, status of the remaining biliary tract, parenchymal functional reserve, and alternative procedures have to be considered. Hepatic resection is only performed for those with recurrent, troublesome and localized severe disease. Disease can be confined to the left lateral segment which is atrophic and contains large number of calculi within cavernous bile ducts. In more extensive disease, the medial segment of the left lobe can also be affected due to a tight stricture in the left hepatic duct. Hepatectomy is performed to remove not only the source of symptoms and sepsis, but also the underlying stricture which has the potential to turn malignant. Liver resection for rightsided disease is unusual. By the time resection is necessary, the right lobe is usually destroyed, with compensatory left lobe hypertrophy. Consequently, a right hepatectomy should lead to little functional disturbance. In one series of 172 patients

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with hepatolithiasis, liver resection was necessary in 37% of patients, of which left lateral segmentectomy and left hepatectomy accounted for most of the resections (90.5%). Right hepatectomy was only performed in one patient (40). Troublesome adhesions between the diseased liver and the diaphragm and adjacent viscera can make liver resection difficult. Severe adhesions and fibrosis around the left hepatic vein and the inferior vena cava can make dissection in the region difficult and severe bleeding from these structures due to injudicious dissection can be a problem. The overall operative mortality in hepatic resection for hepatolithiasis is low (<2%), but the morbidity, such as wound infection, subphrenic collections, and biliary fistulae, from operating on an underlying septic condition is correspondingly high (approximately 30%).

complications In RPC the biliary mud and stones within the common bile duct can lead to acute pancreatitis. In 1971, Ong et al. reported that approximately half of all patients with acute pancreatitis, in Hong Kong, were associated with RPC (41). Another report claims that about 20% of RPC patients had high serum amylase levels but were clinically asymptomatic (42). In some patients, the big common bile duct stones can lead to the formation of a choledochoduodenal fistula. Liver abscesses complicating RPC can present with rupture into the peritoneal cavity or adjacent viscera. A left lobe liver abscess can rupture into the pericardial cavity and cause cardiac tamponade (43), while a right lobe abscess can lead to the formation of a pleurobiliary or bronchobiliary fistula (44). A chronic abscess can, on clinical and radiological grounds, be indistinguishable from an underlying cholangiocarcinoma. The final diagnosis can only be certain after histological examination of the resected specimen. Cholangiocarcinoma complicating RPC has been reported. The higher incidence of cholangiocarcinoma in areas where RPC is also prevalent has been attributed to the presence of Clonorchis sinensis infestation (45). In a necropsy study of 50 cases of cholangiocarcinoma, 92% of the cases were associated with clonorchiasis and intrahepatic stones were found in 20% of the cases (45). In a huge series of 1105 cases of hepatolithiasis studied over the period 1978 to 1990, Chen et al. (46) reported that the incidence of cholangiocarcinoma in these patients increased from 2.4% (between 1978 and 1987) to 13.7% (between 1988 and 1990), despite a decreasing incidence of clonorchiasis in the population. Thrombophlebitis of the branches of the portal vein due to the underlying periductal inflammation can lead to portal venous thrombosis with an enlarged spleen (6). Occasionally, septic emboli to the pulmonary tree can lead to the development of lung abscesses and significant pulmonary hypertension (6,47). Despite multiple operations, RPC patients with long-standing severe disease can develop secondary biliary cirrhosis and liver failure (48). When cirrhosis sets in, portal hypertension and bleeding esophageal varices ensue, thus making further corrective surgery for the underlying stricture(s) more hazardous. In these patients the only available option is liver transplantation.

MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS

conclusions As the name implies, RPC runs a recurrent and unrelenting course with variable frequencies of attacks of cholangitis. Medical therapy is ineffective and surgical treatment is not entirely satisfactory. Despite surgery, stones and strictures can return. In Hong Kong and Taiwan, the peak age incidence of RPC has changed over the years from the third to the fifth decade in the 1950s and 1970s to the seventh decade in the early 1990s (49). This is due to an increasing proportion of patients who have survived previous surgery, only to have RPC recur again in later life. In Hong Kong, young patients in their third and fourth decade of life who present to us with RPC are invariably immigrants from mainland China. RPC is a dying disease in Hong Kong, but is still common in China. Although there are various theories on the pathogenesis of RPC, we believe the condition is closely linked to the level of social and economic conditions of a community. Surgery merely deals with the consequences of the condition, but does not address its roots. With better living conditions and public hygiene, perhaps RPC can be eradicated in this millennium. Until then, a judicious choice of a mixture of treatment, both medical and surgical, is necessary to achieve a satisfactory and long-lasting solution to a recurrent inflammatory condition.

key points ● ● ●

●

●

Calculi are predominantly calcium bilirubinate. Probably secondary to E. coli infection of bile. Presentation: Third and fourth decade Recurrent attacks of cholangitis Obstructive jaundice Preferentially affects left lobe. Investigations: Plain abdominal radiography (AXR) CT ERCP B1 PTC. Complications: Acute pancreatitis Liver abscess Cholangiocarcinoma Portal thrombophlebitis Secondary biliary cirrhosis.

references 1. Digby KH. Common-duct stones of liver origin. Br J Surg 1930; 17: 578–91. 2. Cook J, Hou PC, Ho HC, et al. Recurrent pyogenic cholangitis. Br J Surg 1954; 42: 188–203. 3. Mage S, Morel AS. Surgical experience with cholangiohepatitis (Hong Kong Disease) in Canton Chinese. Ann Surg 1965; 162: 187–90. 4. Harrison-Levy A. The biliary obstruction syndrome of the Chinese. Br J Surg 1962; 49: 674–85. 5. Choi TK, Wong J, Ong GB. The surgical management of primary intrahepatic stones. Br J Surg 1982; 69: 86–90. 6. Chou ST, Chan CW. Recurrent pyogenic cholangitis: a necropsy study. Pathology 1980; 12: 415–28. 7. Federle MP, Cello JP, Laing FC, et al. Recurrent pyogenic cholangitis in Asian immigrants. Use of ultrasonography, computed tomography, and cholangiography. Radiology 1982; 143: 151–6. 8. Lam SK. A study of endoscopic sphincterotomy in recurrent pyogenic cholangitis. Br J Surg 1984; 71: 262–6.

9. Wilson MK, Stephen MS, Mathur M, et al. Recurrent pyogenic cholangitis or ‘oriental cholangiohepatitis’ in occidentals: case reports of four patients. Aust N Z J Surg 1996; 66: 649–52. 10. Menu Y, Lorphelin JM, Scherrer A, et al. Sonographic and computed tomographic evaluation of intrahepatic calculi. AJR 1985; 145: 579–83. 11. Maki T. Pathogenesis of calcium bilirubinate gallstone: role of E. coli, β-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. Ann Surg 1966; 164: 90–100. 12. Ong GB. A study of recurrent pyogenic cholangitis. Arch Surg 1962; 84: 63–89. 13. Maki T. Cholelithiasis in the Japanese. Arch Surg 1961; 82: 599–612. 14. Matsushiro T, Suzuki N, Sato T, et al. Effects of diet on glucaric acid concentration in bile and the formation of calcium bilirubinate gallstones. Gastroenterology 1977; 72: 630–3. 15. Leow CK, Lau WY. Biliary access procedure in the management of oriental cholangiohepatitis. Am Surg 1998; 64: 99. 16. Flinn WR, Olson DF, Oyasu R, et al. Biliary bacteria and hepatic histologic changes in gallstone disease. Ann Surg 1977; 185: 593–7. 17. Thorpe MEC, Scheuer PJ, Sherlock S. Primary sclerosing cholangitis, the biliary tree and ulcerative cholangitis. Gut 1967; 8: 435–48. 18. Ohta G, Nakanuma Y, Terada T. Pathology of hepatolithiasis: cholangitis and cholangiocarcinoma. Prog Clin Biol Res 1984; 152: 91–113. 19. Copher GH, Dick BM. ‘Streamline’ phenomena in portal vein and selective distribution of portal blood in liver. Arch Surg 1928; 17: 408–19. 20. Hahn PF, Donald WD, Grier RC Jr. Physiological bilaterality of the portal circulation; streamline flow of blood into liver as shown by radioactive phosphorus. Am J Physiol 1945; 143: 105–7. 21. Fan ST, Lai ECS, Mok FPT, et al. Acute cholangitis secondary to hepatolithiasis. Arch Surg 1991; 126: 1027–31. 22. Wastie ML, Cunningham IGE. Roentgenologic findings in recurrent pyogenic cholangitis. AJR 1973; 119: 71–7. 23. Itai Y, Araki T, Furui S, et al. Computed tomography and ultrasound in the diagnosis of intrahepatic calculi. Radiology 1980; 136: 399–405. 24. Chan YL, Chan ACW, Lam WWM, et al. Choledocholithiasis: comparison of MR cholangiography and endoscopic retrograde cholangiography. Radiology 1996; 200: 85–9. 25. Park MS, Yu JS, Kim KW, et al. Recurrent pyogenic cholangitis: comparison between MR cholangiography and direct cholangiography. Radiology 2001; 220: 677–82. 26. Araki T, Itai Y, Tasaka A. CT of choledochal cyst. AJR 1980; 135: 729–34. 27. Kaiser JA, Mall JC, Salmen BJ, et al. Diagnosis of Caroli disease by computed tomography: report of two cases. Radiology 1979; 132: 661–4. 28. Mujahed Z, Glenn F, Evans JA. Communicating cavernous ectasia of the intrahepatic ducts (Caroli’s disease). AJR 1971; 113: 21–6. 29. A0Lillemoe KD. Surgical treatment of biliary tract infection. Am Surg 2000; 66: 138–44. 30. Fan ST. Transduodenal sphincteroplasty for impacted stone made unnecessary by electrohydraulic lithotripsy. Surg Gynecol Obstet 1989; 169: 363–4. 31. A0Cosenza CA, Durazo F, Stain SC, et al. Current management of recurrent pyogenic cholangitis. Am Surg 1999; 68: 939–43. 32. Choi TK, Wong J, Lam KH et al. Late result of sphincteroplasty in the treatment of primary cholangitis. Arch Surg 1981; 116: 1173–5. 33. Jeng KS, Yang FS, Ohta I, et al. Dilatation of intrahepatic biliary strictures in patients with hepatolithiasis. World J Surg 1990; 14: 587–93. 34. Ong GB, Kwong KH, Cheng FCY. Extraperitoneal transduodenal choledocho-duodenostomy for removal of overlooked common bile duct stones. Aust N Z J Surg 1970; 40: 166–70. 35. Choi TK, Lee NW, Wong J, et al. Extraperitoneal sphincteroplasty for residual stones: an update. Ann Surg 1982; 196: 26–9. 36. Fan ST, Mok F, Zheng SS, et al. Appraisal of hepaticocutaneous jejunostomy in the management of hepatolithiasis. Am J Surg 1993; 165: 332–5. 37. Lau WY, Chan KL, Li AKC. Surgical treatment of inflammatory strictures of the major bile ducts. Asian J Surg 1990; 13: 51–4. 38. Lau WY, Fan ST, Yip WC, et al. Surgical management of strictures of the major bile ducts in recurrent pyogenic cholangitis. Br J Surg 1987; 74: 1100–2. 39. Hepp J, Couinaud C. L’abord et l’utilisation du canal hepatique gauche dans les reparations de la voie biliaire principale. Presse Med 1956; 64: 947–8.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 40. Fan ST, Lai ECS, Wong J. Hepatic resection for hepatolithiasis. Arch Surg 1993; 128: 1070–4. 41. Ong GB, Adiseshiah M, Leong CH. Acute pancreatitis associated with recurrent pyogenic cholangitis. Br J Surg 1971; 58: 891–4. 42. Wong J, Choi TK. Recurrent pyogenic cholangitis. Prog Clin Biol Res 1984; 152: 175–92. 43. Choi TK, Wong J. Recurrent pyogenic cholangitis. In: Schwartz SI, Ellis H, Husser WC, eds. Maingot’s Abdominal Operations. Volume 2, 9th edn. New Jersey: Prentice-Hall International, 1990: 1519–31. 44. Wei WI, Choi TK, Wong J, et al. Bronchobiliary fistula due to stones in the biliary tree: report of two cases. World J Surg 1982; 6: 782–5.

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45. Chou ST, Chan CW. Mucin-producing cholangiocarcinoma: an autopsy study in Hong Kong. Pathology 1976; 8: 321–8. 46. Chen MF, Jan YY, Wang CS, et al. A reappraisal of cholangiocarcinoma in patient with hepatolithiasis. Cancer 1993; 71: 2461–5. 47. Lai KS, McFadzean AJS, Young RTT. Microemboli pulmonary hypertension in pyogenic cholangitis. Br Med J 1968; 1: 22–4. 48. Jeng KS, Shih SC, Chiang HJ, et al. Secondary biliary cirrhosis. A limiting factor in the treatment of hepatolithiasis. Arch Surg 1989; 124: 1301–5. 49. Fan ST, Choi TK, Lo CM, et al. Treatment of hepatolithiasis: improvement of result by a systemic approach. Surgery 1991; 109: 474–80.

28

Liver abscess: amebic, pyogenic, and fungal Purvi Y. Parikh and Henry A. Pitt

introduction Hepatic abscess is an uncommon disorder that continues to be a challenge to identify and treat. The three major types of hepatic abscesses are (i) pyogenic, most often polymicrobial, due to aerobic and anaerobic bacteria, (ii) amebic, due to Entamoeba histolytica, and (iii) fungal, principally due to Candida species. Pyogenic hepatic abscesses are seen most commonly in temperate climates, and in the United States they account for approximately 80% of the cases. Amebic abscesses account for about 10% of U.S. patients but are relatively more common in semitropical and tropical climates (1). Fungal abscesses are seen in 10% of U.S. cases and are increasing in frequency secondary to more immunocompromised patients as well as those having invasive hepatic procedures with prolonged antibiotic exposure (2,3). This chapter focuses on the pathogens, diagnosis, and current management of liver abscesses.

amebic abscess Amebic liver abscess was not recognized as a separate entity until the nineteenth century. Several European investigators had suggested a relationship between dysentery and liver abscess; however, in 1875 Feder Losch discovered that Entamoeba histolytica was the causal agent. In 1890, Sir William Osler described the first North American case of amebic liver abscess when he found amoeba in a patient’s liver and stool sample (4). Open surgical drainage was the treatment of choice of amebic abscess until the 1930s, when aspiration and emetine became the standard of therapy. During this time, mortality decreased remarkedly from 57% to 14% by using therapeutic aspiration combined with amebicidal therapy (5). Further advancement in management happened with the introduction of serologic tests, improved radiologic imaging, and new amebicidal agents. Epidemiology Amebiasis is a widespread parasitic disease that affects people in developed and underdeveloped countries in tropical climates. Mexico, India, East and South Africa as well as Central and South America have the highest epidemic activity of E. histolytica (6). Worldwide, an estimated 500 million people are carriers of E. histolytica, and 50 million people worldwide develop amebic colitis or amebic liver abscesses resulting in 50,000 to 100,000 deaths each year (7). High-risk groups in the United States include immigrants, tourists who travel to endemic areas, institutionalized people, and the homosexual population. Amebic liver abscess is much more common in men, with a male to female ratio of 10:1. Low socio-economic status and unsanitary conditions are significant risk factors. Other associated risk factors include patients with heavy alcohol consumption, impaired immunity, malnutrition, and chronic infections (8).

Pathogenesis Infection occurs after fecal–oral transmission of E. histolytica, which exists in either an immobile cyst form or the invasive trophozoite form. The main sources of infection are from asymptomatic carriers who transmit the cysts from water to vegetables contaminated with feces, food contaminated by fertilizers, or the hands of infected food handlers (9). The cystic form is swallowed and passes unaffected through the stomach into the intestine where the outer cyst wall is then digested by pancreatic enzymes. The trophozoite form is released into the intestine where it lives and multiplies. In most patients, the trophozoite asymptomatically colonizes the intestine, but some patients may develop amebic dysentery. The trophozoite invades through the intestinal mucosa, enters the mesenteric venules and lymphatics, travels to hepatic venules by the portal vein, and aggregates in the liver parenchyma (7). Accumulation of enough trophozoites leads to thrombosis, and necrosis and formation of an abscess. The outer rim of the abscess wall is infested by E. histolytica. The liquefied hepatic parenchyma has the appearance of “anchovy paste” (10). More than 80% of patients with amebic liver abscess have excess alcohol intake and thus a vulnerable liver to Entamoeba (11). Higher rates of tissue invasion are found in patients with Human Immunodeficiency Virus (HIV), splenectomy, and corticosteroid administration. Diagnosis The clinical presentation of amebic liver abscess is significantly different from pyogenic (Table 28.1). More than 90% of cases occur in men who usually live in or have a travel history to an endemic area in the last 2 to 5 months (5). Typical symptoms include fever, chills, anorexia, right upper quadrant pain, abdominal tenderness, and hepatomegaly with point tenderness over the liver or subcostal region. Diaphragmatic involvement causes right-sided pleural pain or pain referred to the shoulder (12). Patients with amebic liver abscess rarely have concurrent amebic dysentery, but 10% to 35% of patients have gastrointestinal symptoms that include nausea, vomiting, abdominal cramping, or distention (12). Jaundice, septic shock or a palpable mass may rarely be seen. Patients with an amebic liver abscess usually have a mild leukocytosis without eosinophilia (8). Mild anemia with moderate elevation of alkaline phosphatase and other liver function tests also may be present. The most common abnormality is an increased prothrombin time (12,13). Young males who are alcoholics may have normal or increased hemoglobin. If concurrent colitis is present, the wet mount prep will contain trophozoites 70% of the time if three separate stool samples are examined (11). If the patient has no colitis and a solitary liver abscess, stool samples are positive in 40% to 50% of cases (6). The definitive diagnosis of amebic liver abscess is by the detection of E. histolytica trophozoites in the abscess and by

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS finding serum antibodies to the amoeba. Serum antibodies are positive in 85% of patients with invasive colitis, and 99% of patients with liver abscesses (14). However, in endemic countries positive serologies can also be found in asymptomatic carriers. Biopsies of the abscess wall also can reveal trophozoites with periodic acid-Schiff stain (11). Chest radiographs typically show elevation of the right dome of the diaphragm, pleural effusion, and atelectasis. A plain abdominal film will usually show an enlarged hepatic shadow and may demonstrate air in the biliary tree if a communication to the pleural cavity or hollow viscous is present. However, ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) are all excellent at detecting and characterizing hepatic abscesses (13). Ultrasonography is simple, inexpensive, and quick to perform with a diagnostic accuracy of 90% (15). In an acute setting, CT scan does not add to the diagnostic accuracy of US unless it is needed for evaluation of rupture of abscesses. However, the CT scan does show better delineation of other organs in relationship with the liver (13). MRI is not superior to CT for diagnosis of amebic liver abscess. A nuclear hepatic scan with gallium may differentiate a “cold” amebic abscess from a “hot” pyogenic abscess because of the presence of neutrophils (16). Performing a diagnostic aspiration is usually unnecessary if there is a high clinical suspicion of an amebic liver abscess (13). Treatment Treatment for uncomplicated amebic liver abscess is generally amecidal drugs. Selective patients may require further treatment such as aspiration and percutaneous or surgical drainage because diagnosis is questionable or when complications occur. The mainstay of therapy is metronidazole

that is highly effective against both intestinal and extraintestinal infection. The standard dose is 500 mg IV q6 hr with oral administration of 750 mg q8 hr for a total of 7 to 10 days (6). Most patients have rapid clinical improvement in 72 hours, and 90% are cured with metronidazole. Patients who have a persistent abscess and do not respond to metronidazole within 5 days may require the addition of chloroquine (17). Approximately 10% of patients have a recurrence of their abscesses if the intestinal colonization is not treated (18). The majority of patients do not require percutaneous aspiration of the amebic abscess because they respond to amebicidal therapy. Blessmann and colleagues reported that therapeutic aspiration had minor benefit and was insufficient to justify routine needle aspirations (19). A 2009 Cochrane Review also found that simple aspiration of uncomplicated amebic liver abscesses did not help patients (20). However, simple aspiration may be beneficial in patients with failure to respond to drug therapy within 5 to 7 days. Aspiration should also be considered in patients with abscesses greater than 5 cm in size because of the risk of rupture or in patients with abscesses in the left hepatic lobe that have increased frequency of peritoneal leak or rupture into the pericardium and a higher mortality (Fig. 28.1) (21). Aspiration may be indicated if a pyogenic cause needs to be ruled out or for treatment of pulmonary, peritoneal, and pericardial complications. The procedure can be performed safely with US- or CT-guided aspiration. The fluid of an amebic abscess is odorless, and Gram stain and cultures are negative. Amoeba are recovered

Table 28.1 Comparison of Amebic and Pyogenic Abscess Features Age (mean) Male: female ratio Abscess number Travel/emigration history Diabetes mellitus Alcohol abuse Jaundice Pruritus Abdominal pain Diarrhea Elevated bilirubin Elevated alkaline phosphate Elevated transaminase Positive blood culture Positive amebic serology

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Amebic abscess

Pyogenic abscess

20–40 years >10:1 1 in ≥80% Yes

>50 years 1:1 ≥1 in 50% No

Uncommon Common Uncommon Uncommon Common Common Uncommon Common

Common Common Common Common Uncommon Uncommon Common Common

Uncommon

Common

No

Yes

Yes

No

1 2 8

3

B

A

9 4

7 5

6

Figure 28.1 Paths of extension of amebic liver abscesses located within (A) the right hepatic (labels 1–7) and (B) the left hepatic lobe (8,9).

LIVER ABSCESS: AMEBIC, PYOGENIC, AND FUNGAL in 33% to 90% of aspirates with a higher yield in patients with wall scrapings (13). Open surgical drainage of amebic liver abscess is rarely performed because most patients respond to amecidal drug therapy with or without aspiration. Most experts recommend avoidance of open surgical drainage because of concern about secondary bacterial colonization; however, they agree that surgical drainage is often necessary in patients with rupture into the peritoneal cavity, the pleura, lung or pericardium. Thus, open surgical drainage is reserved for patients with complications from rupture, failure to respond to medical therapy, and inadequate aspiration. Outcomes Complications of amebic liver abscesses occur secondary to rupture of the abscess into the peritoneum, pleural cavity, or pericardium. Ruptured amebic liver abscesses occur in 2% to 17% of patients with mortality between 12% and 50% (18). Free rupture into the peritoneal cavity is rare and occurs in patients with poor nutrition or with simultaneous amebic colitis. Peritonitis may occur secondary to rupture or secondary to necrotizing or perforated amebic colitis. Most often, the ruptured liver abscess adheres to the diaphragm or omentum that tends to wall it off. Thoracic amebiasis causing empyema, bronchohepatic fistulas, and pleuropulmonary diseases is the most common complication followed by pericardial amebiasis manifested by acute pericarditis with tamponade (6). When tamponade develops, aspiration of the pericardium, drainage of the liver abscess and anti-amebic drugs are indicated (18). Severely ill patients with sepsis secondary to amebiasis also may develop cerebral amebiasis and experience seizures (6). The overall mortality rates of patients with amebic liver abscess are from 0% to 18%, and high mortality rates suggest delayed diagnosis, secondary bacterial infection or complications (11). Factors that are associated with a poor prognosis are jaundice, advanced age, encephalopathy, decreased albumin, large abscess cavity, or complications such as rupture into the peritoneum or pericardium (22). Patients will have clinical improvements with amecidal therapy much more rapidly than radiologic resolution. Complete radiologic resolution may take up to 9 months. Follow-up imaging studies in patients with resolution of symptoms after treatment for amebic liver abscess is advised.

pyogenic liver abscess Liver abscess was recognized in ancient times, and the first description is credited to Hippocrates in 4000 BC. No new information was identified until the landmark paper by Ochsner and Debakey in 1938 (23). They described the disease as having a 62% survival rate for patients undergoing surgical drainage. With improvements in antibiotics, the combination of surgical drainage and antibiotics became the standard of care. In 1953, McFadzean and associates first reported percutaneous drainage (24). By the mid-1980s, the development of US and CT scans led to numerous reports of patients successfully treated by percutaneous drainage and antibiotics (25,26).

Epidemiology Pyogenic liver abscess is the most common form of liver abscess accounting for approximately 80% of all liver abscesses in the United States (1). The disease process has significantly increased over the past 30 years, presenting in about 15 cases per 100,000 admissions. Seeto and Rocky reported an incidence nearly double that of earlier reports (22 per 100,000) due to a more aggressive management approach to hepatobiliary and pancreatic diseases (27). The predominant etiology of pyogenic liver abscess has changed from an intra-abdominal septic source to a biliary origin with more reports of cryptogenic liver abscesses in recent years. Advanced imaging techniques, improved antibiotics, and numerous treatment modalities have decreased morbidity and mortality. Pathogenesis The liver is a sterile organ that has Kupffer cells that filter out microorganisms. Abscesses form when the normal liver fails to clear the organisms, and the infection causes parenchymal necrosis. Potential sources of these microorganisms are (i) biliary, secondary to ascending cholangitis or biliary malignancy, (ii) portal, pyemia secondary to appendicitis, diverticulitis, or other intra-abdominal source, (iii) arterial, from generalized septicemia, (iv) direct extension, (v) trauma, and (vi) cryptogenic (Table 28.2). Ascending infection of the biliary tree causing obstruction now accounts for 35% to 40% of all pyogenic liver abscesses (1). The etiology of the biliary obstruction has some geographic differences. In Western countries, 40% of pyogenic liver abscesses have underlying malignant disease (28). In Asian countries, hepatolithiasis and associated biliary strictures predominate as the cause of pyogenic liver abscess (29). Percutaneous or endoscopic manipulation or stenting can introduce infection into the biliary tree causing cholangitis, which has the propensity to cause pyogenic liver abscess. Other causes include Caroli’s disease, invasion of the biliary tree by parasites and/or a previous biliary-enteric anastomosis. In the past, the most common source of pyogenic liver abscess was appendicitis. In Ochsner’s study, appendicitis accounted for 43% of all abscesses seeded via the portal vein (23). Today, even though intestinal pathology is responsible for 20% of all pyogenic liver abscesses, appendicitis accounts for only 2% of all pyogenic liver abscesses. Diverticulitis and perforated colon cancers remain more common causes of pyogenic liver abscesses. Hematogenous spread of infection from sources like endocarditis, dental abscess, and intravenous drug abuse are examples of generalized septicemia that may lead to a pyogenic liver abscess. Transarterial embolization or ablative therapies for liver tumors are also associated with liver abscess formation (30,31). Direct extension of empyema of the gallbladder, perforated gastric or duodenal ulcers, and subphrenic abscess also may cause a pyogenic liver abscess. Liver trauma from penetrating or blunt injury may cause parenchymal necrosis, hemorrhage, or intrahepatic biloma that may become infected and develop into pyogenic liver abscess (32). Hepatic artery thrombosis after liver transplantation or ligation after a pancreatobiliary operation may lead to a liver abscess especially following obstructive jaundice. In some

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS patients, no identifiable cause of pyogenic liver abscess can be found; they are labeled cryptogenic abscesses and occur in 10% to 55% of patients (33,34). Cryptogenic abscess tend to be solitary, monomicrobial, and associated with diabetes, immunosuppression, or malignancy. Cryptogenic abscesses usually have a normal bilirubin and no duct dilation on imaging (27). Microbiology With the various routes of infection, identification of microorganisms recovered from blood culture or aspiration of pus from the pyogenic liver abscess is imperative for treatment. Patients with cryptogenic liver abscess are more like to have negative blood cultures. However, liver abscesses from biliary tract disorders are more likely to have positive cultures from blood and pus. The most common organisms cultured are Escherichia coli and Klebsiella pneumoniae (Table 28.3) (35). Other frequently encountered aerobes include enterococci and

Table 28.2 Most Frequent Causes of Pyogenic Liver Abscess Hepatobiliary Benign Choledocholithiasis Hepatolithiasis Biliary-enteric anastomosis Endoscopic biliary procedure Percutaneous biliary procedures Malignant Biliary Gallbladder Ampulla Head of pancreas Portal Benign Diverticulitis Anorectal abscess Pelvic abscess Post-operative abscess Intestinal perforation Pancreatic abscess Appendicitis Inflammatory bowel disease Malignant Colon cancer Gastric cancer Arterial Endocarditis Ear, throat, nose infection Dental infection Direct extension Empyema of the gallbladder Perforated ulcer Traumatic Benign Open or closed abdominal trauma Transarterial embolization Percutaneous ethanol injection Ablation Cryptogenic

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Streptococci viridians. An abscess secondary to biliary tract disease or originating from a gastrointestinal source is more likely to be polymicrobial with aerobic and anaerobic organisms. Bacteroides is the most common isolated anaerobic organism, followed by Fusobacterium (10). The increased use of indwelling biliary stents has resulted in an increased incidence of Klebsiella, streptococcal, staphylococcal, and pseudomonal species in liver abscesses (28). Fifteen percent of patients have a negative culture that may be attributed to poor anaerobic culture technique or the use of broad-spectrum antibiotics prior to abscess drainage. This factor also is thought to be responsible for the increased incidence of fungal abscesses (6). In patients with Acquired Immune Deficiency Syndrome (AIDS) the most common infecting organism for hepatic abscesses is Mycobacterium tuberculosis (36). Diagnosis The clinical presentation of pyogenic liver abscess is nonspecific and includes malaise, nausea, anorexia, weight loss, headaches, and myalgias. These symptoms may be present for many weeks before the appearance of more specific symptoms such as fever, chills and abdominal pain in the right upper quadrant (RUQ) (Table 28.1). The classic triad of fever, jaundice, and RUQ tenderness is present in less than 10% patients. Diarrhea also occurs in 10% of patients (37). On physical examination, some patients may also have a tender and enlarged abdomen. Abscesses adjacent to the diaphragm may cause pleuritic chest pain, cough, and dyspnea. Septic shock may be present in patients with cholangitis or peritonitis after rupture into the peritoneal cavity. Laboratory investigations demonstrate leukocytosis (70% to 90%), hyperbilirubinemia (50% to 67%), and elevated alkaline phosphatase (80%) in a majority of patients. Many patients may also have anemia, hypoalbuminemia, and prolonged prothrombin time (34,37,38). Patients with pyogenic abscesses are also more likely than those with an amebic abscess to have diabetes mellitus. Table 28.3 Spectrum of Microorganisms That Cause Pyogenic Liver Abscess Gram-positive aerobes Streptococcus milleri Staphylococcus aureus Enterococcus spp. Others Gram-Negative Aerobes Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Proteus spp. Enterobacter cloacae Citrobacter freundii Others Gram-positive anaerobes Clostridium spp. Peptostreptococcus spp. Gram-negative anaerobes Bacteroides spp. Fusobacterium spp.

LIVER ABSCESS: AMEBIC, PYOGENIC, AND FUNGAL Imaging studies are essential in establishing the diagnosis of hepatic abscess. Plain films of the abdomen and chest show abnormalities in 50% of patients (39). The films will show rightsided atelectasis, pleural effusion, and hemi-diaphragm on chest x-ray and hepatomegaly, possible portal venous gas, and occassional air/fluid levels. Ultrasound and CT scans have a greater sensitivity in visualizing the liver abscess and providing imageguided therapy. The US has a sensitivity as high as 75% to 95%; however, US has difficulty detecting multiple abscesses or those on the dome of the right lobe (27). A CT scan is more accurate than US in differentiating liver lesions from abscesses and visualizing multiple abscesses throughout the liver (Fig. 28.2). CT also has a sensitivity of 95%, but the advantage of abdominal CT scans is that they may help to identify other intra-abdominal pathology and abscesses as small as 0.5 cm (27). Magnetic resonance imaging is also very accurate but has no advantage over ultrasounds or CT scans in the diagnosis of pyogenic liver abscess.

Treatment The principles of treatment for liver pyogenic liver abscesses are to start appropriate antibiotics, drain the pus, and treat the underlying cause, if identified. Although antibiotics alone may be curative, these patients have a higher risk of recurrence and complications such as abscess rupture. Ultrasound and CT scans have allowed for earlier diagnosis and facilitated treatment by percutaneous aspiration and drainage (Fig. 28.2). The combination of antibiotic therapy and percutaneous drainage has become the first line treatment for most pyogenic liver abscesses (Table 28.4). Initial antibiotic therapy should be started to cover gramnegative and gram-positive aerobes and anaerobes. Multiple single antibiotics such as pipacillin/tazobactam, ticarcillin/clavulanate, imipenem/cilastin, or meropenem may be started initially if a biliary source is suspected. Alternative therapies including a third-generation cephalosporin or a fluroquinolone

(A)

(B)

(C)

(D)

Figure 28.2 (A) CT demonstrating pyogenic abscess with air/fluid level in segment VI of the liver. (B) CT scan showing residual abscess after initial percutaneous drainage. (C) Further percutaneous drainage catheters. (D) CT demonstrating resolution of abscess.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 28.4 Comparison of Liver Abscess: Diagnosis and Treatment Liver abscess

Diagnosis

Treatment

Amebic

Clinical Suspicion US or CT scan Positive amebic serology

Pyogenic

Clinical Suspicion US or CT scan ± Aspiration Immunocompromised patient US or CT scan ± Aspiration

Amebicidal therapy Lumenal agent Drainage of complicated abscess Systemic antibiotics Drainage of abscess

Fungal

Systemic antifungal Drainage of abscess Systemic antibiotics for polymicrobial abscess

Abbreviations: CT, computed tomography; US, ultrasound.

with metronidazole may be administered if the bowel is thought to be the source. Parenteral administration of antibiotics for the first 10 to 14 days followed by oral agents for a total of 4 to 6 weeks is the classic recommendation. However, recent studies suggest that only 2 weeks of antibiotic therapy may be required (40). A combination of an aminoglycoside with either an extended spectrum beta-lactam, such as piperacillin, or a third generation cephalosporin is preferred for patients with K. pneumoniae liver abscesses (41). Multiple abscesses <1.5 cm in size and no other surgical disease may be treated with antibiotics alone. However, patients with multiple small abscesses usually have biliary tract disease and require biliary drainage. Matoba and coworkes recently reported that when percutaneous drainage cannot be performed and intravenous administration of antibiotics are ineffective, intermittent hepatic artery infusion therapy may be a useful alternative (42). Clinicians have questioned when the primary treatment for pyogenic liver abscesses should be aspiration alone or placement of a percutaneous catheter for drainage. Giorgio and associates treated 115 patients with percutaneous needle aspiration with a 98% success rate (43). Half the patients required only one aspiration whereas the remainder needed two to three aspirations. In 2004, C.H. Yu and associates also found that aspiration and catheter drainage had a similar mortality, success rate, and hospital stay (44). On the other hand, Rajak and associates performed a prospective randomized controlled trial comparing aspiration and catheter drainage showing a 100% success rate for catheter drainage compared to only 60% for aspiration (45). In summary, needle aspiration is less invasive and avoids all of the complications associated with catheter care. However, recurrence rates and the requirement for surgical intervention may be increased for patients who undergo aspiration alone. Although highly successful, percutaneous catheter drainage fails in approximately 10% of patients. Incomplete or unsuccessful drainage may result from the catheter being too small, highly viscous material, malposition of the catheter, or premature removal of the catheter. Furthermore, contradictions of percutaneous drainage requiring surgical drainage include patients with (i) large

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or multiple abscess, (ii) abscesses of unknown etiology, (iii) ascites, (iv) a known intra-abdominal source that requires surgery, and (v) abscesses that require transpleural drainage (1). Operative intervention is recommended when complications occur following percutaneous catheter drainage or failure of non-operative treatment. Open abdominal surgical exploration involves localization of the abscess, identification of additional lesions via ultrasound, evacuation of the abscess, insertion a large-bore drainage tube, and treatment of the inciting pathology (Fig. 28.3). Post-operative lavage of the cavity through the drainage tube has been shown to be advantageous. The role of hepatic resection for the treatment of pyogenic liver abscesses remains controversial. Chou and associates published a series of 483 patients with pyogenic liver abscesses where 27 patients had a liver resection with 1 death (3.7%) (46). They concluded that when single or multiple liver abscesses have caused severe hepatic destruction, resection should be considered. Patients with significant liver atrophy and multiple pyogenic liver abscesses secondary to a long term biliary obstruction from hepatolithiasis or intrahepatic biliary stricture may also be best treated by hepatic resection (46). Outcomes Pyogenic liver abscess may be fatal if left untreated. Forty percent of patients with pyogenic liver abscesses develop complications that include pleural effusions, empyema, pneumonia, and generalized sepsis. Pyogenic liver abscesses may also cause hemobilia and hepatic vein thrombosis. Deaths in patients with pyogenic liver abscesses have been attributed to the intra-peritoneal rupture of the abscess. In one analysis, the causative bacteria in 72% of the cases of failed medical treatment were S. milleri and K. pneumoniae (47). Bacteremia, disseminated intravascular coagulopathy (DIC), septic pulmonary emboli, and acute renal failure are common complications of liver abscesses. Since the introduction of broad-spectrum antibiotics and the advancements in image-guided drainage, the mortality from pyogenic liver abscess has drastically decreased. However, the mortality in patients with multiple abscesses remains higher than in those with a solitary abscess. Liver abscesses are now diagnosed earlier and may be treated non-operatively thus reducing the mortality to less than 20% (46). Seeto and Rockey showed in their series a mortality of only 2% (27). Risk factors for mortality include septic shock, jaundice, hypoalbuminemia, malignancy, disseminated intravascular coagulopathy, APACHE II score >10, multiple abscesses, and intra-peritoneal rupture (48).

fungal liver abscesses Bacteria and parasites cause the vast majority of hepatic abscesses; however, fungal liver abscesses account for about 10% of hepatic abscesses (2,3). Most monomicrobial fungal abscesses occur in immunocompromised patients including patients receiving chemotherapy and patients with HIV infections. Patients with biliary malignancies, indwelling stents, and frequent courses of antibiotics tend to develop a polymicrobial fungal abscess in conjunction with pyogenic abscesses. Candida albicans and other Candida species are the predominate organism in about 80% of cases (3). Aspergillus, Cryptococcus and mixed infections make up the remaining fungal pathogens.

LIVER ABSCESS: AMEBIC, PYOGENIC, AND FUNGAL

Ultrasonic probe Aerobic culture

Site of unilocular abscess

T-extension

Deep multiloculated abscess Gallbladder

Loculations within abscess

Liver

Anaerobic culture

Liver

Normal liver parenchyma Antibiotic containing saline solution

Abscess

(A)

(B)

Figure 28.3 (A) Intra-operative ultrasound, aspiration, and anaerobic culture of abscess, and liver incision for pyogenic abscess. (B) Aerobic culture, manual disruption of loculations, and irrigation of the pyogenic abscess. Source: Reproduced from Ref. (51).

Treatment Fungal liver abscesses are treated with intravenous antifungal therapy as well as drainage of the abscess by simple aspiration, percutaneous drainage or open surgical drainage (Table 28.4). Caspofungin is the agent of choice for these patients (49,50). Patients with mixed bacterial and fungal abscesses should also be treated with appropriate systemic antibiotics for the isolated bacteria. An adequate course of caspofungin should be employed as an earlier analysis suggested that inadequate treatment with amphoteracin B was associated with a high mortality. Outcomes Very few patients develop pure fungal abscesses. Most patients have polymicrobial fungal and bacterial abscesses. The overall mortality rate is 50% because patients who do not receive antifungal therapy in early stage develop systemic fungemia (12). In addition, the underlying disease in the majority of these patients is associated with a high mortality. Moreover, the majority of these abscesses are multiple. As a result, patient survival is not influenced by different drainage procedures.

references 1. Pitt HA. Surgical management of hepatic abscess. World J Surg 1990; 14:498–504. 2. Simpfendorfer CH, Henderson JM. Hepatic abscess. In: Cameron J, ed. Current Surgical Therapy, 9th edn. Philadelphia, PA: Elsevier-Mosby, 2008: 317–21. 3. Lipsett PA, Huang CJ, Lillemoe KD, et al. Fungal hepatic abscess: characterization and management. J Gastrointestinal Surg 1997; 1:78–84. 4. Martinez BM. Historical introduction. In: Martinez-Palomo A, ed. Amebiasis. Human Parasitic Diseases, Vol. 2. Amsterdam, Holland: Elsevier; 1986: 1–9. 5. Hughes MA, Petri WA Jr. Amebic liver abscess. Infect Dis Clin N Am 2000; 14: 565–82.

6. Wells CD, Aruqedas M. Amebic liver abscess. S Med J 2004; 97: 673–82. 7. Santi-Rocca J, Rigothier MC, Guillen N. Host-microbe interactions and defense mechanisms in the development of amoebic liver abscesses. Clin Microbiol Rev 2009; 22: 65–75. 8. Tanyuksel M, Petri WA. Laboratory diagnosis of amebiasis. Clin Microbiol Rev 2003; 16:713–29. 9. Salles JM, Moraes LM, Salles MC. Hepatic amebiasis. Braz J Infect Dis 2003; 7:96–110. 10. Leslie DB, Dunn DL. Hepatic abscess. In: Cameron J, ed. Current Surgical Therapy, 8th edn. Philadelphia, PA: Elsevier Mosby; 2004: 298–303. 11. Petri WA Jr, Singh U. Diagnosis and management of amebiasis. Clin Infect Dis 1999; 29: 1117–25. 12. Haque R, Huston CD, Hughes M, et al. Current concepts: amebiasis. N Engl J Med. 2003; 48: 1565–73. 13. Barnes S, Lillemoe K. Liver abscess and hydatid cyst disease. In: Zinner M, Schwartz S, Ellis H, Ashley S, McFadden D, ed. Maingot’s Abdominal Operations, 10th edn. Stamford, CT: Appleton & Lange; 1997: 1513–45. 14. Haque R, Mollah NU, Ali IKM, et al. Diagnosis of amebic liver abscess and intestinal infection with the techLab Entamoeba histolytica II antigen detection and antibody tests. J Clin Microbiol 2000; 38: 3235–9. 15. Sepulveda B, Manzo NTG. Clinical manifestations and diagnosis of amebiasis. In: Martinez-Palomeo A, ed. Amebiasis: Human Parasitic Diseases, No. 2 Amsterdam: Elsevier, 1986; 169–87. 16. Stanley SL Jr. Amebiasis. Lancet 2003; 361: 1025–34. 17. Lodhi S, Sarwari AR, Muzammil M, et al. Features distinguishing amoebic from pyogenic liver abscess: a review of 577 adult cases. Trop Med Int Health 2004; 9: 718–23. 18. Thomas PG, Ravindra KV. Amebiasis and biliary infection. In: Blumgart LH, Fong Y, ed. Surgery of the Liver and Biliary Tract, 3rd edn. London: WB Saunders; 2001: 1147–65. 19. Blessmann J, Binh HD, Hung DM, et al. Treatment of amebic liver abscess with metronidazole alone or in combination with ultrasound-guided needle aspiration: a comparative, prospective and randomized study. Trop Med Int Health 2003; 8: 1030–4. 20. Chavez-Tapia NC, Hernandez-Calleros J, Tellez-Avia FI, et al. Imageguided percutaneous procedure plus metronidazole versus metronidazole alone for uncomplicated amoebic liver abscess (Review). The Cochrane Library 2009 Issue 2.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 21. Weinke T, Grobusch MP, Buthoff W. Amebic liver abscess: rare need for percutaneous treatment modalities. Eur J Med Res 2002; 7:25–9. 22. Sharma MP, Dasarthy S, Verma N, et al. Prognostic markers in amebic liver abscess: a prospective study. Am J Gastro 1996; 91: 2584–8. 23. Ochsner A. Pyogenic abscess of the liver. Am J Surg 1938; 40: 292–353. 24. McFadzean AJS, Chang EPS, Wong CL. Solitary abscess of the liver treated by closed aspiration and antibiotics: a report of the 14 consecutive cases with recovery. Br J Surg 1953; 41: 141–52. 25. Bertel C. Treatment of pyogenic hepatic abscess: surgical versus percutaneous drainage. Arch Surg 1986; 121: 554–8. 26. Gerzof SG, Johnson WC, Robbins AH, et al. Intrahepatic pyogenic abscess: Treatment by percutaneous drainage. Am J Surg 1985; 149: 487–94. 27. Seeto R, Rockey D. Pyogenic liver abscess: changes in etiology, management and outcomes. Medicine 1996; 75: 99–113. 28. Huang CJ, Pitt HA, Lipsett PA, et al. Pyogenic liver abscess: changing trends over 42 years. Ann Surg 1996; 223: 600–9. 29. Kurland JE, Brann OS. Pyogenic and amebic liver abscesses. Curr Gastro Rep 2004; 6: 273–9. 30. Chen C, Chen PJ, Yang PM, et al. Clinical and microbiological features of liver abscess after transarterial embolization for hepatocellular carcinoma. Am J Gastro 1997; 92: 2257–9. 31. de Baère T, Roche A, Amenabar JM, et al. Liver abscess formation after local treatment of liver tumors. Hepatology 1996; 23: 1436–40. 32. Strong RW. Pyogenic liver abscess. In: Blumgart LH, ed. Surgery of the Liver, Biliary Tract and Pancreas, 4th edn. Philadelphia: Saunders/Elsevier, 2007; 1: 927–33. 33. Christians KK, Pitt HA. Hepatic abscess and cystic disease of the liver. In: Zinner M, Ashley S, ed. Maingot’s Abdominal Operations, 11th edn. Stamford, CT: Appleton & Lange 2007; 757–81. 34. Chu KM, Fan ST, Lai ECS, et al. Pyogenic liver abscess: an audit of experience over the past decade. Arch Surg 1996; 131: 148–52. 35. Alvarez Pèrez J, Gonzáles JJ, Baldonedo RF. Clinical course, treatment and multivariate analysis of risk factors for pyogenic liver abscess. Am J Surg 2001; 181: 177–86. 36. Pope IM, Poston GJ. Pyogenic liver abscess. In: Blumgart LH, Fong Y, ed. Surgery of the Liver and Biliary Tract, 3rd edn. London: WB Saunders, 2001: 1135–45.

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37. Branum GD, Tyson GS, Branum MA, et al. Hepatic abscess: changes in etiology, diagnosis and management. Ann Surg 1990; 212: 655–62. 38. Leslie DB, Dunn DL. Hepatic abscess. In: Cameron J, ed. Current Surgical Therapy, 8th edn. Philadelphia, PA: Elsevier Mosby 2004; 298–303. 39. Saini S. Imaging of the hepatobiliary tract. New Engl J Med 1997; 336:1889–94. 40. Ng FH, Wong WM, Wong BC, et al. Sequential intravenous/oral antibiotics vs. continuous intravenous antibiotics in the treatment of pyogenic liver abscess. Aliment Pharmacol Ther 2002; 16: 1083–90. 41. Lederman ER, Crum NF. Pyogenic liver abscess with a focus in Klebsiella pneumoniae as a primary pathogen: an emerging disease with unique clinical characteristics. Am J Gastro 2005; 100: 322–31. 42. Matoba M, Tonami H, Kuginuki M, et al. Intermittent hepatic artery antibiotic infusion for pyogenic hepatic abscess. Acta Radiol 2004; 45: 13–17. 43. Giorgio A, Tarantino L, Mariniello N, et al. Pyogenic liver abscess: 13 years of experience in percutaneous needle aspiration with US guidance. Radiology 1995, 195: 122–4. 44. Ch Yu S, Hg Lo R, Kan PS, et al. Single and multiple pyogenic liver abscess: treatment with needle aspiration. Clin Radiol 1997; 52: 912–6. 45. Rajak C, Gupta S, Jain S, et al. Percutaneous treatment of liver abscess: needle aspiration vs. cathetar drainage. AJR 1998; 170: 1035–9. 46. Chou FF, Sheen-Chen SM, Chen YS, et al. Single and multiple pyogenic liver abscesses: clinical course, etiology and results of treatment. World J Surg 1997, 21: 384–9. 47. Lublin M, Bartlett DL, Danforth DN, et al. Hepatic abscesses in patients with chronic granulomatous disease. Ann Surg 2002; 235: 383–91. 48. Christein JD, Kendrick ML, Que FG. What affects mortality after the operative management of hepatic abscess? HPB 2006; 8:175–8. 49. Lai CH, Chen HP, Chen TL. Candidal liver abscesses and cholecystitis in a 37-year-old patient without underlying malignancy. World J Gastro 2005; 11: 1725–7. 50. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004; 38: 161–89. 51. Cameron JL, et al. Liver abscess. In: Atlas of Surgery. Philadelphia, PA: BC Decker; 1990.

29 Benign solid tumors of the adult liver Mark Duxbury and O. James Garden

introduction As diagnostic radiological imaging techniques have improved and become more widely applied, benign solid lesions of the liver have become an increasingly common incidental finding. These lesions are often detected in asymptomatic patients without significant liver disease and there may be an increasing trend to resect such lesions with the introduction of laparoscopic liver surgery, an issue that remains contentious (1–3). Although the etiology of these lesions is not well understood, benign liver lesions can be classified according to their cellular origin (Table 29.1). Benign solid liver lesions can arise from hepatocytes, biliary epithelium, surrounding mesenchymal structures, or mixtures thereof. Some of these lesions are sufficiently rare that they can be regarded as medical curiosities, although they may present genuine diagnostic and management challenges. A comprehensive understanding of the clinical and pathological features of benign solid liver lesions will facilitate differential diagnosis and allow rational management. The principal issues to be resolved in the management of this group of patients are 1. Confirmation that the lesion is benign. 2. Determining whether the lesion requires surgical treatment. Detailed history addressing relevant risk factors and relevant clinical examination will guide further investigation. While commonly asymptomatic, benign liver lesions may present as surgical emergencies with acute local or systemic symptoms and signs due to hemorrhage, rupture, vascular thrombosis, or necrosis. Commonly, patients present with symptoms that are unrelated to an incidentally detected liver lesion. These patients frequently require further assessment to exclude an alternative cause for their symptoms. Particular aspects of the history may increase the pre-investigation probability of a particular diagnosis, for example, pain, weight loss—malignancy; known gallstones—biliary colic; previous cancer—metastasis; primary sclerosing cholangitis or ulcerative colitis— intrahepatic cholangiocarcinoma; oral contraceptive use: adenoma; cirrhosis, viral hepatitis, inborn errors of metabolism: hepatocellular carcinoma. While liver biochemistry is usually normal, this finding can be helpful in supporting the diagnosis of a benign lesion. Abnormal results may reflect a complication such as hemorrhage, infarction, or the presence of neoplasia. Systemic phenomena, more commonly associated with hepatic malignancies, are exceptional with benign liver lesions. Advances in imaging have meant an increasing majority of benign liver lesions are diagnosed solely on radiological features, particularly in the case of hemangiomata, focal nodular hyperplasia, and confounding focal fatty change. Percutaneous

biopsy or surgical resection may be helpful in cases of diagnostic uncertainty, symptomatic lesions, or potentially premalignant conditions. Our institutional practice is to reserve biopsy for non-surgical candidates and only in cases where the biopsy result will influence subsequent management (recommendation strength: D). The role of percutaneous needle biopsy remains controversial, potential problems including bleeding from vascular lesions and a risk of tumor seeding. Needle biopsy and cytology are also subject to sampling errors which can lead to misdiagnosis. Current challenges for clinicians managing this group of patients include ●

●

●

●

●

Establishing the diagnosis of a radiologically detected solid liver lesion with a satisfactory degree of certainty, a persisting problem being the differentiation of FNH from adenoma and confirming the nature of focal lesions in the cirrhotic liver. Managing patients with lesions identified incidentally at operation Managing patients following complete or partial resection of a lesion Managing patients with an incidental histological diagnosis following resection or biopsy Determining optimal follow-up of these patients based on the natural history of these lesions

In a recent clinical database review, surgery for benign disease accounted for 5% of patients undergoing resectional liver surgery (4). Advances in preoperative assessment, perioperative care, anesthesia, and surgical technique, including the increasing application of minimally invasive laparoscopic approaches, have the potential to decrease the morbidity and mortality rates associated with resectional liver surgery (5,6). A recent European study reported 87 patients treated laparoscopically with zero mortality and a low-postoperative complication rate (5%) (7). These improvements have altered the analysis of clinical risk versus benefit required when managing a patient with a diagnosis of a solid benign liver lesion but should not increase the prevalence of unnecessary liver resection.

imaging Ultrasound (US) is often helpful in confirming an intrahepatic mass and will differentiate most cystic from solid parenchymal lesions. However, axial imaging in the form of contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) is usually required for adequate lesion characterization. Recently developed MRI contrast agents (superparamagnetic iron oxide, SPIO; gadobenate dimeglumine, Gd-BOPTA) have improved the ability to differentiate between solid benign lesions on MRI. Improvements in these modalities mean that angiography is

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 29.1 A Classification of Benign Solid Tumors of the Adult Liver Hepatocellular origin Hepatocellular adenoma Hepatocellular adenomatosis Hepatocellular hyperplasia: Focal nodular hyperplasia Nodular regenerative hyperplasia Regenerative nodule Dysplastic nodules Cholangiocellular origin Biliary hamartoma Biliary adenoma Biliary cystadenoma Congenital hepatic fibrosis Mesenchymal origin Vascular Hemangioma Adult hemangioendothelioma Peliosis hepatis Hereditary hemorrhagic telangiectasia Lymphangioma Adipose Focal fatty changes Lipoma Angiomyolipoma Myelolipoma Smooth muscle Leiomyoma Fibroma Mesothelioma Mixed epithelial and mesenchymal Mesenchymal hamartoma Teratoma Inflammatory pseudotumor Heterotopic tissue Adrenal rests Pancreatic heterotopia

now less commonly a part of initial patient assessment. Positron emission tomography (PET) is undergoing further evaluation as a diagnostic adjunct and laparoscopy is used increasingly to allow direct visualization of liver lesions and can be enhanced by intraoperative US. Nuclear medicine techniques such as single positron emission computerized tomography (SPECT) and tagged RBC scans, although less commonly applied, may facilitate differentiation of hemangioma from hepatocellular carcinoma. 99mTc-sulfur colloid scanning may help differentiate focal nodular hyperplasia from hepatocellular adenoma.

hemangioma ₍adult₎ Hemangiomata are the most common benign solid tumor of the liver. In terms of focal liver lesions they are second only to simple cysts in frequency. Autopsy studies have shown a prevalence of up to 20% (8). Adult hemangioma differs in both presentation and histology from infantile hemangioendothelioma, which is considered elsewhere. An extremely rare adult

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form of hemangioendothelioma with intermediate malignant potential has been reported (9). Hemangiomata are of mesenchymal origin and probably represent a congenital, hamartomatous proliferation of vascular endothelial cells. Approximately 90% are solitary and structurally, 80% are cavernous hemangiomata, the reminder being capillary hemangiomata (10). Over 90% of hemangiomata are less than 5 cm in diameter, which can occasionally make radiological characterization difficult. Current evidence indicates that hemangiomata have no malignant potential.

capillary hemangioma In comparison to the more common cavernous form, capillary hemangiomata are generally smaller in size and are more frequently multiple. These smaller lesions are a common incidental finding in an asymptomatic patient. Once the diagnosis is established, no further treatment is required (recommendation strength: D).

cavernous hemangioma Pathology Cavernous hemangiomata occur in up to 8% of autopsy studies. These lesions are the second most common solid hepatic tumor (10). Cavernous hemangiomata occur principally in women (F:M = 5:1) and are more common in the right liver. Large peripheral lesions may become pedunculated. The mean age at diagnosis is 50 years with most being detected between the third and fifth decade. Their prevalence is greatest in those with higher parity (11,12). Although there is no proven association with oral contraceptive use, the relationship remains controversial. Hemangiomata are generally asymptomatic until they reach diameters of over 10 cm. Symptoms include non-specific abdominal pain, pressure symptoms, and fever. Pain may be due to capsular stretching by larger lesions. Jaundice and rupture are rare. Cavernous hemangiomata may reach massive proportions, with reported lesions reaching several kilograms in weight. Giant hemangiomata are defined as those measuring 5 cm and above in diameter (13) and are multiple in 10% of cases (10). Hepatic cavernous hemangiomata may be associated with similar lesions in other organs (14). Other associated conditions, for example, liver cysts, gallbladder disease, gastroduodenal ulcers, or hiatus hernia are reported in 42% (15). In the rare Kasabach–Meritt syndrome intravascular coagulopathy may progress to systemic fibrinolysis and thrombocytopenia. The condition has a reported mortality rate of 20% to 30% (16). Macroscopically, cavernous hemangiomata appear purplish in color and may collapse on sectioning. A plane can generally be identified between the hemangioma and surrounding liver parenchyma. Thrombosis, fibrosis, and calcification are common features (Fig. 29.1). Cavernous hemangiomata may undergo complete fibrous transformation. Hemorrhage is remarkably rare and rupture exceptional. This lesion probably represents a congenital hamartoma with endothelium-lined spaces and fibrous septa being typical microscopic features. Lesions enlarge through ectasia rather than hypertrophy or hyperplasia.

BENIGN SOLID TUMORS OF THE ADULT LIVER accepted, except as a temporizing measure to facilitate transfer of an emergency patient. The application of radiotherapy and corticosteroids is also reported but is not well supported by evidence.

focal nodular hyperplasia ₍fnh₎ and fnh-like lesions

Figure 29.1 Typical macroscopic appearances of hemangioma on sectioning of resection specimen.

Imaging Features Hemangiomata are usually hyperechoic on US, although US is often inadequate for differentiating between solid liver lesions. Color-flow Doppler shows peripheral vessel filling. Axial imaging with CT or MRI is usually sufficient to confirm the diagnosis. The principle challenge in managing small (<3 cm) hemangiomata is differentiating them from other lesions, particularly in cases with atypical enhancement and significant arterio-venous shunting. Lesions tend to be hypodense on non-contrast CT and show peripheral followed by central enhancement. Isoenhancement with the arteries is typical. Delayed scans show persisting contrast enhancement and features such as corkscrewing and “cotton wool” appearance reflect the abnormal vessels within the lesion. Globular enhancement isodense with the aorta has been shown to be 67% sensitive and 100% specific in differentiating hemangiomata from metastases (17). Hemangiomata are hypointense on T1-weighted sequences. They appear very bright on T2-weighted sequences (the “light bulb sign”). Peripheral nodular enhancement on dynamic gadolinium-enhanced images and a non-intact ring appearance immediately after contrast with centripetal enhancement (maximal at 90s) are typical. Hemangiomata do not take up SPIO or manganese dipyridoxyl ethylenediamine diacetate (bis)phosphate (Mn-DPDP) as they do not contain Kupffer cells or hepatocytes. 99mTc-SPECT is effective in assessing hemangiomata but appears inferior to MRI (18). Management Biopsy of hemangiomata is generally contraindicated given the risk of hemorrhage and samples obtained from hemangiomata may resemble fibrosis. Resection may be justified rarely for symptomatic lesions and in cases where the diagnosis cannot be established despite investigation. Surgical resection or enucleation remains the principal effective therapies (19). Use of liver transplantation has been reported for unresectable disease in association with Kasabach–Merritt (20). The use of arterial ligation and embolization has not been widely

Pathology FNH occurs in up to 3% of the population and is the second most common solid benign liver lesion after hemangioma (21,22). Ninety percent of patients are females in their second and third decades, although cases have been reported in males. Less than 10% of FNH is symptomatic and, in contrast to hepatocellular adenomata, hemorrhage and rupture are rare (23). Presence of hemorrhage raises the possibility that a hepatocellular adenoma has been misdiagnosed as FNH. The incidence of FNH is increasing, although this increase appears unrelated to oral contraceptive introduction. The effects of female sex hormones on the natural history of FNH remain controversial. However, discontinuing oral contraceptive use may be associated with a decrease in size of FNH (24,25). There is insufficient evidence to recommend avoiding pregnancy in the presence of FNH. FNH usually forms a firm lobulated lesion in otherwise normal liver (Fig. 29.2) and is more common in the right liver (26). Lesions are typically well circumscribed but lack a definite capsule. Differentiating FNH from other focal liver lesions, particularly hepatocellular adenoma, remains a challenge. The “classical” finding of a central scar (Fig. 29.3) may be absent in approximately 40% of FNH cases (27). Twenty percent of patients exhibit multifocal FNH and up to 20% of FNH coexist with hemangiomata (28). FNH and adenomata may also coexist. A histological diagnosis of FNH does not mean coexisting lesions will also be FNH. Furthermore, co-existing malignancy is reported in 6% of patients with an indeterminate presumed benign liver lesion (29). NH has a microscopic appearance similar to that of cirrhosis, exhibiting regenerative nodules. Normal hepatocytes with intervening connective tissue septa and bile ductules are typical. FNH is thought to be a hyperplastic response to abnormal vascularization, rather than a neoplastic process and is not regarded as having malignant potential (23). Moderate lymphocytic infiltration and mild cholestasis are common. It is unusual for FNH to undergo rapid changes in size and this should call the diagnosis into question. Calcification is a less common finding, occurring in approximately 1.4% of cases (30), and should alert the clinician to the possibility of fibrolamellar hepatocellular carcinoma. Telangiectatic FNH Telangiectatic FNH (TFNH) accounts for 10% to 15% of FNH cases and usually presents with multiple soft nodules without a central scar (31). Intra-lesion bleeding is more common in TFNH than in FNH. TFNH lesions commonly exhibit high levels of angiopoietin 2 gene expression (32). Although the origin of TFNH remains controversial, it is regarded by some as a neoplastic lesion and may in fact represent a variant of HA rather than a subtype of FNH.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Figure 29.2 Characteristic lobulated appearance of focal nodular hyperplasia.

FNH-Like lesions FNH-like lesions have close histological similarity to FNH. Although due to a variety of processes, the common etiological factor appears to be abnormal liver vascularity, specifically increased arterial flow and decreased venous flow. Investigators have noted that FNH and hepatic adenomata occur more often in patients who have coexisting vascular tumors, portal venous thrombosis or occlusion, and those with significant portohepatic venous shunts (33,34). Other conditions associated with FNH-like lesions include Budd–Chiari syndrome, hereditary hemorrhagic telangectasia, and congenital hepatic fibrosis. FNH-like lesions have a tendency to increase in number or size, unlike “classical” FNH. Imaging Features Radiological diagnosis of FNH can be challenging and a multimodality approach is often required. CT has a reported 82% sensitivity and 97% specificity (35). A well-defined hypervascular lesion with a single central artery and spoke wheel centrifugal vessel filling is typical. FNH and FNH-like lesions are hyperintense T1-weighted MRI and hypointense on T2-weighted series. Strong arterial enhancement is often observed. MRI has a reported sensitivity of 70% and a specificity of 98% (36). In a recent study, differentiation between HA and FNH was not possible on the basis of precontrast or dynamic phase images alone. However, images acquired 1 to 3 hours after gadobenate dimeglumine enhancement, allowed differentiation between FNH and HA/adenomatosis with a specificity, PPV, NPV, and overall accuracy of 96.9%, 100%, 100%, 96.4%, and 98.3%, respectively (37). Management Management of patients with FNH and FNH-like lesions depends on the level of certainty of diagnosis. Once the diagnosis of FNH is established with confidence, no further intervention is required. In cases of diagnostic uncertainty, laparoscopic or open biopsy may be helpful and may be preferable to percutaneous needle biopsy. Although observation may be more appropriate for some patients, resection or

264

Figure 29.3 Classical central scar of focal nodular hyperplasia.

enucleation is preferred in most cases if surgery can be achieved safely (recommendation strength: D).

hepatocellular adenoma Pathology Hepatocellular adenoma is usually identified as a solitary lesion in an otherwise normal liver. Adenomata are well defined but lack a capsule. Approximately 90% occur in women, most being diagnosed in the third to fifth decade. The lesions occur more commonly in the right liver. Adenomata are significantly less common than both hemangiomata and FNH. Ninety percent of patients report oral contraceptive use. The incidence is 3–4/100,000/year if oral contraceptive use has exceeded 2 years and their diagnosis has increased following the introduction of the oral contraceptive (38). Higher dose and longer duration of oral contraceptive use appear to promote adenoma development. Anabolic steroid use is also a risk factor for the development of a hepatocellular adenoma. Patients may present with pain due to hemorrhage into or rupture of an adenoma. The risk of bleeding is increased in larger and rapidly growing adenomata, and in patients using OCP, particularly when use is prolonged (39). Hepatocellular adenomata are associated with abnormalities of carbohydrate metabolism. Adenomata are observed more frequently in glycogen storage disease type 1 (glucose-6phosphatase deficiency), type 3 (glycogen debrancher deficiency), galactosemia, and iron overload. In these patients, adenomata develop at an earlier age and tend to show a male preponderance (2:1) (40,41). Sectioning reveals a yellow or pale brown tumor with surrounding normal tissue and a variable degree of encapsulation (Fig. 29.4). There may be evidence of hemorrhage (Fig. 29.5). Adenomata are generally uniform masses consisting of benignappearing hepatocytes without ducts or portal triads. Hepatocytes are pale due to increased levels of glycogen or fat. Venous lakes (peliosis hepatis, vide infra) may be present. Initially, Kupffer cells were thought to be absent from adenomata but molecular techniques have confirmed their presence in these lesions. However, adenomata generally do not sequester 99m Tc-sulfur colloid which is taken up preferentially by Kupffer

BENIGN SOLID TUMORS OF THE ADULT LIVER

(A)

(B)

Figure 29.4 (A) Intraoperative image of pedunculated peripheral hepatocellular adenoma. (B) Section through resected hepatocellular adenoma.

PET appears to be useful in differentiating benign from malignant liver lesions (43) and 11C-acetate PET may have additional benefit in detecting HCC. In a study by Ho et al., benign tumors, such as adenomata and hemangiomata, were not 11C-acetate-avid. FNH showed only mild 11C-acetate uptake (44).

Figure 29.5 Recent hemorrhage into hepatocellular adenoma.

cells. Adenomata fall into three molecular pathological subgroups: (1) those with inactivated hepatocyte nuclear factor 1-alpha (HNF-1alpha, chromosome 12q)-, (2) those with betacatenin activation, and (3) those with inflammatory changes. These subtypes reportedly display differing characteristics on MRI (42). Imaging Features Hepatocellular adenomata are usually heterogeneous in appearance on US. CT appearances are iso/hypodense precontrast with variable enhancement. There may be evidence of recent hemorrhage or infarction. MRI demonstrates a well-defined fatty lesion which is iso/ hyperintense on T1 sequences and mildly hyperintense on T2 MRI. Gadolinium-enhanced studies show hypervascularity in the arterial phase. Enhancement is often heterogeneous. Angiography demonstrates a peripherally supplied hypervascular lesion with areas of hypovascularity due to hemorrhage or infarction. Isotope scanning may help differentiate hepatocellular adenoma from FNH, an adenoma appearing as a filling defect (“black hole sign”).

Management In cases of acute hemorrhage, resuscitation may be combined with hepatic arterial embolization or laparotomy and packing to facilitate transfer to a specialist center. Formal hepatic resection represents optimal treatment for this group of acute patients, although this may be deferred in a stable patient with confined hemorrhage (recommendation strength: D). Discontinuing oral contraceptive use is probably advisable since there have been reports of lesion regression on their cessation, although there is little compelling evidence to support this position for all patients (recommendation strength: D). Although adenomata may regress following discontinuation of the oral contraceptive (45,46), malignant transformation has also been reported despite its discontinuation and in contraceptive-naive patients (47). Adenomata are currently thought to be premalignant with an approximate transformation rate of 10% (48). Transformation should be suspected in adenomata that increase in size, particularly in conjunction with increasing alpha-fetoprotein levels. The risk of malignant transformation is higher in males and in patients with large lesions. Difficulties in differentiating adenomata from FNH or HCC are commonly encountered in young female patients. Because of the abnormal vasculature typical of these lesions, biopsy is associated with a significant risk of hemorrhage and is generally contraindicated. In summary, if a focal liver lesion is suspected to be an adenoma, surgical resection should be considered, especially for symptomatic or large (5 cm or more in diameter) adenomata, provided resection can be accomplished safely (49) (recommendation strength: C).

hepatocellular adenomatosis Pathology Hepatocellular adenomatosis is a rare condition, first recognized by Flejou et al. in 1985 (40). The condition is defined

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS arbitrarily as the presence of 10 or more adenomata (50). Adenomatosis appears to be a different pathological entity from the solitary adenoma, having a more equal sex distribution and no association with oral contraceptive use (48). Hepatocellular adenomatosis is associated with maturity-onset diabetes of the young (MODY). Adenomatous hyperplasia is often observed between lesions. Intervening cells are smaller with cytoplasm that appears lighter than normal. Mutations in the transcription factor 1 gene (TCF1) occur in MODY (the most common form, termed MODY3) and biallelic inactivation of TCF1 has been reported in hepatic adenomas. In contrast, TCF1 inactivation is not a feature of FNH. Management Patients with hepatic adenomatosis and a TCF1 mutation should be monitored for future onset of diabetes mellitus, if not already diagnosed. Family members of patients with the TCF1 mutation should be considered for genetic screening for such mutations or liver imaging. Liver adenomatosis also carries a risk of malignant transformation, similar to that of the solitary adenoma. Close follow-up in asymptomatic patients with regular liver imaging and serum alpha-fetoprotein estimation is advised to monitor for the potential complications of hemorrhage and malignant transformation (recommendation strength: D). In rare situations, orthotopic liver transplantation has been employed to treat extensive disease that progresses to liver failure, for malignancy, or for unresectable solitary lesions (51,52). Regenerative Changes Regenerative Nodules The cirrhotic liver is defined by the presence of fibrosis and nodules, which include regenerative nodules, dysplastic nodules, and hepatocellular carcinoma. Terms such as macroregenerative nodule and adenomatous hyperplasia have been superseded by a new classification of regenerative nodule, with or without low- or high-grade dysplasia (Terminology of nodular hepatocellular lesions, International Working Party (53)). Currently, agreed nomenclature envisages a progression of carcinogenesis from regenerative nodule to low-grade dysplastic nodule to high-grade dysplastic nodule to small then large hepatocellular carcinoma. Macroscopically, regenerative and dysplastic nodules appear similar although they may differ in color. In addition to the cirrhotic liver, these lesions may develop in the context of Budd–Chiari syndrome. These lesions are generally 0.8 to 3 cm in diameter. Dysplastic nodules may show signs of nuclear atypia, increased cytoplasmic fat or glycogen, and focally decreased reticulin staining is common. Differentiating dysplastic nodules from hepatocellular carcinoma by imaging or histopathology remains problematic. Imaging Features and Management US features are variable. CT may show high attenuation on pre-contrast CT with low attenuation on arterial phase although regenerative nodules in the context of Budd–Chiari are often hypervascular and multiple. MRI: T1 variable, T2 low intensity. Reliable differentiation of regenerative nodules from dysplastic nodules is beyond the

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capacity of current MRI technology (54), although high-grade dysplastic nodules may increase in size, display high intensity on T1-weighted MRI, and show increased vascularity (55). Any nodule within the cirrhotic liver that increases in size, shows altered signal or increased enhancement warrants correlation with alpha-fetoprotein and early serial imaging and should be regarded as suspicious for hepatocellular carcinoma (recommendation strength: D). Nodular Regenerative Hyperplasia This often asymptomatic condition usually affects patients over 50 years of age and is reported to occur in 2% autopsy livers (56,57). The etiology of NRH remains unclear, although it is associated with a range of lymphoproliferative and rheumatological disorders and may occur post-transplantation. Associations with a range of therapeutic drugs are reported. NRH is a benign diffuse nodular transformation and differs from the regenerative nodules found in cirrhosis and FNH. The hepatic parenchyma is entirely replaced by nodules between 0.1 and 4 cm in diameter. Hepatocyte hyperplasia separated by atrophic parenchyma with reticulin collapse and sinusoidal dilatation is typical. The diagnosis should be considered in patients with portal hypertension and mild liver function abnormalities without cirrhosis on liver biopsy. Portal hypertension and cholestasis may occur due to intrahepatic compression. Laparoscopic or open biopsy is usually required for diagnosis but NRH may be difficult to differentiate from hepatocellular adenoma, which forms a discrete lesion as opposed to the diffuse changes of NRH, on isolated biopsy. Needle biopsy may also not uncommonly yield normal liver tissue. Imaging Features and Management Imaging is often non-specific or normal, although NRH may cause pseudotumor formation. The lesions appear hypo/ isoechoic on US and display variable enhancement on CT. Lesions appear hyperintense on T1-weighted MRI and iso/ hypointense on T2-weighted sequences. NRH may rarely undergo malignant transformation and monitoring is therefore recommended (recommendation strength: D). Treatment involves the management of associated portal hypertension. NRH may result in liver failure that may necessitate liver transplantation. Biliary Hamartoma (Von Meyenburg complex) Biliary hamartomata are benign developmental abnormalities of the liver. Although biliary hamartomata occur in over 5% of the population, they are principally of clinical interest due to the frequency of their submission for intraoperative frozen section to differentiate them from metastases. They are usually less than 5 mm in diameter and multiple lesions are common. Imaging Features and Management Such lesions are often not apparent on preoperative imaging because of their size and US features are non-specific. CT usually shows a hypodense lesion without contrast enhancement. MR features are hypointense on T1-weighted images and strongly hyperintense on T2-weighted MRI. MRI contrast

BENIGN SOLID TUMORS OF THE ADULT LIVER enhancement is variable although rim enhancement may occur due to compression of adjacent parenchyma. Microscopic features include bile ductules with enlarged lumina, inflammatory infiltrate, and fibrosis. Association with adult polycystic disease has been reported. No treatment is required (recommendation strength: D). Biliary Adenoma This benign cholangioma is a generally well defined and often subcapsular lesion, usually less than 1 cm in diameter. Microscopically a proliferation of non-cystic biliary structures with fibrous stroma is observed. The presence of mucin, but not bile, is typical. Although histological differentiation from hamartomata may be challenging, the practical significance of this is limited. Imaging Features and Management Early nodular enhancement, which is prolonged is usual on CT. Bile duct adenomata have no malignant potential but may require excisional biopsy to allow differentiation from the bile duct proliferations found in FNH as well as from some poorly differentiated adenocarcinoma of the biliary tract type. Once diagnosed no treatment is required (recommendation strength: D).

congenital hepatic fibrosis This rare autosomal recessive fibropolycystic condition results from malformation of the ductal plate and may lie on a continuum with Caroli’s disease, the latter involving larger ducts, in contrast to CHF. This is a multisystem disorder (58), the kidneys being most commonly affected (usually autosomal recessive polycystic kidney disease). CHF is associated with overexpression of transforming growth factor-beta1 and thrombospondin-1 (59). Presentation is usually in adolescence, although presentations in the neonatal period and late adulthood are reported. Intrahepatic portal hypertension is typical, but patients may present a cholangitic or mixed picture. Focal solid liver lesions are reported (60,61). The diagnosis can be often established on axial imaging (62). Management of the manifestations of portal hypertension is the mainstay of treatment. Focal Fatty Variants Steatosis of the liver is usually a diffuse process but fat distribution may be heterogeneous leading to a focal lesion. The diagnosis should be apparent from imaging alone and particularly MRI. Focal Fatty Sparing This diagnosis is usually made radiologically and is most commonly encountered in the posterior aspect of segment 4. These lesions are hypoechoic on US and hyperdense on CT. Hypointensity on T1-weighted MRI is usual. Focal fatty sparing is of no pathological or surgical significance other than requiring differentiation from other focal liver lesions. Focal Fatty Change This abnormality of parenchymal fat distribution usually occurs adjacent to the falciform ligament and may be associated

with obesity, diabetes, alcoholism, steroids, total parenteral nutrition, chemotherapy, and antiretroviral therapy. Imaging Features and Management These fatty lesions are hyperechoic on US and hypodense on CT. Their fat content results in a hyperintense appearance on T1-weighted MRI. Radiological diagnosis usually suffices. If multiple areas of focal fatty change occur, pseudotumoral steatosis may result which can be mistaken for other tumors, and may require confirmatory biopsy. Angiomyolipoma This rare tumor consisting of fat, epithelioid, and smooth muscle cells with thick-walled blood vessels and may occur in association with tuberous sclerosis. Ten percent of patients with tuberous sclerosis and renal angiolipomata have either angiomyolipomata or lipomata (63). Women are predominantly affected. While these lesions often become large and may cause compressive effects requiring resection, malignant transformation has been reported, although this is extremely rare (64). Imaging Features and Management The reliability of diagnostic imaging is impaired by the variable proportion of fat (10–90%) and other constituents the angiomyolipomata contain. Lesions with low-fat content may mimic hepatocellular carcinoma. US examination usually demonstrates a hyperechoic lesion. The lesion is hypodense with arterial enhancement and central opacification on CT. Macroaneurysms may be observed. On MRI, the T1-weighted signal is high. Fat suppressed MR may help confirm the diagnosis. Management consists of observation with resection reserved for patients with symptomatic lesions (recommendation strength: D). Lipoma Hepatic lipomata are less common than angiomyolipomata. Lipomata are generally well defined and homogenous. Imaging Features and Management CT shows a hypodense, non-enhancing lesion. MRI features are hyperintense on T1-weighted series and moderately hyperintense on T2-weighted series. Decreased signal with fat suppression is typical. These lesions consist of well-differentiated adipose tissue and require no treatment (recommendation strength: D).

pseudolipoma These unusual lesions consist of well-differentiated subcapsular adipose tissue and may occur if an adherent fatty structure becomes detached and incorporated into the liver parenchyma. Pseudolipomata may require differentiation form metastasis, although they require no specific treatment. Peliosis Hepatis Peliosis hepatis refers to the development of multiple abnormal vascular channels with secondary fibrosis. This condition is associated with anabolic steroid use as well as with tuberculosis and, in some cases, other tumors.

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Imaging Features and Management The lesion is usually well defined. Arterial enhancement is observed on CT. Peliosis hepatis is hyperintense on T2-weighted MRI and contrast enhancement is observed. Management priorities include withdrawal of potential causative agents and treatment of primary/secondary infection. Malignant transformation is not a feature of peliosis hepatis. Hereditary Hemorrhagic Telangiectasia Hepatic involvement in HHT is recognized (65) and presents as a spectrum from small telangiectasia to large volume lesions, which may be associated with arteriovenous shunting. These lesions are usually asymptomatic and do not generally warrant treatment, although hepato-hepatic fistulas can induce highoutput cardiac failure and hepato-portal fistulas may induce portal hypertension (66). Heterotopic Tissue A choristoma, formed by the abnormal development of tissue of a type not normally found at that site, is an uncommon cause of a focal liver lesion. Intrahepatic heterotopic tissue formation can often be diagnosed radiologically but may require resection or biopsy for definitive diagnosis. Adrenal tissue tends to occur in the subcapsular region and may mimic adenoma. Heterotopic pancreatic tissue is an occasional finding. The origin of these lesions is uncertain although they are probably congenital. Acquired splenic choristoma formation can occur post-splenectomy through autotransplantation of splenic tissue. Nuclear medicine is specific in diagnosing this abnormality. In each of these cases, once the diagnosis of heterotopic tissue is established, no specific treatment is required (recommendation strength: D). Inflammatory Pseudotumor These inflammatory myofibroblastic lesions may exhibit radiological features suggestive of neoplasia. A male preponderance is reported and the average age at diagnosis is 35 years (67). The history is often suggestive of an infective etiology. Pseudotumor formation may occur secondary to thrombosis or infarction, may represent an immune reaction, or may occur as an abscess resolves. Imaging Features and Management The lesion is typically well defined, hyper, or hypoechoic on US hypodense on CT and hyperintense on T2-weighted MRI. Angiography usually confirms a hypervascular lesion. In some cases, pseudotumors can be structurally diffuse and locally destructive. Histopathological examination reveals myofibroblasts, immunocytes, and fibrous tissue. These lesions usually resolve spontaneously and are generally managed non-operatively, although resection may be indicated in some cases to prevent reactivation of infection (recommendation strength: D).

myxoid background with cellular mesenchymal components, hepatocytes, bile ducts, and cystic changes are characteristic. Liver function may be compromised through enlargement and resection may be required. Other rare tumors include myxoma, mesothelioma, leiomyoma, and fibroma. Benign teratoma of the liver is reported although this generally occurs in the pediatric population.

key points ●

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appendix Recommended Grading of Categories of Evidence Ia: Ib: IIa: IIb: III:

Miscellaneous Rare Benign Solid Liver Lesions These lesions are individually very uncommon but as a group represent a significant proportion of benign solid liver lesions. Mesenchymal hamartomas are probably congenital, usually occur in infants but are reported in adults. Histologically a

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Benign liver tumors are increasingly detected due to greater use of improved diagnostic imaging There may be an increasing trend to resect benign lesions with the introduction of laparoscopic surgery Successful management of patients with benign liver lesions requires accurate diagnosis and an understanding of the natural history Most patients with benign liver tumors do not have associated liver disease Benign liver tumors rarely require surgery although, when necessary, centralized expert management minimizes associated morbidity and mortality Inappropriate investigation can lead to morbidity and compromises definitive treatment Hemangioma is the most common solid benign liver tumor Hepatocellular adenomata are rare but are associated with significant complications, are viewed as premalignant and generally warrant resection Hepatocellular adenomata are associated with oral contraceptive use. While controversial, no established links exist for hemangiomata or focal nodular hyperplasia A focal lesion in a cirrhotic liver should be regarded as malignant until proven otherwise Progressive symptoms, an enlarging tumor, complications or raising tumor markers are relative indications for resection

IV:

evidence from meta-analysis of randomized controlled trials evidence from at least one randomized controlled trial evidence from at least one controlled study without randomization evidence from at least one other type of quasiexperimental study evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and case–control studies evidence from expert committee reports or opinions and/or clinical experience of respected authorities

BENIGN SOLID TUMORS OF THE ADULT LIVER Recommended Strengths of Management Recommendation A: B:

C:

D:

directly based on category I evidence directly based on category II evidence or extrapolated recommendation from category I evidence directly based on category III evidence or extrapolated recommendation from category I or II evidence directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence

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30 Liver trauma

Timothy G. John, Myrddin Rees, and Fenella K. Welsh

introduction The size and location of the liver account for its high susceptibility to both blunt and penetrating trauma. The type and severity of liver injuries vary greatly and associated organ injuries are common. The leading cause of death is hemorrhage, with road traffic accidents accounting for an ever increasing proportion of blunt liver injuries. It also presents a large target for penetrating injuries to the trunk and these, including gunshot wounds, can be difficult to manage. The intimate connections between the liver capsule, the major hepatic veins, and the retrohepatic inferior vena cava anchor the liver within the upper abdominal cavity and most of the venous return from the lower body flows within these thin-walled veins. Injuries to these vulnerable, high-volume-flow “juxtahepatic” vessels pose a uniquely challenging aspect of severe liver trauma. Dramatic advances in the management of liver trauma have been reported in recent years and algorithms of management continue to evolve. The last two decades have witnessed a major paradigm shift in the management of liver trauma, with Non-Operative Management of Liver Injury (NOMLI) now firmly established as the standard of care for the majority of patients. For those undergoing surgery, the philosophy of damage control at abbreviated laparotomy prevails and the technique of perihepatic packing has come to serve a dominant role. Multidisciplinary interventions are indispensible in managing both the inevitable consequences of NOMLI and as adjuncts to surgical intervention. Unsurprisingly, little or no Grade I–II evidence exists from randomized or controlled studies of liver trauma, and recommendations for management are based on large descriptive studies, including multiinstitutional prospective cohort studies, and the clinical experience of respected authorities in the field.

classification of liver trauma The importance of a standardized method of classifying liver trauma is fundamental to meaningful comparisons of treatment outcomes. The modern system of injury grading and standardization of care is based on the central role of computerized tomography (CT) in the assessment of liver trauma. The classification of liver injuries described by Moore and coworkers in 1989 (1), revised in 1994 (2), has now been adopted as the “industry standard” by the American Association for the Surgery of Trauma (AAST) (Table 30.1). Early attempts to validate the AAST Organ Injury Scale (OIS) noted good correlation between operative score severity on one hand and transfusional requirements and methods of operative management necessitated on the other (3). Similar conclusions were drawn from a study of 170 liver injury patients (90% blunt trauma) where blood transfusions, surgical interventions, and liver-related morbidity and mortality all correlated well with the grade of injury (4). However, the liver

OIS as determined by pre-operative CT can be fallible and instances of both understaging and overstaging by CT have been documented (3). A recent attempt to validate the AAST OIS identified 14,919 isolated hepatic injuries, and 21,532 with associated injuries, in the American College of Surgeons National Trauma Databank between 2000 and 2004 (5). A significant increase in outcomes including mortality, organ-specific operative rate, and hospital charges were associated with increasing OIS grades.

initial assessment and diagnosis of liver trauma Initial management of the patient with suspected liver trauma follows Advanced Trauma Life Support (ATLS) principles (6) with rapid identification of life-threatening injuries and aggressive fluid resuscitation. The importance of preventing systemic hypothermia during resuscitation and transfer deserve particular emphasis (7). The concept of the “Focused Assessment for the Sonographic examination of the Trauma patient” (FAST) has gained widespread acceptance in the initial rapid screening of the trauma patient for the presence of hemoperitoneum (8). A landmark study of surgeon-performed FAST in 1540 patients with blunt and penetrating truncal injuries reported high sensitivity (83.3%) and specificity (99.7%) for the technique, most pronounced following blunt injury (9). In this way, the invasive, overly sensitive, and non- organ-specific technique of diagnostic peritoneal lavage has become obsolete in the initial assessment of the trauma patient with suspected liver injury. Immediate laparotomy to control intra-abdominal bleeding remains the standard of care in the persistently hemodynamically unstable patient. The Western Trauma Association’s study of death in the operating room following major trauma at eight North American Level I trauma centers between 1985 and 1992 (10) reported uncontrolled hemorrhage as the primary cause of death in 82% of patients, while delays in transfer to the operating room and inadequate perioperative resuscitation were implicated in half the intra-operative deaths judged to have been preventable. Thus, shocked patients not responding to aggressive fluid resuscitation require immediate operation to attempt arrest of intra-abdominal hemorrhage. Alternatively, and more controversially, it has been suggested that selective hepatic arterial embolization may be effective in arresting hepatic arterial bleeding in the hemodynamically unstable patient, especially those who respond to initial fluid resuscitation, and its role extended as an alternative to surgery (11,12) (Fig. 30.1). Ciraulo and colleagues reported an encouraging experience with “resuscitative” angioembolization in “bridging” operative and non-operative management (13). Seven out of 11 patients with CT-determined Grade IV–V blunt hepatic injuries and requiring continuous resuscitation

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS Table 30.1 AAST Liver Injury Scale (1994 Revision) (2) I. II. III.

IV. V. VI.

Gradea

Injury descriptionb

Hematoma Laceration Hematoma Laceration Hematoma

Subcapsular, non-expanding, <10% surface area Capsular tear, non-bleeding, <1 cm parenchymal depth Subcapsular, 10–50% surface area; Intra-parenchymal, <10 cm in diameter 1–3 cm parenchymal depth, <10 cm in length Subcapsular, >50% surface area or expanding Ruptured subcapsular or parenchymal hematoma Intra-parenchymal hematoma >10 cm or expanding >3 cm parenchymal depth Parenchymal disruption involving 25–75% of hepatic lobe or 1–3 Couinaud’s segments within a single lobe Parenchymal disruption involving >75% of hepatic lobe or >3 Couinaud’s segments within a single lobe Juxtahepatic venous injuries; i.e., retrohepatic vena cava / central major hepatic veins Hepatic avulsion

Laceration Laceration Laceration Vascular Vascular

a

Advance one grade for multiple injuries to the same organ. Based on most accurate assessment at autopsy, laparotomy, or radiological study.

b

hemoperitoneum (17) and demonstration of associated intraperitoneal and retroperitoneal injuries (Fig. 30.2). Technical refinements such as the development of rapid spiral CT scanners, protocols optimizing vascular contrast enhancement, and CT-scanning suites adjacent to the emergency department and equipped for critical care monitoring have established the central role of CT in the management of all but the most unstable cases of liver trauma (16). Despite concerns regarding the reliability of CT in the detection of hollow vicious injuries (18), the incidence of missed injuries following non-operative management based on clinical and CT findings is reported to be as low as 0.2% (7). Although reliable predictors of failure of non-operative management are lacking, contrast extravasations (“pooling” or a “blush”) merits emphasis as a cardinal sign of active hemorrhage mandating prompt (angiographic and / or surgical) intervention (7,15,16,19,20) (Fig. 30.3). Fang and colleagues reported contrast pooling in eight out of 150 stable patients treated non-operatively, six of whom (75%) developed hemodynamic instability requiring liver-related laparotomy (20). Figure 30.1 Selective hepatic angiography (right hepatic artery arising from superior mesenteric artery) demonstrates contrast extravasation (arrows). Angioembolization was performed.

were successfully managed by hepatic embolization as definitive therapy. The “alternative” management of hemorrhage from Grade V juxtahepatic venous lacerations by percutaneous hepatic venous stenting has also been reported (14). Clearly much depends on the timing of such intervention and the prompt availability of appropriate expertise (with an operating room on standby) (12,15). Abdominal CT is established as the primary screening modality for the hemodynamically stable patient with suspected blunt liver trauma (16). Detailed cross-sectional imaging of the abdominal organs permits precise delineation of the type and extent of the liver injury, estimation of the volume of

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Non-operative Management of Blunt Liver Trauma (NOMLI) Non-operative management of the majority of patients presenting with blunt liver injury (NOMLI) represents a major paradigm shift in liver trauma management during the last two decades (Fig. 30.2). Analysis of 35,510 hepatic injuries documented in the American College of Surgeons National Trauma Databank revealed a highly significant increase in NOMLI from 75% to 87% between 1994 and 2003 (95.1% for blunt liver injuries) (21). Factors heralding this change include (i) the recognition that as many as two-thirds of patients undergoing surgery on the basis of positive diagnostic peritoneal lavage were found to have relatively trivial injuries during non-therapeutic laparotomy (22–24), (ii) the improved imaging with abdominal CT and less concern regarding missed injuries (15,25), (iii) the precedents for successful nonoperative management of solid organ injuries documented in

LIVER TRAUMA

Figure 30.2 Grade V blunt liver trauma associated with right renal hematoma in a hemodynamically unstable patient responding to fluid resuscitation and angioembolization.

the pediatric literature (26–30), (iv) a better understanding of the pathophysiology and natural history of the injured and healing liver (31), and (v) the availability of adjunctive interventional techniques to deal effectively with the inevitable consequences of the non-operated liver injury (15). High success rates with NOMLI have been reported. Pachter and Hofstetter’s multi-center study of 404 patients in 1995 reported NOMLI in 98.5% of patients with just two liverrelated deaths (32). A collective review of 16 published series comprising 609 adult patients with liver trauma managed non-operatively between 1988 and 1997 reported success rates of 84% to100%, mean hospital stays of 11.5 to 16.6 days and mean transfusional requirements of 1 to 4 units (19). Others confirm that NOMLI may be undertaken in 85% to 95% of all adult patients with blunt liver trauma (15,23,24,30,33,34). It is generally accepted that the adoption of non-operative management, in place of the pre-1990s practice of liberal operative intervention, has heralded a substantial reduction in the mortality historically, associated with severe blunt liver injuries (7,15). Although it remains difficult to predict in whom NOMLI will fail, increased experience and confidence has lowered the threshold for attempting non-operative treatment to include all hemodynamically stable patients (i.e., systolic blood pressure >90 mmHg) without the signs of peritonitis, regardless of age, injury grade, or associated injuries (35). It should be emphasized that it is hemodynamic status and not the grade of liver injury which determines decision making. The patient typically at risk of failure of NOMLI, most often because of intra-abdominal bleeding, has been characterized as having a high-grade liver injury and remaining dependent on ongoingfluid resuscitation with persisting acidosis (35). Complications of Non-operative Management Contamination of the peritoneal cavity with blood and bile is an inevitable consequence of non-operative management of the fractured liver and both localized peritoneal signs and a

Figure 30.3 Abdominal CT performed after perihepatic packing for blunt liver trauma showing intra-parenchymal contrast extravasation (arrow). The patient was transferred from the referring hospital and underwent day 1 relaparotomy because of deteriorating LFTs and evidence of the abdominal compartment syndrome.

systemic inflammatory response may be expected. The anticipation and management of specific complications is integral to the successful non-operative management of severe liver injuries. Typically these include arterio-venous fistulas, bile leaks, intra- or peri-hepatic abscesses, and vascular-biliary communications (bilhemia and hemobilia). Such complications should be regarded as virtually obligatory consequences of non-operative management (36). This re-defines the philosophy of surgical abstention recognizing that delayed surgery and/or interventional procedures should be deemed an inherent part of the overall management plan rather than treatment failure. Carillo and colleagues reported that 32 patients out of 135 (24%) with severe blunt liver trauma managed non-operatively during 1995 to 1997 developed such complications (15). Strategies employed in their treatment included angioembolization (37%), CT-guided drainage of collections (31%), ERCP (25%), and laparoscopic drainage of collections (7%). A more recent multicenter study of 453 patients with Grades 3 to 5 blunt liver trauma managed by NOMLI at seven urban level 1 American trauma centers between 2000 and 2003 revealed 87 complications in 61 patients (13%)(37). Similarly, these comprised bleeding, biliary complications, abdominal compartment syndrome, and infective complications, which required 86 multimodality interventions. Hemorrhage Ongoing or recurrent bleeding in the non-operatively managed patient is typically recognized by hemodynamic instability with a gradually declining hematocrit and the requirement for repeated transfusions at an early stage. Angioembolization is usually effective for the relatively small proportion of patients who exhibit the signs of early ongoing hemorrhage or late re-bleeding, though this is unusual beyond 3 days postinjury (37). Liver enzyme derangement is common in the

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS aftermath of severe blunt liver trauma, though escalating serum transaminases reflect ongoing hepatocellular damage and may prompt further intervention. An algorithm for management of delayed hemorrhage following blunt liver injury instituted by Carillo and colleagues (15,19) is shown in Fig. 30.6. Biliary Complications (Algorithm from Wahl et al. (38)) Clinically significant biliary complications following NOMLI affect less than 5% of patients (7,34,39) and are typically heralded by elevated serum bilirubin and worsening abdominal pain. Bile collections are amenable to percutaneous drainage that, alone, may lead to resolution in 70% of cases (40). Biliary decompression by ERCP, sphincterotomy, and endobiliary stent insertion is indicated if a bile leak persists (15,41,42). Biliary complications tend to occur at a later stage than bleeding (mean 12 days post-injury (37)) and it has been suggested that screening with HIDA scans may increase detection and facilitate earlier intervention, especially in patients who have undergone angioembolization (38). Bile peritonitis may require laparotomy, although laparoscopic peritoneal washout of the old blood and bile with drain insertion has obvious advantages and has become mainstream therapy (15,36–38,43). Biliary stricture formation following intra-hepatic bile duct disruption is a less well understood aspect of the pathophysiology of blunt liver injury and seems to be rare. Disruption of the gall bladder or extra-hepatic bile ducts is also rare and usually follows more severe trauma in association with hepatic parenchymal or pancreatic injuries (44). Interventional procedures are unlikely to suffice following major central biliary injuries and surgery is usually required. Cholecystectomy, operative cholangiography, temporary external drainage, and delayed bilio-enteric reconstruction are the mainstays of treatment. Hemobilia and bilhemia are uncommon consequences of traumatic vascular–biliary communication. Intra-hepatic pseudoaneurysm formation is implicated in hemobilia which is characterized by pain, deranged liver function tests, jaundice, anemia, and overt gastrointestinal bleeding. Angioembolization, with or without ERCP (for evacuation of blood from the biliary tree) fulfill both diagnostic and therapeutic roles in the management of traumatic hemobilia (15,45–48). Bilhemia occurs because of hepatic venous-biliary disruption and is characterized by jaundice with a massive rise in serum bilirubin (>2000 μmol/L) disproportionate to any abnormality of liver enzymes. Successful resolution has been reported following endoscopic biliary decompression, hepatic venous embolization, and/or occlusion of the fistula with selective endobiliary tissue glue injection (49,50). Intra-abdominal Sepsis The prime role of CT in the diagnosis and guided drainage of delayed intra-hepatic abscesses or perihepatic collections following NOMLI is well established (15), although some patients may still require operative drainage. Abscesses typically complicate liver necrosis in patients with high grade liver injury managed non-operatively, particularly following angioembolization (35), and also following hepatic artery ligation in the operated patient where liver resection may be required (37).

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Abdominal Compartment Syndrome It has been recognized relatively recently that Abdominal Compartment Syndrome (ACS) may complicate NOMLI, as well as the better recognized scenario following laparotomy. Intra-abdominal hypertension (pressure > 25 mmHg) complicating NOMLI has been associated with high volume resuscitative infusions of fluid and blood and in patients managed by angioembolization in particular (51,52). Intra-abdominal pressure monitoring, the recognition of the clinical manifestations of ACS and expedient decompression by laparotomy (35), laparoscopy (51), or percutaneous drainage (52) are required to drain the responsible blood and/or bile-stained intra-abdominal fluid. Consequently, respiratory, renal, and gastrointestinal complications are usually resolved without necessarily compromising the tamponade effect on the underlying liver injury. Follow-up of Liver Injuries In practice, sequential CT scanning is commonly performed, particularly in those with higher grade liver injuries (53). However, there is little evidence to support routine repetition of scans. Cox and colleagues reviewed the outcomes of NOMLI in 530 patients and reported a change of management (angiography or percutaneous drainage) based on repeat CT findings in just three cases in whom clinical signs were anyway apparent (54). Finally, although early mobilization may seem counterintuitive during NOMLI, a large retrospective study recently reported that routine mobilization within 72 hours of admission seemed not to contribute to the risk of delayed hemorrhage (55). Gunshot Wounds to the Liver—The Role of Non-operative Management Liver gunshot wounds (LGSWs) present unique problems because of extensive hepatic parenchymal fragmentation together with a high incidence of associated organ and vascular injuries. Operative management has traditionally been regarded as mandatory. Non-operative management of LGSWs is therefore controversial and its role has tend to be restricted to very carefully selected patients in an environment of intensive monitoring (35,56). The challenge of managing LGSWs nonoperatively was highlighted by Demetriades and colleagues who reported that, of nearly 1000 patients presenting with abdominal gunshot wounds to a level I trauma center, successful non-operative management was accomplished in just 11 out of 16 selected cases (7% of all liver injuries or 21% of isolated liver injuries) (57). Important pre-requisites for non-operative management of LGSWs include: hemodynamic stability without blood transfusion, minimal, localized abdominal signs, and the absence of associated injuries which preclude adequate serial physical examination, and abdominal CT scanning plays a key role in this regard (58,59). Accordingly, a report from Cape Town, South Africa, describes successful non-operative management of LGSWs in 31 out of 33 selected patients regardless of liver injury grade (59). A recent update from the same group cites successful NOMLI for LGSWs in 58 out of 63 patients (92%) without mortality (60).

LIVER TRAUMA Angioembolization plays an important role in this group of patients for treatment of false aneurysms or active bleeding (56,57). It remains to be seen whether diagnostic laparoscopy will be increasingly adopted to identify the isolated non-bleeding LGSW as suggested by some (61–64). Early Decision Making During Laparotomy Arrest of hemorrhage is the priority at initial operation and rapid decision making is required of the surgeon who encounters major liver injury at laparotomy. Most liver injuries are relatively minor and can be dealt with by simple maneuvers such as bimanual compression of the adjacent parenchyma, diathermy or suture ligation of visible bleeding points. Ongoing bleeding which is not easily controlled in this way requires temporary vascular inflow control by the Pringle maneuver, which serves both therapeutic and diagnostic roles. Grade IV–V injuries with hepatic venous/caval lacerations may not respond to inflow occlusion and any attempts to mobilize the liver or inspect the retrohepatic space may be met with profuse venous bleeding. Consideration of perihepatic packing as the mainstay of the Damage Control Laparotomy (DCL) should now occur (65–67). Perihepatic Packing Perihepatic packing is acknowledged as one of the most important factors in reducing the mortality following liver trauma in recent years (7). Temporary resuscitative packing may be distinguished from definitive therapeutic packing. The former aims to achieve hemodynamic stability, allows the surgeon to regain his composure, repair other priority vascular injuries, await more experienced surgical assistance, and/or facilitate transfer to a major trauma or hepatobiliary center for definitive treatment (67,68). Pack tamponade is the key maneuver underpinning the philosophy of “surgical restraint” and “damage control” during abbreviated laparotomy (69). Its judicious use may pre-empt the rapid cascade of events leading to refractory hypotension, dilutional coagulopathy, hypothermia, acidosis, and metabolic failure. A decision can then be taken either to attempt definitive control of bleeding or to proceed with therapeutic packing with abdominal closure and staged reoperation. The timing of the decision to pack is critical and the avoidance of packing as a desperate last resort when all other measures have failed should be emphasized (70). Indeed, a multicenter study identified failure to recognize the value of timely packing as the most common scenario in which patients died from fatal exsanguinations in the operating room (10). Furthermore, initially effective packing may engender a false sense of security when a “pack and peek” sequence develops and it is important to avoid the vicious cycle of repeated packing, resuscitation, unsuccessful attempts at definitive hemostasis, and repeated re-bleeding into shock (71). Perihepatic packing requires careful insertion of large, folded, dry gauze laparotomy packs around the diaphragmatic surfaces of liver and aims to restore its external contours (66,67) (Fig. 30.3). Sufficient packs must be inserted to provide adequate external counterpressure to achieve tamponade (without causing abdominal compartment syndrome), most of this

external force being provided by the body wall and rib cage following wound closure. In this regard, Krige and colleagues describe a “six-pack technique”(72). The patient is later returned to the operating room for re-laparotomy and pack removal according to the progress of metabolic recovery. The Cape Town experience supports delay of liver pack removal beyond 48 hours without increased risk of septic complications or bile leaks, whereas early re-look laparotomy performed within 24 hours was associated with re-bleeding (73). A refinement in therapeutic perihepatic packing is the “mesh hepatorrhaphy” technique which employs a synthetic (polyglycolic acid or polygalactin) absorbable mesh and obviates the need for re-laparotomy (74). The technique seems logical for extensive lobar stellate lacerations, but unsurprisingly is ineffective in instances of juxtahepatic or caval injury and does not seem to have achieved widespread acceptance. Similarly, the use of a non-permeable “liver bag” following failure of conventional packing has been described (75). Refractory Bleeding Following Perihepatic Packing Continued bleeding through the packs that ceases with the Pringle manouevre and recurs with its release indicates hepatic arterial bleeding. Selective hepatic artery ligation remains an option although is regarded by some authorities as obsolete (76,77) and of historical interest only (78). Rather, postoperative transfer to the angiography suite for selective angioembolization has been identified as a major advance in this scenario (42,79). Asensio and colleagues reported early angioembolization as an adjunct to surgical intervention in 23 out of 57 survivors (40%) with grades IV–V liver trauma, and the use of angiography in this way was identified as a significant independent predictor of outcome associated with decreased mortality (80). Persistent bleeding despite inflow occlusion suggests retrohepatic caval or hepatic venous injury and critical decisions must be made regarding the next level of intervention and whether to attempt definitive control of parenchymal / vascular bleeding with or without debridement of devascularized parenchyma (Fig. 30.4). Definitive Surgical Procedures in Complex Liver Trauma The latter option requires the use of one or more recognized manouevres. Although these techniques all have their proponents and detractors, they are nevertheless not mutually exclusive. No controlled trials exist to provide an evidence base for the superiority of one particular method over the other and much depends on anecdote, local expertise, and individual experience. Hepatotomy and Selective Vascular Ligation Rapid exposure and selective vascular suture/ligation of deepseated, actively bleeding, intra-hepatic vessels under hepatic inflow control have long been advocated as a mainstay in some centers (7). In the series of 107 patients with Grade III–IV liver injuries reported from New York, finger-fracture hepatotomy technique was successful in controlling hemorrhage in no less than 100 cases (93.5%) for a cumulative mortality of 15% (81). It should be noted, however, that 83% of these patients had penetrating injuries. Similarly, Beal reported the use of

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

Figure 30.4 Laparotomy and perihepatic packing was performed for postangioembolization hemodynamic instability. The patient continued to bleed and re-laparotomy with hepatic segmentectomy 7/8 and repair of a middle hepatic vein laceration was performed.

hepatotomy in 53 out of 121 patients (44%) with complex liver trauma, citing success in 87% of cases (71). The popularity of the technique in large North American trauma centers during the 1980s is evidenced by its reported use in approximately 43% of nearly 3000 collected cases of complex hepatic trauma (71,82,83), and in 28 out of 85 (33%), such cases reported from Cape Town (72). Non-anatomic Resection In the nomenclature of non-anatomic liver resection for trauma, Strong and colleagues emphasized that such procedures are appropriately defined as either partial resections, where devascularized liver peripheral to the fracture line is removed, or resectional debridement, which involves limited removal of non-viable liver bordering the injury (76). Such atypical liver resections may be performed during the index operation after hemostasis has been achieved, or during subsequent staged re-operations following therapeutic perihepatic packing. The limited removal of non-viable tissue in this way has gained popularity as part of the philosophy of surgical restraint in the management of severe liver trauma, as distinct from the more aggressive approach of definitive anatomical hepatic resection. Specific Manouevres for Control of Hemorrhage from Juxtahepatic/Caval Injuries Liver injuries involving the retrohepatic vena cava and hepatic veins are the most difficult and deadly, and are associated with mortality rates of 50% to 80% (81,83–86). Buckman and colleagues have classified two patterns of juxtahepatic injury: Type A intra-parenchymal hepatic venous injuries, and Type B extraparenchymal venous wounds (86). Type A injuries are probably more common, with predominant bleeding through the associated disrupted hepatic parenchyma and capsule. Restoration of containment by perihepatic packing may achieve tamponade of hemorrhage from high flow or low pressure intra-parenchymal veins in such cases. Thus, Beal reported success with packing in 20 patients with Grade 5 venous injuries (71). Similarly, Strong and colleagues observed that this manouevre, while not

276

always achieving complete hemostasis and hemodynamic stability, nevertheless permitted patient transfer and avoided early death from exsanguinations (76). Type B juxtahepatic injuries implicate extra-hepatic venous avulsion with uncontained hemorrhage around the liver, and are likely to require additional operative measures when the severity of hemorrhage defies control by perihepatic packing (86). Such injuries are more likely to require exposure and direct vascular control. Total hepatic vascular isolation, with cross-clamping of both suprahepatic and infrahepatic segments of the IVC (87), may seem a daunting prospect to the uninitiated in the face of heavy bleeding, and the hypovolaemic patient may not tolerate trial caval occlusion without circulatory collapse. Also, reperfusion with gut endotoxins may cause tachyarrhythmias following clamp removal. However, good results have been reported for direct repair of penetrating juxtahepatic IVC injuries when total vascular isolation techniques were employed (88). Khaneja and co-workers reported operative survival in nine out of ten such patients presenting with Grade V stab and gunshot wounds between 1988 and 1996 for an overall survival of 70% (88). Others have reported more modest survival rates of 42% following direct venous repair (89). The concept of atrio-caval shunting (84,85,90) seems logical but in reality outcomes have been poor with >90% mortality and the technique is generally regarded as obsolete (77). Anatomical Hepatic Resection The decision to embark upon an anatomical liver resection for complex liver trauma must be regarded as one of the most difficult and controversial as most authorities emphasize a policy of conservative surgery and damage limitation. Detractors of formal resection cite prohibitive mortalities of 40% to 60% (71,91), and observe its dwindling usage (2% to 4% incidence) in the trauma centers of North America (7). Others recommend limiting hepatic resection to the management of the rare instance of major burst injuries with extensive lobar devitalization (72). The rationale for hepatic resection is nevertheless logical in fulfilling the dual role of eradicating both the site of hemorrhage and source of necrosis (Figs. 30.5–30.7). Although there is a paucity of evidence for anatomical resection in this scenario, the principles of surgical restraint observed in most North American trauma centers have also been challenged by surgeons in Japan (92) and France (93). Data supporting an enhanced role for anatomic resection in severe liver trauma from Brisbane comprised 37 such patients (76). Right hepatectomy was the most commonly performed procedure (27 cases (73%)), and Grade V juxtahepatic venous injuries were encountered in 11 patients (30%). There were no on-table deaths, three post-operative deaths, the overall mortality was 8% and re-exploration was performed in seven instances (three of which were for removal of post resection packs) (76). This experience should be considered in the context of a specialist hepatobiliary team with experience in elective liver resection and transplant techniques. Initial laparotomy had previously occurred at the referring hospital in two thirds of cases, and in this regard the life-saving role of perihepatic packing prior to transfer was emphasized.

LIVER TRAUMA

Figure 30.5 Hemodynamically unstable patient with severe blunt liver trauma underwent laparotomy, common hepatic artery ligation, liver suture, perihepatic packing, and was transferred for definitive management. Re-laparotomy and pack removal on day 1 revealed that active bleeding had stopped but the gall bladder was necrotic and there was a major bile leak from the sutured right liver laceration.

Figure 30.7 Abdominal CT performed 2 weeks later shows satisfactory hypertrophy of the remnant left hemiliver and no complications.

tion was still <1%, and the availability of experienced hepatobiliary and liver transplant surgeons at this institution was again a significant factor (95). It remains to be seen whether such results are reproducible widely, or whether the role of major resections in this context will remain the preserve of the surgical virtuoso. For deep penetrating liver injuries, including central bilobar LGSWs, balloon tamponade is an innovation which offers the chance of salvage (96–98). Total hepatectomy is the ultimate strategy in desperate circumstances when hemorrhage from a shattered liver cannot be controlled, or when a Grade VI avulsion injury renders the liver remnant non-viable. However, the logistical and ethical dilemmas presented by this scenario are daunting as the future survival of the patient depends at the very least on the availability of a suitable donor organ. While an increasing number of reports have testified to the feasibility of this approach (99,100), the reality was illustrated by the Hannover experience in which six out of eight such patients died (101). The authors emphasize the importance of the (early) timing of hepatectomy, but stress that this approach can only be justified in exceptional circumstances.

references

Figure 30.6 Formal right hepatectomy was performed and the patient made an uncomplicated post-operative recovery.

Subsequent reports by Tsugawa and colleagues (94), and the University of Pittsburgh group (95), support further the role of hepatic resection in selected patients with severe liver trauma requiring operative intervention. A mortality of 9% and hepatic-related morbidity of 30% were achieved in the latter series. However, the overall rate of formal major hepatic resec-

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31

Portal hypertension Michael D. Johnson and J. Michael Henderson

introduction Portal hypertension has undergone major changes in understanding its pathophysiology, investigation, and management over the past 3 decades. It has moved from a dominantly surgical syndrome to a predominantly medical one, but in day-today practice includes a broad group of disorders that require a multidisciplinary team for evaluation and management. Basic science has defined the pathophysiology, allowing the introduction of pharmacologic therapies for treating many of the complications of portal hypertension. Technology advances in endoscopic therapies and endovascular stenting have changed the treatment options for variceal bleeding. The coming of age of liver transplantation has dramatically altered the management of patients with end stage liver disease and portal hypertension, and is now the dominant surgical option for suitable patients. This chapter will address these changes and present the evidence supporting management choices for the main clinical presentations of portal hypertension.

etiology Portal hypertension can be divided into prehepatic, intrahepatic, and posthepatic causes based on the location of obstruction to portal blood flow—Table 31.1. Most of the prehepatic causes have a normal liver which improves overall prognosis for this group. Portal vein thrombosis should prompt a workup for hypercoagulable states (1). Rarely, a procedural induced arteriovenous fistula or functional fistulae associated with Osler Weber Rendu disease (Hereditary hemorrhagic telangiectasia) (2,3), can cause portal hypertension. Intrahepatic portal hypertension is usually secondary to cirrhosis with its multiple causes. The severity of the liver disease is the most important factor in determining prognosis. Intrahepatic presinusoidal obstruction occurs in congenital hepatic fibrosis and schistosomiasis, and liver function is well preserved. Schistosomiasis accounts for 200 million cases of portal hypertension worldwide (4,5). Posthepatic portal hypertension is rare and includes Budd– Chiari Syndrome (BCS) and veno-occlusive disease. BCS results from obstruction of either the hepatic veins or suprahepatic vena cava, and is often associated with a myeloproliferative or hypercoagulable disorder. Outcome is determined by the extent of hepatic vein involvement, the rapidity of development, and the underlying liver function (6,7).

pathophysiology Portal hypertension occurs when portal venous pressure rises above the normal pressure of 8 mmHg and becomes clinically important above 10 to 12 mmHg. The cascade of events that follow portal flow obstruction are illustrated in Figure 31.1. As portal pressure rises, additional dynamic factors come into play as a result of neurohormonal changes. Vasoconstriction

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with endothelins (8), norepinephrine, angiotensin II, vasopressin whose levels are elevated in cirrhotic patients plays a role (9). Insufficiency of local vasodilators, such as nitric oxide and carbon monoxide has been implicated, and while levels of Nitric Oxide Synthase (NOS) are normal, NOS activity is depressed, partly due to increased expression of caveolin (10). Splanchnic vasodilation and the development of portosystemic collateral are influenced by Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF). VEGF receptor inhibition has been shown to prevent the formation of portosystemic collaterals in animal models (11,12) and reverse the adverse hemodynamic consequences of established portal hypertension (13). These neurohumoral changes lead to increased splanchnic hyperemia and a hyperdynamic systemic circulation with a low arterial blood pressure and increased cardiac output.

clinical manifestations Variceal Bleeding Variceal bleeding is one of the major complications of portal hypertension requiring medical and surgical therapies (14). Screening endoscopy in cirrhotics shows that patients with more advanced liver disease and a lower platelet count are more likely to have varices (15). Epidemiologic studies have shown linear progression of varices over time (16). All patients with cirrhosis should undergo an initial screening upper endoscopy for varices: if none are present this should be repeated every 2 years. If present, intervention with prophylactic therapy to prevent bleeding (primary prophylaxis) should be considered. Ascites Ascites is a marker of advanced liver disease that develops later than varices. Refractory ascites which does not respond to salt restriction and diuretics and has consistently been linked to increased mortality (17). In addition, refractory ascites is potentially complicated by fluid and electrolyte imbalances, spontaneous bacterial peritonitis, and a higher incidence of abdominal wall hernias (18). Hypersplenism Portal hypertension can lead to splenomegaly and hypersplenism, with anemia, leukopenia, and thrombocytopenia. Blood is sequestered and destroyed in the spleen due to morphologic changes (19). Hypersplenism improves with decompression of the portal hypertension and rarely is splenectomy needed. Partial splenic embolization has been advocated by some (20), but is less effective. Pulmonary Syndromes Hepatopulmonary syndrome (HPS) is characterized by hypoxemia with the development of right-to-left intrapulmonary

PORTAL HYPERTENSION shunts and a widened alveolar-arterial oxygen gradient (21). Treatment is with liver transplantation which usually reverses the syndrome with survival rates similar to non-HPS cohorts (22). Pulmonary hypertension is also seen in patients with portal hypertension and carries a more sinister prognosis than HPS. Unless pulmonary arterial pressure can be reduced to normal ranges, liver transplant is contraindicated in these patients. Hepatocellular Carcinoma (HCC) Hepatocellular carcinoma is a common cause of death among patients with cirrhosis and has increased in importance as other causes of mortality have declined (23). The most common conditions leading to HCC are hepatitis B and C and alcoholism. Screening is recommended for patients with cirrhosis using hepatic ultrasound. However effectiveness of this approach has been questioned (24). Early detection of HCC in patients with well-compensated cirrhosis who are eligible for resection or can be prioritized for transplantation is the goal.

evaluation The three essential components in evaluating patients with portal hypertension are (i) assessment of liver function, (ii) endoscopic study, and (iii) radiologic imaging. Liver Function is assessed from clinical and laboratory parameters. Ascites, jaundice, muscle wasting, and encephalopathy are markers for advanced liver disease. Biochemical and hematologic lab profiles include a complete blood count, prothrombin time, serum electrolytes, and liver chemistries. Specific markers of liver disease include hepatitis panels, antinuclear antibody, antimitochondrial antibody, iron and copper levels, alpha 1 antitrypsin, and alpha fetoprotein for HCC screening. The Child-Pugh and MELD scoring systems combine clinical and laboratory variables to determine prognosis in chronic liver disease. Endoscopy focuses on the presence, extent and size of esophageal and/or gastric varices and Portal Hypertensive Gastropathy (PHG). Grading of varices, using, for example, the North Italian Endoscopic Club (NIEC) system, risk-stratify based on variceal size, severity of red wale markings. When combined with Child–Pugh class, such grading can help to guide therapy (25,26). Similar grading systems have been developed and validated for PHG and gastric varices (27,28).

Table 31.1 Causes of Portal Hypertension Prehepatic

Intrahepatic

Post hepatic

Portal or splenic vein trombosis Arteriovenous fistula Extrinsic portal vein compression Pre-sinusoidal: Schistosomiasis Hepatic fibrosis Sarcoidosis Early primary biliary cirrhosis Sinusoidal—Alcoholic liver disease Most causes of Cirrosis Hepatic vein thrombosis Veno occlusive disease Caval and hepatic vein webs

Source: Adapted from (77).

Radiologic Imaging includes ultrasound as a versatile, low cost, low-risk tool for imaging of the liver parenchyma and the portal and hepatic venous systems. The addition of Doppler allows portal venous velocity assessment. Ultrasound can aid to guide percutaneous liver biopsy and paracentesis, screen for hepatocellular carcinoma, and define vessels. Computed tomography (CT) provides better anatomic detail, especially with newer multidetector array scanners and digital reconstruction of images in different planes and in three dimensions. Magnetic resonance imaging (MRI) is an imaging modality that may be preferred by some over CT scan, and can provide more information about the bile and pancreatic ducts. Visceral angiography and hepatic venography are occasionally indicated. The Hepatic Venous Pressure Gradient (HVPG) is calculated by measuring the hepatic venous wedge pressure with a balloon occlusion catheter minus the free hepatic vein pressure. In patients treated with pharmacotherapy, it has been shown that variceal bleeding rarely occurs when the HVPG is below 10 mmHg and if the HVPG can be reduced to below 12 mmHg or by 20% from baseline after an initial variceal bleed (29,30).

management of variceal bleeding Primary Prophylaxis Figure 31.2 presents a management algorithm for primary prophylaxis to prevent an initial variceal bleed. This is based on data from multiple randomized controlled trials (Grade 1a evidence). If small, low-risk varices or no varices are discovered repeat endoscopy should be performed in 2 to 3 years. If small

Obstruction to portal flow (cirrhosis/PVT/etc.)

Increased portal venous pressure

Increased production vasoconstrictors Increased hepatic vascular tone Increased hepatic vascular resistance

Increased production vasodilators

Peripheral, ↓ BP

Splanchnic hyperemia

Activate neurohumoral

Na and H2O retention

Increased C.O.

Increased collateral flow

Portal hypertension Copyright 2007 by Saunders, an imprint of Elsevier Inc. Figure 31.1 Pathophysiology of portal hypertension demonstrating complex vascular and neurohormonal responses. BP, blood pressure; CO, cardiac output; PVT, portal vein thrombosis. Source: From Ref. (97).

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS varices (<5 mm) are found, but there are other risk factors (Child B/C or presence of red wale marks), non-selective betablockers should be started. The presence of medium or large esophageal varices is an indication for starting a noncardioselective beta-blocker (propranolol or nadolol). Treatment of the latter two populations reduces the risk of first variceal hemorrhage from 30% to 14% (31). Endoscopic Variceal Ligation (EVL) can be used in patients that are intolerant to beta blocker therapy or have large high-risk varices. In a meta-analysis of 12 studies, EVL was slightly better at preventing a first variceal bleed than beta-blocker therapy without any improvement in mortality (32). Beta-blocker therapy is first-line therapy in primary prophylaxis and reduction of the HVPG to less than 12 mmHg or by 20% from baseline is the goal of therapy (33–36). Acute Variceal Hemorrhage Accurate diagnosis of acute upper GI bleeding in patients with cirrhosis requires differentiation of variceal bleeding from Mallory Weiss lesions, portal hypertensive gastropathy, and peptic ulcer disease. Figure 31.3 shows a management approach for acute variceal bleeding. Management starts with conservative resuscitation in a closely monitored setting with large bore IV access in the setting of massive bleeding, recognizing that orotracheal intubation may be required. Blood product transfusion should be individualized based on hemoglobin, platelet count, INR, and overall hemodynamic profile. Over-resuscitation should be avoided as this may exacerbate bleeding by increasing portal venous pressure. In patients known to have cirrhosis, pharmacologic therapy with octreotide (Sandostatin—Novartis Pharmaceuticals) or terlipressin (Glypressin—Ferring Pharmaceuticals), and the Algorithm for prophylaxis of variceal bleeding Cirrhosis

Endoscopy

No varices: f/u endoscopy 2 yrs

Varices (moderate or large)

administration of intravenous antibiotics should precede endoscopy (37,38) (Grade 1a evidence). Terlipressin, a longacting synthetic vasopressin, in a meta-analysis of seven randomized controlled trials afforded a 34% relative risk reduction in all-cause mortality compared to placebo (39). Octreotide, was compared to terlipressin in two randomized controlled trials and both agents were found to be similarly effective (40,41). Endoscopy should be performed early for diagnosis and treatment. EVL and injection sclerotherapy are effective at controlling acute bleeding, especially when combined with pharmacologic treatment (42). When compared to sclerotherapy, banding is associated with a lower rate of rebleeding with fewer complications and endoscopy sessions (43) (Grade 1b evidence). In the 5% to 10% of patients not responding to the above measures, balloon tamponade may be necessary as a rescue measure until emergency Transjugular Intrahepatic Portosystemic Shunt (TIPS) can be performed. In-hospital mortality from acute variceal hemorrhage has steadily declined over the last couple of decades to 14.5%, thanks in large part to better resuscitation strategies, lower rates of rebleeding, and prevention of infectious complications (44). Prevention of Recurrent Variceal Bleed A first variceal bleed changes the odds of subsequent bleeding. Without specific therapy, approximately 60% of patients will rebleed within 1 to 2 years (31,45). This emphasizes the need for optimal strategies to prevent rebleeding and at the same time not accelerate the rate of progression of any underlying liver disease (46). Figure 31.4 illustrates a management algorithm. Pharmacologic and Endoscopic Therapy The best results for prevention of rebleeding have been obtained using a combination of pharmacologic therapy with non-selective beta-blockers (sometimes in combination with

Suspected variceal bleed

1. Somatostatin/octreotide 2. Conservative resuscitation 3. Antibiotics

Small varices (<5 mm) f/u endoscopy 1 yr

Non-cardioselective β-blocker (Propanolol or Nadolol)

Endoscopy

-Diagnostic -Therapeutic: sclerotherapy or ligation

Intolerance to β-blockers or high-risk varices Continued bleed or rebleed Band ligation Figure 31.2 Primary prophylaxis to prevent an initial variceal bleed. Management algorithm based on variceal size. Source: From Ref. (97).

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-Balloon tamponade -TIPS

Copyright 2007 by Saunders, an imprint of Elsevier Inc. Figure 31.3 Acute variceal bleed. A management algorithm for diagnosis and management of acute variceal bleeding. Source: From Ref. (97).

PORTAL HYPERTENSION nitrates) and EVL (Grade 1b evidence). The latter should be performed in 2 to 4 sessions, 7 to 10 days apart until variceal obliteration is achieved. Combination therapy has succeeded in lowering rebleeding rates to as low as 14% at 2 years (47). The lowest rates of rebleeding are found in patients deemed “responders” based on HVPG measurements as mentioned earlier. Patients with a HVPG < 12 mmHg or a 20% decrease in HVPG have a 10% rebleeding rate (48–50). Some have argued that pharmacologic therapy should be tried first, with EVL added for “non-responders.” In a meta-analysis of 12 randomized controlled trials comparing TIPS to endoscopic therapy for preventing variceal rebleeding, TIPS performed better in the prevention of rebleeding and deaths due to rebleeding, albeit with a higher rate of encephalopathy (51) (Grade 1a evidence). However, half of the studies used sclerotherapy alone for secondary prophylaxis. Subgroup analysis showed EVL was statistically equivalent to TIPS in terms of rebleeding, mortality, and encephalopathy. The data suggest TIPS should be used only once the combination of pharmacologic and endoscopic therapies has failed. Variceal Decompression Variceal decompression, either with a radiologic shunt (TIPS) or a surgical shunt, is indicated in patients that continue to bleed despite adequate medical and endoscopic therapy. TIPS has largely replaced surgical shunts both for patients with good hepatic reserve, and as a bridge to transplantation.

Acute bleed controlled with banding

Evaluation

β-blocker and course of banding

Varices obliterated

Persistent high-risk varices or rebleeding

β-blocker

-Repeat banding -or decompress TIPS DSRS End-stage liver disease

Transplant Copyright 2007 by Saunders, an imprint of Elsevier Inc. Figure 31.4 Prevention of recurrent variceal bleeding with cascading therapy options. TIPS, transjugular intrahepatic portosystemic shunt; DSRS, distal splenorenal shunt. Source: From Ref. (97).

TIPS Since its introduction in the 1990s TIPS has undergone a number of modifications, allowing it to become the primary means of portal decompression with a rebleeding rate at 1 year of about 13% (52). It is functionally an intrahepatic side-toside portocaval shunt which lowers the portal venous pressure and sinusoidal pressure. Initially, the main limitation of TIPS was stenosis, with the need for frequent surveillance and reintervention in the first year (50 % to 80%). The use of polytetrafluoroethylene (PTFE)-covered stents has markedly reduced the need for reintervention to <25%. Two randomized trials demonstrated improved primary patency rates with no impact on rate of encephalopathy or survival (53,54) (Grade 1b evidence). The other main side effect of TIPS is the development or worsening of encephalopathy which occurs in approximately 30% of patients (52). This is often amenable to medical management or modification of the TIPS itself. TIPS Procedure Venous access is usually obtained through the right internal jugular vein into the right or middle hepatic veins. The main right portal vein is identified by a retrograde hepatic venogram, and the portal venous system is entered above the bifurcation. After a contrast portal venogram confirms correct positioning, the TIPS is placed with a gentle curve to the prosthesis to prevent kinking. It is also important to choose a stent of the correct length, not extending too far into either the hepatic vein or the portal vein. At the same time, the entire hepatic vein segment should be covered to prevent the development of a stenosis at this end. Portal venous pressures are measured before and after the TIPS is deployed, and a completion venogram is obtained. The goal is a portal vein to right atrial gradient of <10 mmHg. Recurrence of variceal bleeding often heralds TIPS dysfunction and warrants recatheterization of the shunt to assess for patency and measure the gradient. Surgical Shunts Surgical shunts can be classified as total, partial, or selective. Total shunts divert all portal venous blood flow either a direct side-to-side portocaval shunt or an H-graft shunt using a 10-mm or greater PTFE graft. Portal decompression and resolution of variceal bleeding are excellent at greater than 90%; however, encephalopathy develops in up to 45% (55). Partial shunts use an 8 mm graft to partially decompress the portal venous system while preserving some hepatopedal blood flow. Prevention of variceal rebleeding remains greater than 90% with lower rates of encephalopathy compared to total shunts (56,57) (Grade 3 evidence). Selective shunts, such as the Distal Splenorenal Shunt (DSRS), selectively decompress gastroesophageal varices while maintaining portal hypertension (Fig. 31.5). These became the most widely used surgical shunts from 1980s to 1990s. Most series demonstrated rebleeding rates from 5% to7% and encephalopathy in 5% to 19% range. An NIH-funded prospective, randomized trial (1997 to 2003) compared DSRS to TIPS in patients with Child’s class A and B cirrhosis (58) (Grade 1b evidence). At the close of this study (mean follow-up of 46 ± 26 months with a range 24 to 96 months), the survival rates were not different at 2 and

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS 5 years (DSRS 81% and 62%; TIPS 88% and 61%). The overall rebleeding rates were not significantly different (5.5% in the DSRS group, 10.5% in the TIPS group), and the occurrence of a first episode of any degree of encephalopathy was 50% in each arm. The reintervention rate was significantly higher (p < 0.001) at 82% in the TIPS group versus 11% in the DSRS group. This study was conducted before covered stents were available for TIPS and the use of covered stents has lowered the shunt dysfunction rate at 1 year to 13% (53,54).

Transplantation Liver transplantation constitutes the ultimate “shunt” with normalization of portal venous hemodynamics and restoration of liver synthetic function. Ongoing improvements in operative techniques and immunosuppression are responsible for a modern 5-year patient survival rates approaching 75% (62). The major shortcoming of transplantation remains a shortage of available donor organs. Strategies to deal with this have included “split liver” and living-related transplantation.

Devascularization Procedures These series of operations were devised to decrease variceal inflow, while preserving portal hypertension and therefore decreasing the rate of encephalopathy. These have been used much more extensively in the Mid and Far East on patients with non-alcoholic liver disease with good results. In their original series of 276 patients, Sugiura and Futagawa reported an operative mortality of 4.3% and 2.3% rate of variceal recurrence (59). Various modifications have been made to the procedure that generally consists of splenectomy, devascularization of the upper two-thirds of the greater and lesser curvature of the stomach and 7 cm of distal thoracic esophagus, esophageal transection and reanastomosis, and pyloroplasty (60). Outside Japan, experience with gastroesophageal devascularization has not been quite as impressive. In the largest series in the Western hemisphere, Orozco et al. reported an operative mortality of 22% and rebleeding rate of 10% but included patients with Child’s class C cirrhosis (61). Encephalopathy rates have generally been less than 10% in most series. Currently, devascularization procedures are most appropriate for patients with extensive thrombosis of the portal venous system with recurrent variceal bleeding and preserved liver function who lack “shuntable” veins (Grade 3 evidence).

ascites This is the most common complication of cirrhosis and portal hypertension and is an important source of morbidity and mortality. Figure 31.6 presents a management algorithm. Ascites develops as a result of sinusoidal portal hypertension and the concomitant vasodilatation within the splanchnic circulation with an imbalance between hepatic lymph production and return to the systemic circulation. A relative hypovolemia is sensed by the kidneys due to reflex systemic vasoconstriction that, in turn, activates the renin–angiotensin system leading to sodium and water retention. Paracentesis is used in the diagnosis and management of ascites. For diagnosis, a Serum-Ascites Albumin Gradient

Treatment of ascites Ascites

Mild/moderate

1. Diet, sodium restriction (2 gm/day) 2. Spironolactone (100 mg/day) 3. May add Lasix (40 mg/day)

Refractory Persistent ascites Large volume paracentesis ± albumin infusion Increased frequency TIPS

? Transplant Figure 31.5 Distal splenorenal shunt selectively decompresses gastroesophageal varices while maintaining portal perfusion through the superior mesenteric and portal veins. Source: From Ref. (97).

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Figure 31.6 Ascites. A management algorithm based on severity and response to therapy. TIPS, transjugular intrahepatic portosystemic shunt. Source: From Ref. (97).

PORTAL HYPERTENSION (SAAG) greater than 1.1 is highly suggestive of cirrhosis. Other causes of ascites (malignancy, infection, pancreatic ascites) usually have a SAAG less than 1.1. In the cirrhotic patient with ascites, abdominal pain and signs of infection, paracentesis should be performed to evaluate for possible spontaneous bacterial peritonitis, which carries a mortality of around 37% (63). Diagnosis of SBP requires the presence of at least 250 polymorphonuclear cells per cubic millimeter of ascitic fluid (64). As with gastroesophageal varices, a systematic approach should be taken in the management of ascites. The cornerstones of treatment of mild to moderate ascites are sodium restriction, to less than 2 g/d and diuretics (65). Spironolactone is the first-line diuretic acting as an aldosterone antagonist. Therapy starts with 100 mg daily and can be titrated up to a maximum dose of 400 mg daily. Furosemide can be added to assist with natriuresis and reduction of peripheral edema, but caution must be exercised to prevent overdiuresis. Refractory ascites fails to respond to maximum medical management and carries a poor prognosis. It interferes significantly with quality of life and requires a more aggressive approach that may include Large Volume Paracentesis (LVP), TIPS, or transplant. LVP removes 5 or more liters of ascites, with or without concomitant albumin infusion. A metaanalysis of four randomized trials comparing LVP to TIPS, showed that TIPS was superior to LVP in terms of control of ascites and transplant-free survival but carried a higher risk of hepatic encephalopathy (66) (Grade 1a evidence). Patients with refractory ascites are best served with transplantation for long-term survival.

portopulmonary syndromes Lung dysfunction may develop for a variety of reasons in patients with cirrhosis and portal hypertension, with the two main clinical entities of hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH). (Figure 31.7 summarizes key features of these two syndromes. HPS is characterized by a defect in arterial oxygenation in the setting of liver disease due to arteriovenous shunting in the pulmonary vascular bed (21). HPS manifests most commonly with dyspnea, digital clubbing, cyanosis, and hypoxemia. Diagnosis of this syndrome requires (1) advanced liver disease, (2) arterial hypoxemia (PaO2 < 80 mmHg or alveolar-arterial oxygen gradient > or = 15 mmHg), and (3) pulmonary vascular dilatation (67). The precise etiology for the pulmonary vascular changes that take place are not entirely known, but are thought related to elevated pulmonary nitric oxide levels. Diagnosis can

be made with the use of contrast-enhanced transthoracic echocardiography with agitated saline to produce microbubbles. In the presence of the abnormally dilated pulmonary vascular bed typical of HPS, microbubbles can be seen in the left atrium within 3 to 6 cardiac cycles. Alternatively, a more sensitive method involves the injection of technetium-99m-labeled microaggregated albumin into a peripheral vein with quantitative uptake in the brain. Liver transplantation is the only known definitive treatment for HPS with a 5-year survival of 76% in one series compared to 23% for patients not undergoing transplant (22) (Grade 3 evidence). Given the progressive nature of the disease and inferior outcome after transplant for those with severe hypoxemia (PaO2 < 50 mmHg), patients diagnosed with HPS should be prioritized for transplantation. Portopulmonary hypertension is defined by the presence of the following in the setting of portal hypertension: elevated pulmonary artery pressures (>25 mmHg), elevated pulmonary vascular resistance (>240 dyne s–1 cm–5), and pulmonary artery occlusion pressures <15 mmHg (68). As with HPS, the presence or severity of PPH does not seem to correlate with the degree of liver disease or portal hypertension. The hyperdynamic circulation that accompanies portal hypertension leads to increased sheer stress and vascular remodeling in the pulmonary vasculature which, in turn, leads to elevated resistance. The most common symptom is dyspnea on exertion but fatigue, syncope, palpitations, and chest pain can also be seen. Transthoracic echocardiography is a good initial screening test to perform if PPH is suspected with right-heart catheterization used to confirm the diagnosis along with its severity. Milder cases of PPH may be reversible with liver transplant, but severe PPH is associated with high post-transplant mortality (69) (Grade 3 evidence). Aggressive medical therapy with prostanoids and other pulmonary vasodilators is mandatory prior to considering patients for transplantation.

portal hypertension and the general surgeon Although the role of surgical shunts has diminished greatly over the last couple of decades, general surgeons should be familiar with the pathophysiology and surgical risks in patients with cirrhosis and portal hypertension. Surgery in these patients is associated with higher morbidity and mortality in a wide range of surgical procedures (70–73) (Grade 3 evidence). The Child–Turcotte–Pugh (CTP) scoring system has been used to predict postoperative morbidity and mortality for 3 decades. Recently the Model for End-Stage liver Disease

Variables

Hepatopulmonary Syndrome (pO2 < 70)

Portopulmonary Hypertension (RVSP > 40)

Prevalence

8–20%

3–12%

Pulmonary vascular changes

Vasodilatation

Vasoconstriction

Contributors

Liver dysfunction portal hypertension

Portal hypertension

Transplant?

Curative

Contraindicated

Figure 31.7 Pulmonary syndromes in liver disease: characteristics and management. RVSP, right ventricular systolic pressure. Source: From Ref. (97).

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SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS (MELD) score, developed to predict TIPS outcome, and used as the basis for the allocation of cadaveric livers for transplantation, has become a useful prognostic tool for predicting postoperative outcomes in non-transplant surgery. CTP involves subjective grading of ascites and encephalopathy, but the MELD score utilizes objective, continuous variables derived from a linear regression model. Northrup et al. found MELD score to be the only statistically significant predictor of 30-day mortality among patients undergoing a wide range of surgical procedures (74). Likewise, in a larger retrospective series, Teh et al. identified MELD score, age, and American Society of Anesthesiologists (ASA) class as the only significant predictors of mortality in multivariate analysis (75). General surgery in patients with cirrhosis is complicated by higher rates of usual postoperative complications, and unique complications, such as decompensation of liver function, ascites leak, and impaired wound healing. Weighing risk versus benefit of operation is particularly difficult in these patients. When an elective procedure is indicated, measures taken to lessen the chances of perioperative complications include nutritional optimization, TIPS, and aggressive management of ascites (76). Surgeons must also take into account the potential conversion of an elective procedure, such as hernia repair, into an emergent procedure down the road. Emergent surgery in this patient group has been associated with significantly higher morbidity and mortality than in the elective setting, and may warrant accepting the lower, albeit elevated, risk of an elective procedure (70). Along with the surgeon, there are a number of other specialists in the multidisciplinary team charged with caring for patients with portal hypertension. Hepatologists perform an essential “quarterback” role by diagnosing and managing the underlying liver pathology and directing patients to other providers. Endoscopists diagnose gastroesophageal varices and manage bleeding in the emergent setting. Interventional radiologists have assumed an increasingly prominent role through the performance of TIPS, as well as portal venography and pressure measurements to guide medical therapy. Lastly, critical care physicians come into play during acute episodes of variceal bleeding and other events to help stabilize patients until more definitive treatment can be delivered. The general surgeon should never operate on a patient with portal hypertension without involving some or all of this team, and the importance of communication between all members of team in the management of these complex patients cannot be overemphasized.

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