Recent Advances in Liver Surgery

MEDICAL INTELLIGENCE UNIT Renzo Dionigi DIONIGI MIU Recent Advances in Liver Surgery Recent Advances in Liver Surgery...

Author: Renzo Dionigi

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MEDICAL INTELLIGENCE UNIT

Renzo Dionigi DIONIGI MIU

Recent Advances in Liver Surgery


Medical Intelligence Unit

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

Landes Bioscience Austin, Texas USA

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

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

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

About the Editor...

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

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

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

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

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

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

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

EDITOR Renzo Dionigi

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

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

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

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

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

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

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

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

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

Chapter 24

Chapter 21

Chapter 19

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

Chapter 10

Chapter 12

Chapters 7, 10

Chapter 21

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chapter 25

Chapter 22

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

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

Milo Hindennach MeVis Bremen, Germany Chapter 5

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

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

Chapter 8

Chapter 24

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Heinz Otto Peitgen MeVis Bremen, Germany Chapter 5

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

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

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

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

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

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

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

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

Chapter 13

Chapter 5

Chapters 9, 20

Chapter 11

Chapter 21

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

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

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

Chiara Recaldini Department of Radiology University of Insubria Varese, Italy

Chapter 23

Chapters 14, 15

Chapter 9

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

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

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

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

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

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

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

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

Chapter 1

Liver Surgery: A Historical Account

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

Abstract

T

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

Introduction

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

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

2


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

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

Renaissance

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


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

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

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

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


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

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

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

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


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

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

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

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

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

Early Sporadic Liver Resections

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


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

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

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

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


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

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

Elective Surgery

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

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

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


Figure 12. Emil Ponfick.

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Figure 13. Carl Johan August von Langenbuch.

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

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

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

In-Flow Vascular Occlusion

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


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

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

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

Anatomic Surgery and Intraoperative Sonography

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

Figure 16. Couinaud’s classification of liver segments.


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

Conclusions

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

References

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

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


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

Chapter 2

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

Introduction

H

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

Chromosomal Aberrations

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

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


Genetics of Hepatocellular Carcinoma

p53

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

22


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

Wnt Signalling Pathway

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


23

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

TGFβ Pathway

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

24


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

Ras Signalling

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


25

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

PDGF Signalling

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

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

Rb

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

Genome-Scale Analysis of Gene Expression in HCC

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


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

Altered DNA Methylation in HCC

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

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

Databases of Genetics of HCC

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

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Chapter 3

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

Abstract

A

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

Introduction

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


36


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

Staging Systems

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

37

Staging Algorithms for Patients with HCC and Prognostic Indicators

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

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

Tumor Morphology

Liver Function

Clinical Performance

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

X X X X X X X X X

X X (Symptoms only) X -

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

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

38

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

System not Validated

Validated for Prognosis in

Citation

Limitations/Notes

AJCC/UICC TNM, Modified 6th Edition

Japanese TNM, BCLC, CLIP, JIS

Disease free survival after transplant

Vauthev et al2 Kee et al3 -

Okuda, CLIP, BCLC

-

All patients varied treatments

Kung et al4

BCLC

-

Varied treatments

Cillo et al5

All patients varied treatments Varied treatments 6

JIS

BCLC

Varied treatments Early detection

Toyoda et al

Varied treatments

Tokyo

BCLC

Cirrhosis percutaneous treatments

Tadeishi et al7

-

8

BCLC

-

Resectable

Cillo et al

CP

Okuda, LCSGJ, BCLC

TACE unresectable

Georgiades et al9

10

TNM

Okuda, CLIP, JIS

XRT unresectable

Seong et al

TNM

CLIP,Okuda

Resectable

Huang et al11

Hep B -

Cirrhosis

Gianni et al

CLIP L large JIS small

Resection

Chen et al13

CUPI

Cirrhosis

Leung et al14

Varied treatments Hep B

GRETCH

Early cirrhosis

Giannini et al15

Hep C

CLIP,Okuda

-

All treatments

continued on next page


12

-

System Validated

System not Validated

Validated for Prognosis in

Citation

Limitations/Notes

JIS

TNM CLIP CP

Resection

Nanashima et al16 17

LCSGJ TNM

-

Resection

Ikai et al

MELD

-

Transplantation waiting list mortality

De la Mata et al18

Hep B -

11

-

TNM

-

Resection early/no cirrhosis

Huang et al

-

Tokyo score

-

Percutaneous ablation

Tateishi et al19

-

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


Table 2. Continued

39

40


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

Prognostic Variables

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

41


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

# Staging Systems Included

Citation

Portal Vein Invasion (N vs Y)

25 vs 5

5

Marrero et al20 6/12

AFP (44)

30 vs 10

3.0


Performance Status 0/1/2

30/16/6

1/2.7/5


Histology (Trabecular vs adenoid)

43 vs 15

2.8

Gianni et al12

T.Bilirubin (1.5 mg/dl)

57 vs 21

2.7

Huo et al

p53 Overexpression (N vs Y)

43 vs 16

2.7

Gianni et al12

21

21

0/12 9/12 0/12

Encephalopathy (N vs Y)

37 vs 13

2.6

Huo et al

4/12

Ascites (N vs Y)

46 vs 19

2.4

Huo et al21

7/12

21

5/12 7/12

INR (1.5)

41 vs 22

1.9

Huo et al

Albumin (>3.5 vs 2 cm, < 5 cm, solitary or multiple, no vascular invasion

IIIa

T3

N0

M0

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

IIIb

T4

N0

M0

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

Any

N1

M0

N1, regional lymph nodes

Any

Any

M1

M1, distal metastasis

IV

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

Stage

PST Morphology

Okuda

Portal Total Hypertension Bilirubin Child-Pugh

A1

0

Uninodular

I

No

Normal

A2

0

Uninodular

I

Yes

Normal

A3

0

Uninodular

I

Yes

Elevated

A4

0

< 3 lesions, Each 5 cm, Multinodular

I-II

A-B

C

1-2

Vascular Invasion and/ or Metastases

I-II

A-B

D

3-4

Any

III

C

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

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

1

2

3

None None ≥ 3.5 ≤ 2.0 < 4.0

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

Severe Severe 3.0 >6.0


Cancer of the Liver Italian Program (CLIP) Score Variable

Score

Child-Pugh Class A

0

B

1

C

2

Tumor Morphology Uninodular, 500 ng/mL

2

Bilirubin (μmol/L) 52

4

Alkaline Phosphatase >200 IU/L

3

45

46


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

1

2

3

>80%

Karnofsky Index Bilirubin (mg/dl)

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

Vascular Embolotherapy in Hepatocellular Carcinoma

117

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

Drug Eluting Beads

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

Conclusion

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

118


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

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Chapter 10

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

Abstract

M

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

Introduction

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

Rationale Portal Vein Embolization

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


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

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

Transcatheter Arterial Chemoembolization

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

History

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

Hospital Beaujon’s Experience

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

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Technique

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

Results of Sequential Arterial and Portal Vein Embolization

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

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

Comparison with PVE Alone in Patients with HCC

In our experience, the FLR and the mean increase in percentage FLR were significantly higher in the patients who had sequential arterial and portal venous embolization than that in patients with PVE alone (12% versus 8%).17 Examination of the resected specimens showed that complete necrosis of the tumor induced by TACE combined with PVE occurred in 83%, compared with 5% following PVE alone.17 There was a clear relationship between the increase in percentage FLR volume and postoperative risk. The overall postoperative morbidity rate was 18%, 67% and 100% if the increase in percentage FLR volume was >10%, between 5 and 10% and 10%, between 5 and 10% and 30%), moderate (30 < hematocrit > 20%), or severe (hematocrit < 20%).16 The target hematocrit with ANH is variable but is often around 25% to 30%. Severe hemodilution (e.g., 20%) is likely to be more efficacious with regards to blood conservation, but the risks are greater, particularly for patients with preexisting medical conditions such as coronary heart disease.69 ANH should be taken into consideration for patients with good initial hematocrits who are assumed to be deprived of more than two units of blood (900 to 1000 mL) during surgery. This technique works better in healthy, young adults, but it has been successfully employed in children and the elderly patients. ANH has been used in vascular, orthopedic and in some general surgical procedures. In addition, Jehovah’s Witnesses patients accept this technique with the modification that we keep the blood moving and in direct contact with the patient’s vascular system. Some Jehovah’s Witnesses will agree to ANH if the blood is maintained in a closed circuit continuous flow system.70 ANH is contraindicated in cardiac disease, since the main compensatory mechanism for the induced anemia is an increase in the cardiac output, when renal function is impaired, since large amounts of infused fluids need to be excreted and when baseline hemoglobin is below 110 gm/L (11 g/dL). Furthermore low concentrations of coagulation proteins, inadequate vascular access and the absence of appropriate monitoring capability indicate that ANH should not be used.71 In the last twenty years several groups reported the use of ANH during major hepatic resections72-76 and the overall conclusion is that ANH, in selected patients, is a safe and effective technique that appears to reduce the number of patients requiring homologous blood transfusion as well as the number of units transfused per patient. Furthermore, Jehova’s Witnesses with hepatic tumors represent a major problem for liver surgeons to achieve good outcome, in fact these patients, because of their religious beliefs, refuse transfusion of blood and blood products. In order to avoid transfusion Barakat et al75 have recently described the use of ANH in a Jehova’s Witness who underwent a combined left trisegmentectomy and caudate lobectomy to treat a large intrahepatic cholangiocarcinoma. ANH is considered a simple and inexpensive procedure and has the advantage that fresh autologous blood is readily available. Numerous studies of its efficacy, however, have produced conflicting results, perhaps because of the heterogeneity of the surgeries in which it was used, differences in study protocol and differences in the definition of outcome variables.77,78

Discussion

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

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

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

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

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

Conclusions

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


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

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

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

Chapter 13

Inferior Vena Cava Resection for Infiltrating Hepatic Malignancy

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

Abstract

L

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

Introduction

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


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

Surgical Anatomy

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

Anomalies

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


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

Diagnosis

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

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

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


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

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

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

Treatment

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

Inferior Vena Cava Resection Without Replacement

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

Inferior Vena Cava Partial Resection

If less than 30% of the circumference of the IVC wall is involved or infiltrated for a short segment, (2 cm), to prevent lumen stenosis (Fig. 5). Since the resection should always be carried out at a safe distance from the tumor, partial resection of the IVC followed by direct suture or prosthetic patch angioplasty is rarely adequate to be considered curative.

Inferior Vena Cava Complete Segmental Resection

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


Figure 4. Partial IVC resection and longitudinal suture.

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

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160


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

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

Discussion

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

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

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

RL-wCR

HTVE

Partial

Direct suture 507

2820

43: dead

2

RL-wCR

HTVE

Partial

Patch

470

3100

46: alive

3

RL-sCR

HTVE

Segmental

Graft

386

2180

13: dead

4

LTS-wCR

Partial Hypothermic perfusion

Patch

670

1820

14: dead

5

RL-wCR

HTVE

Partial

Direct suture 350

2450

22: dead

6

RL-sCR

HTVE

Segmental

Graft

412

4150

16: dead

7

RL-wCR

HTVE

Partial

Patch

280

1940

14: alive

8

LTS-sCR

HTVE

Segmental

Graft

358

3245

12: dead

9

LTS-wCR

HTVE

Partial

Direct suture 310

1750

12: alive

10

LTS-sCR

Two step VE

Segmental

Graft

474

3875

10: alive

11

RL-sCR

HTVE

Segmental

Graft

330

2960

8: alive

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

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

Conclusion

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

References

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


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

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


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

Chapter 14

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

Abstract

I

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

Introduction

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


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

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

General Preoperative Examination for Liver Functional Reserve

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

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

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

Right Anterior Sectionectomy (Figs. 1-3)

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

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

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


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

Hemihepatectomy (Figs. 4-10)

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

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

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

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


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

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

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

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


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

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

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

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

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


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

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

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

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

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

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


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

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

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

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

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


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

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

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

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


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

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

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


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

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

Conclusions

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

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

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

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


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

References

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

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

Chapter 15

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

Abstract

H

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

Introduction

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


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

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

Surgical Strategies and Technique for Hilar Cholangiocarcinoma

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

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

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

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

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

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


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Figure 6. Peroral cholangioscopy shows a papillary tumor.

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

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

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

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

Preoperative Management

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


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

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

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

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

Surgery General Procedures in Resectional Surgery for HC

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


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

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

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

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

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

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


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

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

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

Figure 16. Legend viewed on following page.


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

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

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

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

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

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

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


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

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

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

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


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

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

204


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

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

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

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

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


205

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

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

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

206


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

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


207

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

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

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

208


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

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


209

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

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

210


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

Hepatopancreatoduodenectomy (Figs. 5-8, 30)

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

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


211

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

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

212


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

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

Conclusions

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

References

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


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

Chapter 16

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

Abstract

T

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

Noncolorectal Hepatic Metastases

Many series combine multiple tumor types to be able to achieve adequate numbers of patients for analysis. However, the number of patients in these series remains small. Recent advances in imaging and understanding of segmental anatomy have provided an environment in which hepatic resections can be performed safely. Advances in surgical technique and perioperative care have decreased the post operative mortality to 24 months as independent prognostic factors. O’Rourke et al published on 114 hepatic resections for noncolorectal non neuroendocrine metastases in 102 patients with a mortality of 5 cm in size and extra-hepatic nodal disease. The largest series was published by the Association Francaise de Chirurgie which analyzed 1452 patient who underwent hepatic resection for noncolorectal, nonneuroendocrine hepatic metastases.3 Patients with adrenal, breast, choroid melanoma, cutaneous melanoma, exocrine pancreatic, gastric/gastroesophageal junction/esophageal, head and neck, ovarian, pulmonary, Table 1. Series of resected neuroendocrine hepatic metastases First Author

Year

n

Operative Mortality(%)

Survival

Chen5 Chamberlain6 Grazi7 Jaeck8 Nave9 Sarmiento10 Touzios11 Musunuru4

1998 2000 2000 2001 2001 2001 2005 2006

15 34 19 13 31 170 37 13

0 6 0 0 0 1.2 5 0

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

*Value is approximate.

216


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

Habibullah et al35 FHF (n = 7) Pooled blood group-matched human foetal hepatocytes

6 × 107/kg

Intraperitoneal

Patients (n = 2) with Grade III encephalopathy Survived; but with grade IV Only 1 recovered

Strom et al2,62

7.5 × 106-1.7 × 108

Intraportal

With FHF, 6 bridged to OLT; 1 recovered; 4 died.

Mito et al118

Soriano et al109

FHF (n = 11),

Hepatocytes cryopreserved for 1.5 weeks-8 months

LC (n = 2), Ch (n = 1)

(n = 5) or 48-h cultured hepatocytes (n = 1)

FHF (n = 3) Cryopreserved hepatocytes (duration?)

Hepatocyte Transplantation

Table 3. Clinical trials related to human hepatocyte transplantation in acute liver failure patients

All died with LC and Ch. 4 × 107-4 × 109

Intrasplenic

Two patients died One patient recovered

119,120

Bilir et al

FHF (n = 5),

Hepatocytes cryopreserved for 1-8 months

LC (n = 3)

NA

Fisher et al121

FHF (n = 1) Not available

3 × 10

9

Intraportal

All alive 4 years later

NA 8.8 × 108

4 FHF patients survived

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