Professional Documents
Culture Documents
This book
demonstrates the
wisdom of the
new knowledge
and technical skills
of these diverse
disciplines where
cooperative efforts
contribute toward
the benefit of the
patients with HPB
disorders.
Also Available
Hepatocellular Carcinoma:
A Practical Approach
Edited by Bandar Al Knawy, K. Rajendra Reddy
and Luigi Bolondi
ISBN: 9780415480802
e-ISBN: 9780203092880
An in-depth coverage of benign and malignant disorders of the liver, pancreas, and
bile ducts and gallbladder
With a Foreword by
Yuji Nimura, MD, President
of the Aichi Cancer Center,
Japan, and Past President
of the IHPBA
Second
Edition
www.informahealthcare.com
Surgical
Management of
Hepatobiliary
and Pancreatic
Disorders
Second Edition
Edited by
Graeme J. Poston
Michael DAngelica
Ren Adam
Michael DAngelica MD
Weill Medical College of Cornell University
and
Memorial Sloan-Kettering Cancer Center
New York, New York, USA
and
Contents
List of contributors
Foreword
Preface
I
vii
x
xi
1
17
3 Hepatic resection
166
154
Kaori Ito
ANATOMY/IMAGING/SURGICAL TECHNIQUE
1 Surgical anatomy of the liver and bile ducts
18 Chemotherapy-associated hepatotoxicity
173
180
36
46
53
63
73
81
89
192
197
8 Pancreatic resection
ii. Primary
Lawrence H. Schwartz
216
223
208
229
233
II LIVER
A. Malignant
i. Metastases
12 Liver metastases: detection and imaging
109
135
242
B. Benign
253
261
148
30 Liver trauma
271
CONTENTS
31 Portal hypertension
280
A. Malignant
288
301
308
Adriano Tocchi
324
401
407
414
432
B. Benign
329
47 Acute pancreatitis
439
333
Yuji Nimura
48 Chronic pancreatitis
451
343
49 Pancreatic injury
463
B. Benign
39 Choledochal cyst detected in adulthood
A. Malignant
380
37 Extrahepatic cholangiocarcinoma
IV PANCREAS
50 Pancreas transplantation
354
470
Khalid Khawaja
360
Steven M. Strasberg
vi
373
478
Index
489
List of contributors
Ghassan K. Abou-Alfa MD
Assistant Attending, Memorial Sloan-Kettering Cancer Center, and
Assistant Professor, Weill Medical College at Cornell University,
New York, New York, USA
Hamid Abdollahi MD
Senior Resident (General Surgery), Department of Surgery, Thomas
Jefferson University, Philadelphia, Pennsylvania, USA
Ren Adam MD, PhD
AP-HP Hpital Paul Brousse, Centre Hpato-Biliaire, Inserm,
Unit 785, and Universit Paris-Sud, UMR-S 785, Villejuif, France
Steven A. Ahrendt MD
Associate Professor of Surgery, University of Pittsburgh
Medical Center, UPMC Passavant Cancer Center, Pittsburgh,
Pennsylvania, USA
Peter J. Allen MD
Department of Surgery, Memorial Sloan-Kettering Cancer Center,
New York, New York, USA
Bilal Al-Sarireh MBBCh, FRS, PhD
Consultant Hepatopancreatobiliary and Laparoscopic Surgeon,
Swansea University, and Department of Surgery, Morristown Hospital,
Swansea, UK
Junichi Arita MD, PhD
Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and
Transplantation Division, Department of Surgery, Graduate School of
Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Kai A. Bachmann
Department of General, Visceral and Thoracic Surgery, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
Galinos Barmparas
Division of Trauma and Surgical Critical Care, University of Southern
California, Los Angeles, California, USA
David L. Bartlett
Department of Surgery, University of Pittsburgh, Pittsburgh,
Pennsylvania, and National Cancer Institute, National Institutes
of Health, Bethesda, Maryland, USA
Eliano Bonaccorsi-Riani
Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires
St Luc Universit catholique de Louvain, Department of Abdominal
and Transplantation Surgery, Brussels, Belgium
Jason A. Breaux MD
Surgical Oncology Fellow, University of Pittsburgh Medical Center,
UPMC Cancer Pavilion, Pittsburgh, Pennsylvania, USA
Murray F. Brennan
Benno C. Schmidt Clinical Chair in Oncology, Department of Surgery,
Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Karen T. Brown MD
Attending Radiologist, Memorial Sloan-Kettering Cancer Center, and
Professor of Clinical Radiology, Weill Medical College at Cornell
University, New York, New York, USA
C. Ross Carter
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow,
Scotland, UK
Jooyeun Chung MD
Department of Surgery, The Methodist Hospital, Houston, Texas, USA
Kevin Conlon
Professor of Surgery, University of Dublin, Trinity College Dublin, and
Professorial Surgical Unit, Education Centre, AMNCH, Dublin,
Ireland
Michael DAngelica MD
Weill Medical College of Cornell University and Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Dowmitra Dasgupta MD, FRCS
Consultant Hepato-Pancreatico-Biliary Surgeon, Department of Upper
GI Surgery, Castle Hill Hospital, Cottingham, UK
Matthew P. Dearing
Department of Surgery, Norfolk & Norwich University Hospital,
Norwich, UK
R. DeMatteo
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New
York, New York, USA
Demetrios Demetriades
Division of Trauma and Surgical Critical Care, University of Southern
California, Los Angeles, California, USA
Mark Duxbury
Clinical Surgery, University of Edinburgh Royal Infirmary,
Edinburgh, UK
Stephen W. Fenwick MD, FRCS
Consultant Hepatobiliary Surgeon, North Western Hepatobiliary Unit,
University Hospital Aintree, Lower Lane, Liverpool, UK
Yuman Fong MD
Hepatobiliary Service, Department of Surgery, Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Helmut Friess
Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar,
Technische Universitt Mnchen, Munich, Germany
O. James Garden
Regius Professor of Clinical Surgery, Clinical and Surgical Sciences
(Surgery), University of Edinburgh, Royal Infirmary, Edinburgh, UK
Thilo Hackert
Department of Surgery, University of Heidelberg, Heidelberg, Germany
Lisa J. Harris MD
Senior Resident (General Surgery), Department of Surgery, Thomas
Jefferson University, Philadelphia, Pennsylvania, USA
J. Michael Henderson
Chief Quality Officer, Cleveland Clinic, Cleveland, Ohio, USA
Stephen N. Hochwald MD
Chief, Division of Surgical Oncology, University of Florida, Gainesville,
Florida, USA
Markus W. Bchler
Department of General Surgery, University of Heidelberg, Heidelberg,
Germany
Michael G. House MD
Assistant Professor, Department of Surgery, Indiana University School
of Medicine, Indianapolis, Indiana, USA
vii
LIST OF CONTRIBUTORS
Lucy Hann MD
Professor of Radiology, Weill Cornell Medical Center, and Director of
Ultrasound Memorial Sloan-Kettering Cancer Center, New York,
New York, USA
Julie K. Heimbach
Mayo Clinic, Rochester, Minnesota, USA
Steven N. Hochwald
University of Florida Medical School, Box 100286, Gainesville,
FL 326100286, USA
E. Hoti
AP-HP Hpital Paul Brousse, Centre Hpato-Biliaire, Villejuif, France,
and Liver Transplant Unit, Saint Vincents University Hospital,
Dublin, Ireland
Shin Hwang
Professor, Division of Hepatobiliary Surgery and Liver
Transplantation, Department of Surgery, University of Ulsan College
of Medicine, Seoul, Korea
Hiromichi Ito MD
Department of Surgery, Michigan State University,
Lansing, Michigan, USA
Kaori Ito MD
Department of Surgery, Michigan State University, Lansing, Michigan,
USA
Jakob R. Izbicki FACS
Department of General, Visceral and Thoracic Surgery, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
William R. Jarnagin MD
Hepatobiliary Service, Department of Surgery, Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Timothy G. John MD, FRCSEd (Gen)
Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS
Foundation Trust, Basingstoke, UK
Michael D. Johnson MD
Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
Robert Jones MB, ChB, MRCS
Clinical Fellow, North Western Hepatobiliary Centre, Aintree
University Hospital, Liverpool, UK
C. Kahlert
Department of Surgery, University of Heidelberg, Heidelberg, Germany
Vincent Karam
Centre Hpatobiliaire, Hpital Paul Brousse, Villejuif, France
Steven C. Katz MD
Director of Surgical Immunotherapy, Roger Williams Medical Center,
Providence, Rhode Island, USA
Khalid Khwaja MD
Director of Kidney and Pancreas Transplantation, Senior
Staff Surgeon, Lahey Clinic, Burlington, Massachusetts, USA
Nancy E. Kemeny MD
Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Jrg Kleeff
Department of Surgery, Klinikum rechts der Isar, Technische
Universitt Mnchen, Munich, Germany
Norihiro Kokudo MD, PhD
Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and
Transplantation Division, Department of Surgery, Graduate School of
Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Asad Kutup
Department of General, Visceral and Thoracic Surgery, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
viii
W. Y. Lau
Faculty of Medicine, The Chinese University of Hong Kong, Prince of
Wales Hospital, Shatin, New Territories, Hong Kong, SAR
C. K. Leow
Mount Elizabeth Medical Centre, Singapore, Singapore
Keith D. Lillemoe MD
Jay L. Grosfeld Professor and Chairman, Department of Surgery,
Indiana University School of Medicine, Indianapolis, Indiana, USA
Sung-Gyu Lee
Professor, Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Ulsan College of Medicine,
Seoul, Korea
Michael P. La Quaglia MD
Department of Surgery, Pediatric Surgery Service, Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Jan P. Lerut MD, PhD, FACS
Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires
St Luc Universit catholique de Louvain, Department of Abdominal
and Transplantation Surgery, Brussels, Belgium
Duan Li MD
Assistant Attending Radiologist, Memorial Sloan-Kettering Cancer
Center, New York, New York, USA
Chung Mao Lo
Professor, Department of Surgery, Queen Mary Hospital,
The University of Hong Kong, Hong Kong, China
J. Peter A. Lodge MD, FRCS
Professor and Clinical Director, HPB & Transplant Unit, St. James
University Hospital, Leeds, UK
Ajay V. Maker MD
Director of Surgical Oncology, Creticos Cancer CenterAdvocate
Illinois Masonic Medical Center; Departments of Surgery and
Microbiology/Immunology, University of Illinois at Chicago, Chicago,
Illinois, USA
Masatoshi Makuuchi MD, PhD
Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and
Transplantation Division, Department of Surgery, Graduate School of
Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Hassan Malik MD, FRCS
Hepatobiliary Unit, Department of Surgery, University Hospital
Aintree, Liverpool, UK
Oliver Mann
Department of General, Visceral and Thoracic Surgery, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
Maureen McEvoy MD
Department of Surgery, Pediatric Surgery Service, Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Colin J. McKay
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow,
Scotland, UK
Andr L. Mihaljevic
Department of Surgery, Klinikum rechts der Isar, Technische
Universitt Mnchen, Munich, Germany
David M. Nagorney
Mayo Clinic, Rochester, Minnesota, USA
Yuji Nimura MD
President, Aichi Cancer Center, Chikusaku, Nagoya, Japan
Giuseppe Orlando
Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires St
Luc Universit catholique de Louvain, Department of Abdominal and
Transplantation Surgery, Brussels, Belgium
LIST OF CONTRIBUTORS
Nicholas ORourke MBBS, FRACS
Royal Brisbane Hospital, Brisbane, Queensland, Australia
Martin Palavecino MD
Department of Surgical Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas, USA
Purvi Y. Parikh MD
Department of Surgery, Albany Medical College, Albany, New York,
USA
Samir Pathak MD, ChB, MSC, MRCS
Clinical Fellow, North Western Hepatobiliary Centre, Aintree
University Hospital, Liverpool, UK
Henry A. Pitt MD
Indiana University, Indianapolis, Indiana, USA
Graeme J. Poston MS, FRCS (Eng), FRCS (Ed)
Centre for Digestive Diseases, University Hospital Aintree, and
Department of Surgery, The Royal Liverpool University Hospitals,
Liverpool, UK
Derek G. Power MD
Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Myrddin Rees MS, FRCS, FRCS (Ed)
Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS
Foundation Trust, Basingstoke, UK
Michael Rhodes
Department of Surgery, Norfolk & Norwich University Hospital,
Norwich, UK
Charles B. Rosen
Mayo Clinic, Rochester, Minnesota, USA
Jason W. Smith MD
Chief Resident, Department of Surgery, Loyola University Medical
Center, Maywood, Illinois, USA
Nick Stern
Consultant Gastroenterologist, Digestive Diseases Department,
University Hospital Aintree, Liverpool, UK
Richard Sturgess
Consultant Gastroenterologist and Clinical Director, Digestive Diseases
Department, University Hospital Aintree, Liverpool, UK
Adriano Tocchi
Head of 1st Department of Surgery and Chief of the Gastro-intestinal
and Hepato-biliary Surgical Service, University of Rome Sapienza
Medical School, Rome, Italy
Ludovic Trinquart
Department of Radiology, Assistance-Publique Hpitaux de Paris,
Hpital Beaujon, Clichy, France
Bernard Van Beers
Department of Radiology, Assistance-Publique Hpitaux de Paris,
Hpital Beaujon, Clichy; Universit Paris; and Centre de recherche
biomdicale Bichat-Beaujon, Paris, France
Jean-Nicolas Vauthey MD
Department of Surgical Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas, USA
Valrie Vilgrain
Department of Radiology, Assistance-Publique Hpitaux de Paris,
Hpital Beaujon, Clichy; Universit Paris; and Centre de recherche
biomdicale Bichat-Beaujon, Paris, France
Gerardo Sarno MD
Clinical Fellow, North Western Hepatobiliary Centre, Aintree
University Hospital, Liverpool, UK
Vanessa de Villa
Assistant Professor, Department of Surgery, Queen Mary Hospital,
The University of Hong Kong, Hong Kong, China
J. Weitz MD
Department of Surgery, University of Heidelberg, Heidelberg, Germany
Beat Schnriger
Division of Trauma and Surgical Critical Care, University of Southern
California, Los Angeles, California, USA
Lawrence H. Schwartz
Department of Radiology, Columbia University College of Physicians and
Surgeons, and Radiologist-in-Chief, New YorkPresbyterian Hospital/
Columbia University Medical Center, New York, New York, USA
Margo Shoup MD, FACS
Chief, Division of Surgical Oncology, Department of Surgery, Loyola
University Medical Center, Maywood, Illinois, USA
Jason K. Sicklick
Department of Surgery, Memorial Sloan-Kettering Cancer Center,
New York, New York, USA
Steven M. Strasberg MD, FRCS(C), FACS, FRCS (Ed)
Pruett Professor of Surgery and Head Hepato-Pancreato-Biliary and
Gastrointestinal Surgery, Washington University in Saint Louis and
Barnes-Jewish Hospital, Saint Louis, Missouri, USA
ix
Foreword
As recent progress in hepato-pancreato-biliary (HPB) surgery
has been evident since the first edition of this book was published eight years ago, Dr. Graeme Poston, Dr. Mike
DAngelica, and Dr. Ren Adam, internationally recognized
authorities in HPB surgery, have attempted to rewrite the second edition, joined by selected numerous worldwide specialists renowned as expert authors in each field to present a
current view of the surgical and non-surgical management of
benign and malignant HPB disorders.
This book demonstrates the wisdom of the new knowledge
and technical skills of these diverse disciplines where cooperative
Preface
Hepato-pancreato-biliary (HPB) surgery is now firmly
established within the repertoire of modern general surgery.
Indeed, in many major tertiary centers there are now specific
teams for both pancreatic and liver surgery. However, in most
hospitals outside these major centers the day-to-day management and decision-making for patients with these disorders
remains the remit of the general surgeon.
Following the launch of the highly successful first edition of
this book eight years ago there have been considerable
advances in the surgical management of HPB disorders. Many
of these relate to related specialties (radiology, oncology, gastroenterology, and anesthesia) and also directly to surgery
(liver transplantation, caval bypass and replacement, laparoscopic surgery to name but a few). As such the second edition
has been completely rewritten from scratch.
As with the first edition, the purpose of this edition is
twofold. First, it is intended to cover the spectrum of common
xi
Historically, the liver was described according to its morphological appearance (1,2). However, these three tenets have
altered the approach to surgery, and the liver is now considered from a functional and therefore surgical perspective.
morphological anatomy
Historically, when viewed at laparotomy, the liver appears
divided into a larger right lobe, and a smaller left lobe by
the umbilical fissure and falciform ligament (Figs. 1.1 and
1.2) (3). Situated on the inferior surface of the right lobe is the
transverse hilar fissure, which constitutes the posterior limit of
the right lobe. The quadrate lobe was defined as the portion
of the right lobe lying anterior to this transverse hilar fissure
and to the right of the umbilical fissure, its other margin being
defined by the gallbladder fossa. The caudate lobe, which is
anatomically and functionally separate from the rest of the
liver, lies posterior to the hilum, between the portal vein and
the inferior vena cava (IVC) (4).
This historical anatomical approach does not consider the
vasculature or biliary drainage of the liver and is of only limited use when planning surgical resection.
IVC
Left lobe
Right lobe
IVC
Cantlie's line
Gallbladder
Umbilical
fissure
Cantlie's line
Gallbladder
Quadrate lobe
Couinaud, who in 1957 produced a huge number of vasculobiliary casts of the liver (23,24). Couinaud was able to demonstrate that the liver appeared to consist of eight anatomical
segments, each of which could potentially be separately resected
without affecting the physiological viability of the other segments. Couinaud redefined the caudate lobe as segment 1 and
Goldsmith and Woodburnes left lobe as segments 2 and 3. The
quadrate lobe was termed segment 4, and more recently has
been subdivided by further studies of its portal blood supply
into 4A (superiorly) and 4B (inferiorly). The right liver consists
of segments 5 (anteroinferiorly), 6 (posteroinferiorly), 7 (posterosuperiorly), and 8 (anterosuperiorly) (Fig. 1.7). Couinaud
later suggested a further clarification, in which the caudate lobe
to the left of the IVC remained segment 1, with that to the right
being redefined as segment 9 (25).
Resections based on these anatomical segments enable the
surgeon to safely operate following the three central tenets
described above; remove all pathologically involved tissue,
preserve the maximal amount of nonpathological liver tissue,
and perform safe resection, while ensuring an adequate blood
Left liver
IVC
Right
hepatic vein
Right inferior
hepatic vein
(variable)
IVC
Gallbladder, note that the middle vein
may lie superficially in the gallbladder fossa
Figure 1.4 Venous drainage of the liver.
IVC
Right hepatic
vein in right
portal scissura
3
1
4
Right
posterior
sector
Falciform ligament
6
5
Medial segment of left lobe
Right anterior sector
Right liver
Portal vein
Left liver
(A)
(B)
(C)
(D)
(E)
Figure 1.6 Formal hepatectomies: (A) right hepatectomy; (B) left hepatectomy; (C) left lateral segmentectomy; (D) extended left hepatectomy; (E) extended right
hepatectomy.
8
8
3
1
5
4
5
6
6
(A)
(B)
Figure 1.7 Functional division of the liver and of the liver segments according to Couinauds nomenclature (A) as seen in the patient and (B) in the ex vivo position.
(A)
(B)
(C)
(D)
(E)
Figure 1.8 Other hepatic sectorectomies: (A) right posterior sectorectomy; (B) right anterior sectorectomy; (C) left medial sectorectomy (segments 4A and 4B);
(D) right inferior hepatectomy; (E) right superior hepatectomy.
Figure 1.11 Exposing the hilar plate by raising the inferior surface of segment
4B, thus demonstrating the condensation of Glissons capsule, which will
cover the extra hepatic confluence of the right and left hepatic ducts.
Figure 1.12 Exposing the recessus of Rex by distraction of the falciform ligament to demonstrate the bifurcation of segment 3 and segment 4 bile ducts.
RHD
RHA
4
(ant.)
3
CHD
PV
HA
Recessus of Rex
Figure 1.13 Biliary and vascular anatomy of the left liver. Note the position of
segment 3 duct above the corresponding vein and its relationship to the recessus of Rex.
Figure 1.14 Demonstration of the right hepatic duct lying within the gallbladder fossa.
5
7
Posterior
sectoral
duct
LHD
LPV
6
LHA
CHD
HA
PV
Figure 1.15 Biliary and vascular anatomy of the right liver. Note the horizontal course of the posterior sectoral duct and the vertical course of the anterior sectoral duct.
Segment 4
Glisson's
capsule
Lig.teres
RHD
RHA
LPV
LHD
LHA
RPV
Cystic artery
Cystic duct
Gallbladder
CHD
Umbilical
fissure
HA
Line of incision of
hilar plate to expose
left hepatic duct
CBD
Retroduodenal
artery
Gastroduodenal
artery
Splenic
vein
Cystic plate
Hilar plate
(A)
(B)
(D)
(E)
(G)
biliary anomalies
(C)
(F)
(H)
Figure 1.18 The eight most common variations in the anatomy of the arterial
supply (cystic artery) to the gallbladder.
(A)
The cystic duct arises from the neck of the gallbladder and in
80% of people descends to join the common hepatic duct in its
supraduodenal course. Its length varies widely but its luminal
diameter is usually between 1 and 3 mm. The mucosa of the
cystic duct is arranged in spiral folds (valves of Heister) (33).
In a small number of cases, the cystic duct joins the right
hepatic duct or occasionally a right hepatic sectoral duct.
The gallbladder receives its blood supply by the cystic artery,
the anatomy of which varies widely (Fig. 1.18). The most common variant arises directly from the right hepatic artery, then
dividing into an anterior and posterior branch. The venous
drainage of the gallbladder is directly through the gallbladder
fossa to the portal vein in segment 5 (Fig. 1.19).
(B)
Figure 1.19 (A) Venous drainage of the gallbladder. (B) The lymphatic drainage of the gallbladder towards the coeliac axis.
10
ra
ra
rp
Ih
Ih
rp
12%
57%
(A)
(B)
ra
ra
Ih
rp
Ih
rp
20%
4%
16%
C2
C1
(C)
ra
ra
rp
rp
Ih
Ih
1%
5%
6%
D2
D1
(D)
4
4
ra
ra
rp
2
rp
1
3%
2%
1%
E1
E2
(E)
ra
rp
Ih
2%
(F)
Figure 1.20 Main variations of the hepatic duct confluence.
11
6
91%
7
8
7
86%
7
8
6
5%
4%
(A) seg V
5
10%
2%
2%
(B) seg VI
7
6
80%
6
5
20%
a 67%
b 1%
2
3
d 25%
e 1%
2
3
f 1%
2
3
g 4%
(D) seg IV
Figure 1.21 Variations of the intrahepatic biliary anatomy.
12
(A)
(B)
(D)
liver split to the left of the umbilical fissure in order to widen the
fissure to achieve adequate access to the biliary system.
Access to the right liver system is less readily achieved than
to the left as the anatomy is more imprecise. However, intraoperative ultrasonography greatly enhances the ability of the surgeon to locat e these ducts at surgery. The ideal approach on
the right side is to the segment 5 duct (52), which runs on the
left side of its corresponding portal vein (23). The duct is
exposed by splitting the liver over a short distance to the right
of the gallbladder fossa, commencing at the right side of the
porta hepatis. The segment 5 duct should lie relatively superficially on the left aspect of the portal vein to that segment.
(C)
(A) 75%
(B) 20%
(C) 5%
Figure 1.23 Different types of union of the cystic duct and common hepatic
duct: (A) angular (75%); (B) parallel (20%); (C) spiral (5%).
hepatic veins
In an oblique ultrasonic view, the three hepatic veins join the
IVC to form a characteristic W, with its base on the IVC. A
similar view can be seen on CT scan. These veins are usually
easily seen: the left hepatic vein separating segment 2 from segments 3 and 4, the middle hepatic vein separating segment 4
from 5 and 8, and the right hepatic vein separating 5 and 8
from 6 and 7.
portal system
The portal supply to the left lobe, when viewed obliquely, can
be seen as a side-on H, with the left portal vein giving its
13
3 o'clock artery
9 o'clock artery
Common hepatic artery
Retroduodenal artery
Gastroduodenal artery
(A)
M.H. artery
L.H. artery
R.H. artery
Left gastric
Cystic
Aorta
Proper hepatic
Celiac trunk
Right gastric
Splenic
Supraduodenal
Common hepatic
Gastroduodenal
(B)
Figure 1.24 (A) The biliary duct blood supply; (B) conventional arterial anatomy of the liver (50%).
14
key points
A full understanding of the lobar, sectoral, and segmental anatomy of the liver and biliary system is
an essential prerequisite for successful liver surgery.
The surgeon must appreciate the wide variation in
extrahepatic biliary anatomy.
4a
8
(A)
IVC
(B)
(C)
(D)
(E)
(F)
Figure 1.27 CT scan of upper liver in venous phase showing the left, middle
and right hepatic veins draining into the inferior vena cava (IVC).
Figure 1.28 CT scan of the liver in portal phase showing the left portal vein
passing anteriorly between segments 3 and 4 within the recessus of Rex.
RAPV
LPV
RPPV
Figure 1.26 Portal phase CT scan through porta hepatis showing the left
portal vein (L) lying centrally and the anterior (RA) and posterior (RP)
divisions of the right portal vein (R).
MPV
15
references
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2. Rex 1888. Cited in Hobsley M. The anatomical basis of partial hepatectomy. Proc R Soc Med Engl 1964; 57: 5504.
3. Schwartz SI. Historical Background. In: McDermott WV Jr, ed. Surgery of
the liver. Boston, MA: Blackwell Scientific, 1989: 312.
4. McIndoe AH, Counsellor VX. A report on the bilaterality of the liver. Arch
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6. Mikesky WE, Howard JM, DeBakey ME. Injuries of the liver in three hundred consecutive cases. Int Abstr Surg 1956; 103: 3234.
7. Dalton HC. Gunshot wound of the stomach and liver treated by laparotomy and suture of the visceral wounds. Ann Surg 1888; 8: 81100.
8. Luis A. Di un adenoma del fegato. Centralblatt fur chirg 1887; 5: 99.
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9. Langenbuch C. Ein Fall von Resektion eines linksseitigen Schnurlappens
der Leber. Berl Klin Wosch 1888; 25: 378.
10. Tiffany L. The removal of a solid tumor from the liver by laparotomy.
Maryland Med J 1890; 23: 531.
11. Lucke F. Entfernung der linken Krebsiten Leber Lappens. Cantrallbl Chir
1891: 6: 115.
12. Cattell RB. Successful removal of liver metastasis from carcinoma of the
rectum. Lehey Clin Bull 1940; 2: 711.
13. Wangensteen OH. The surgical resection of gastric cancer with special
reference to: (1) the closed method of gastric resection; (2) coincidental
hepatic resection; and (3) preoperative and postoperative management.
Arch Surg 1943; 46: 879906.
14. Keen WW. Report of a case of resection of the liver for the removal of a
neoplasm with a table of seventy six cases of resection of the liver for
hepatic tumor. Ann Surg 1899; 30: 26783.
15. Cantlie J. On a new arrangement of the right and left lobes of the liver. J
Anat Physiol (Lond) 1898; 32:49.
16. Wendel W. Beitrage zur Chirurgie der Leber. Arch Klin Chir Berlin 1911;
95: 88794.
17. Ton That Tung. La vascularisation veineuse du foie et ses applications aux
resections hepatiques. These, Hanoi, 1939.
18. Raven RW. Partial hepatectomy. Br J Surg 1948; 36: 397401.
19. Lortat-Jacob JL, Robert HG. Hepatectomie droite regle. Presse Med 1952;
60: 54950.
20. Healey JE Jr, Schroy PC. Anatomy of the biliary ducts within the human
liver. Arch Surg 1953; 66: 599616.
21. Goldsmith NA, Woodburne RT. Surgical anatomy pertaining to liver
resection. Surg Gynaecol Obstet 1957; 195: 31018.
22. Hjortsjo CH. The topography of the intrahepatic duct systems. Acta Anat
1951; 11: 599615.
23. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Paris: Masson,
1957.
24. Couinaud C. Lobes et segments hepatiques. Note sur larchitecture
anatomiques et chirurgicales du foie. Presse Med 1952; 62: 70912.
25. Couinaud C. Anatomy of the dorsal sector of the liver. In: Couinaud C, ed.
New Considerations on Liver Anatomy. Paris: Couinaud, 1998: 3961.
26. Ton That Tung. Les Resections Majeures et Mineures Du Foie. Paris: Masson, 1979.
27. Caprio G. Un caso de extirpacion die lobulo izquierdo die hegado. Bull
Soc Cir Urag Montevideo 1931; 2: 159.
28. Bismuth H, Houssin D, Castaing D. Major and minor segmentectomies
reglees in liver surgery. World J Surg 1982; 6: 1024.
29. Mancuso M, Nataline E, Del Grande G. Contributo alla conoscenza della
struttura segmentaria del fegato in rapportto al problema della resezione
epatica. Policlinico, Sez Chir 1955; 62: 25993.
16
tributary ducts coming off at near right angles and that this
duct opened into the duodenum, and he saw that there were
occasionally two ducts in the gland (1). It was Santorini who
finally concluded that, in the normal condition, there existed
two ducts with the smaller of the two emptying into the duodenum by way of a small papilla approximately 2 cm nearer to
the stomach than the major duct and this smaller duct bears
his name (5). The smaller duct is patent all the way to the duodenum in only 60% of specimens and the duct of Wirsung
represents the larger of the two; however, in about 10% of
specimens, the duct of Santorini is the main drainage for the
pancreas. Also in about 10% of cases, the two ducts are not in
communication with each other (1) (Fig. 2.2). The parenchyma of the pancreas consists of small lobules divided by
connective tissue. These lobules are centered around the main
tributary ducts that run to the main pancreatic duct. Smaller
branches off of these tributaries define further septated regions
within the lobules of pancreatic tissue. The main branches of
the pancreatic duct tend to meet the main duct on its superior
and inferior aspect. The diameter of the main pancreatic duct
is reported to be between 2.6 and 4.8 mm in the head, 2.0 and
4.0 mm in the body, and 0.9 and 2.4 mm in the tail (3). The
duct runs in a relatively superficial position in the tail and after
traversing the neck of the pancreas it dives deep into the parenchyma as it crosses the head and is near the dorsal surface of
the pancreas as it nears the confluence with the common bile
duct (CBD) and the duodenum (1).
The lower portion of the CBD lies in contact with the head
of the pancreas for between 2 and 7 cm and 40% of the time it
lies in a groove between the surface of the pancreas and the
duodenum. In the remainder of cases, it lies within the parenchyma of the pancreas (7). During embryological development, the lower duct of Wirsung arises in the ventral pancreatic
bud adjacent to the early hepatic duct. Therefore, the association of the duct of Wirsung with the CBD is a consistent feature of the ductal anatomy of the pancreas (1). The duct of
Wirsung and the CBD unite 6 to 8 mm within the papilla and
form a common channel, which is slightly dilated and referred
to as the ampulla of Vater. In just over 10% of cases, the two
ducts do not form a short common channel and instead enter
the duodenum independently on the papilla (5).
17
Figure 2.1 Overview of the relationship of the pancreas to other important structures in the upper abdomen. Plate 1098, From Anatomy of the Human Body,
Henry Gray 1918.
(A)
(B)
(C)
Figure 2.2 (A) Duct of Santorini is patent all the way to the duodenum. (B) Duct of Santorini is the main drainage. (C) The two ducts are not in communication
with each other.
18
(PSPD) artery is seen arising from the GDA prior to the right
gastroepiploic takeoff. The anterior superior pancreaticoduodenal (ASPD) artery has a caliber between 1 and 3 mm and is
considered the most important blood supply to the head of the
pancreas. In the majority of cases, it is a terminal branch of the
GDA after it has given off the PSPD and the right gastroepiploic arteries. The ASPD can be duplicated in up to 7% of
cases and rarely is absent. Case reports of extremely rare
anomalies exist, reporting the origin of this artery from almost
all of the major branches of the celiac and SMAs (9).
Posterior Superior Pancreaticoduodenal Artery
This artery forms the superior portion of the posterior arcade
that forms anastomoses with the posterior branch of the IPD
artery. The PSPD artery is most commonly found as a branch
of the GDA 1 to 2 cm after the takeoff of the hepatic artery (10).
Up to 10% of cases may see the PSPD arise from the superior
Cystic artery
a
S
C r e
a t o
r
O x e n t e
Figure 2.3 Arterial anatomy of the pancreas, the celiac axis and its major branches. Plate 532, From Anatomy of the Human Body, Henry Gray 1918.
19
S t o m a c h
Figure 2.4 Arterial anatomy of the pancreas, demonstrating the gastroduodenal and its branches of the anterior and posterior pancreaticoduodenal arteries forming the anastomotic arcades with the branches from the superior mesenteric artery. Plate 533, From Anatomy of the Human Body, Henry Gray 1918.
20
12
12p1
12b1
12a1
10
9
12p2
11
12a2
3
8a
16
8p
10
14a
2
6
4
14b
13a
17a
14c
18
14d
17b
14V
13b
15
14d
numerous small bridging veins between the head of the pancreas and the SMV and PV as they course behind the pancreas,
which must be carefully ligated during a resection. The fact
that there are rarely venous branches that enter the SMV or PV
on their anterior surfaces makes the dissection along the plane
anterior to these vessels possible during pancreaticduodenectomy. Two large veins drain the body and tail of the pancreas,
the splenic vein, which courses along the superior edge of the
pancreas and the transverse pancreatic vein along the
inferior margin.
The portal vein is formed on the posterior surface of the
neck of the pancreas by the confluence of the splenic vein and
the SMV. The inferior mesenteric vein may join at this point as
well, but more commonly joins the splenic vein or SMV proximal to the confluence (Fig. 2.4).
while the right side drains the lower portion of the head, which
developed from the ventral bud and constitutes the retroportal
lymphatics (15,16). The superior pancreatic nodes drain the
upper half of the neck, body and tail of the pancreas, and a
portion of the head. They primarily lie along the superior border of the gland or in the gastropancreatic fold and gastrohepatic ligament (17). The inferior pancreatic nodes similarly
drain the inferior half of the gland and lie along the inferior
border as well as draining into the superior mesenteric nodes
or the periaortic nodes. The anterior nodes are located along
the surface of the pancreas that lies adjacent to the duodenum
and are called the infrapyloric lymph nodes and the pancreaticoduodenal nodes. These anterior nodes may also drain into
nodes along the root of the transverse colonic mesentery that
is adjacent to the head of the pancreas. The posterior nodes
run along the posterior pancreaticoduodenal border and
include the nodes along the lower portion of the common bile
duct, portal vein and nodes at the origin of the SMA. The tail
of the pancreas forms several lymphatic trunks that reach out
into the hilum of the spleen and form the superior and inferior
lymph nodes (3,16). This simplified lymphatic mapping system is that adapted by the International Union against Cancer
(UICC). A more comprehensive and clinically useful system
was developed by the Japanese Research System, which divides
lymph node stations into 18 different designations and rates
them according to the likelihood of metastatic spread. Nodal
stations 13 and 17 are the most likely to harbor disease with
21
Portal vein
PSPD-V
Gastrocolic trunk
First jejunal
tributary
ASPD-V
Figure 2.6 Major venous drainage for the pancreas.
22
references
1. Opie EL. Anatomy of the Pancreas and its Variations. Disease of the Pancreas: Its Cause and Nature, 1st edn. Philadelphia, PA: J.B. Lippincott
Company, 1903: 359.
2. Saisho Y, Butler AE, Meier JJ, et al. Pancreas volumes in humans from
birth to age one hundred taking into account sex, obesity, and presence of
type-2 diabetes. Clin Anat 2007; 20: 93342.
3. Skandalakis LJ, Colborn GL, Skandalakis JE. Surgical anatomy of the pancreas. In: Baker RJ, Fischer JE, eds. Mastery of Surgery, Vol. 2, 4th edn.
Philadelphia, PA: Lippincott Williams & Wilkins, 2001: 2448.
4. Kuroda A, Nagai H. Surgical anatomy of the pancreas. In: Howard J,
Idezuki Y, Ihse I, Prinz R, eds. Surgical Diseases of the Pancreas, 3rd edn.
Baltimore, MD: Lippincott Williams & Wilkins, 1998: 869.
5. Cattell RB, Warren KW. The anatomy and physiology of the pancreas. In:
Cattell RB, Warren KW, eds. Surgery of the Pancreas. Philadelphia, PA:
Saunders, 1953.
6. Hollinshead WH. The thorax, abdomen and pelvis. In: Hollinshead WH,
ed. Anatomy for Surgeons. Vol. 2. New York: Medical Department, Harper
and Row Publishers, 1971: 430.
7. Anson BJ, McVay CB, Callander CL. The Abdomen. Surgical Anatomy.
Philadelphia, PA: Saunders, 1971.
8. Woodburne RT, Olsen LL. The arteries of the pancreas. Anat Rec 1951;
111: 25570.
9. Bertelli E, Di Gregorio F, Bertelli L, Mosca S. The arterial blood supply of
the pancreas: A review. I. The superior pancreaticoduodenal and the anterior superior pancreaticoduodenal arteries. An anatomical and radiological study. Surg Radiol Anat 1995; 17: 97106, 1013.
10. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood supply of the pancreas: A review. II. The posterior superior pancreaticoduodenal
artery. An anatomical and radiological study. Surg Radiol Anat 1996; 18: 19.
11. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood
supply of the pancreas: A review. III. The inferior pancreaticoduodenal
artery. An anatomical review and a radiological study. Surg Radiol Anat
1996; 18: 6774.
12. Bertelli E, Di Gregorio F, Bertelli L, Orazioli D, Bastianini A. The arterial
blood supply of the pancreas: A review. IV. The anterior inferior and posterior pancreaticoduodenal aa., and minor sources of blood supply for the
head of the pancreas. An anatomical review and radiologic study. Surg
Radiol Anat 1997; 19: 20312.
13. Bertelli E, Di Gregorio F, Mosca S, Bastianini A. The arterial blood supply
of the pancreas: A review. V. The dorsal pancreatic artery. An anatomic
review and a radiologic study. Surg Radiol Anat 1998; 20: 44552.
14. Navas V, OMorchoe PJ, OMorchoe CC. Lymphatic system of the rat pancreas. Lymphology 1995; 28: 420.
15. Pissas A. Anatomoclinical and anatomosurgical essay on the lymphatic
circulation of the pancreas. Anat Clin 1984; 6: 25580.
16. Donatini B, Hidden G. Routes of lymphatic drainage from the pancreas:
A suggested segmentation. Surg Radiol Anat. 1992; 14: 3542.
23
Hepatic resection
Ajay V. Maker and Michael DAngelica
introduction
Though liver anatomy and physiology have been studied for
centuries, liver surgery still is a relatively young field. Just
30 years ago, the mortality of major hepatic resection neared
25%. This high mortality limited its utility and deterred
patients and referring physicians from considering surgery.
The current generation of hepatobiliary surgeons has an
increased understanding of the segmental anatomy of the
organ and has seen a dramatic decrease in the mortality of
liver surgery to nearly 1% largely due to a dramatic decrease in
blood loss (1). This chapter will address the basic principles
and techniques to safely approach liver resection.
basic principles
Surgical Indications: Benign vs. Malignant Disease
Though this chapter focuses on the technical aspects of
hepatic resection, an understanding of when liver resection
is indicated is of paramount importance. Due to advances
in modern imaging techniques and an increased knowledge of the natural history of liver lesions, tumors that may
have been resected in the past for diagnostic uncertainty
are now often observed. Similarly, malignant lesions that
were not resected in the past but referred for nonsurgical
therapy are now being treated with resection. Indications
for specific benign and malignant processes are outlined
in other chapters; however, the general principles are
mentioned here.
Benign Disease
Partial hepatectomy for benign conditions should be parenchymal preserving and reserved for lesions that are symptomatic, have premalignant potential, or carry an unclear diagnosis.
Wide margins are not necessary, therefore in some cases, for
example, focal nodular hyperplasia (FNH) or hemangiomas,
enucleation may be safely performed, although in some instances an anatomic segmental resection may be the safest
approach (24). This is addressed at the end of the chapter and
detailed in other chapters.
Malignant Disease
Partial hepatectomy for malignant conditions must obtain a
clear surgical margin, and is suitable for well-selected patients
with both primary and metastatic cancer. We have found
increased patient survival with margins of at least 1 cm in
patients undergoing resection for metastatic colorectal cancer
(513), though other series suggest that a negative margin,
regardless of the distance, is sufficient (14,15). The exception
may be in slow-growing tumors with multiple liver metastases, such as neuroendocrine tumors, where tumor debulking
may be of value. As long as the functional remnant liver is
adequate, usually about 25% liver volume in otherwise
24
HEPATIC RESECTION
hilar cholangiocarcinomas are also at increased risk of liver
failure postoperatively.
The functional residual liver volume should be calculated to
insure adequate liver function postresection. A healthy, noncirrhotic individual requires a functional hepatic reserve of at
least 20% of the original nontumoral liver volume. The regenerative capacity of the liver should enable full functional compensation within weeks of resection; once greater than 70% of
liver volume is resected, however, there is a risk of clinically
significant liver insufficiency. This risk is minimal if specimen
volume has been replaced with tumor, in which case compensatory hypertrophy will have already occurred.
Preoperative Imaging (See Also Chapters 3, 4, and 11)
Fine-cut triphasic helical computed tomography (CT) with
CT angiogram is the single most useful study in preoperative
evaluation of liver tumors. When the study includes the chest,
abdomen, and pelvis, preoperative staging is reliable and can
identify areas outside of the liver that may need further evaluation or confirm nonoperative candidates. CT can define the
vascular anatomy, identify anatomical variants, determine
resectability, estimate the functional liver residual volume, and
identify preoperative biliary drainage strategies, thereby obviating the need for further radiographic studies. CT angiography in particular has almost prevented the need for traditional
angiography. 3-D reconstruction of the vasculature is particularly helpful in identifying vascular anomalies quickly and
temporally. Furthermore, 3-D reconstruction of the vascular
anatomy may lead to more accurate visualization of tumor
vessel relationships and may be a more accurate study to predetermine the operative line of transection (25). Magnetic
resonance imaging can also provide high-quality vascular and
volumetric assessments of the liver but its principal role is in
characterizing liver tumors of unclear etiology.
In experienced hands, ultrasound is a fast, inexpensive, and
noninvasive modality that can quickly obtain information
regarding tumor size and the amount of liver involvement,
particularly in gallbladder and biliary tumors. It is especially
helpful in distinguishing cysts from solid tumors and should
be used in addition to CT to evaluate cysts for the presence of
septations or mural thickening, which would suggest cystadenoma or a cystadenocarcinoma. Duplex ultrasound is also
particularly helpful as a dynamic study to identify vasculature
in relation to tumor masses.
Anesthetic Techniques
Operative and perioperative morbidity and mortality have
been decreased in part due to changes in anesthetic practices
over the evolution of hepatic resection. A focus on maintaining low central venous pressure (CVP) can greatly reduce
blood loss and keep the operative field clean for proper visualization of the biliary and vascular anatomy during parenchymal transaction. This is accomplished by positioning the
patient in mild Trendelenberg and minimizing intravenous
fluid to maintain systolic blood pressures above 90 mmHg and
urine output to about 25 mL/h. If the IVC is still distended
after mobilization of the liver, parenchymal transection can
wait until central venous pressure is decreased through use of
narcotics, vasodilatory inhalation agents, or direct vasodilators. A central venous pressure of less than 5 mmHg can be
maintained during the periods of liver mobilization and
parenchymal transection. Though a cental venous catheter is a
useful tool to follow the CVP, the surgeon can also look for a
nondistended IVC and for blood coursing through flat intrahepatic veins. If transection is performed under Pringle control, bleeding is generally from hepatic veins, therefore, with a
low hepatic venous pressure, even large tears in hepatic veins
can be visualized to allow ligation or repair without massive
hemorrhage. By Poiseuilles law, blood flow is exponentially
proportional to the radius of the vessel; therefore, even minor
decreases in venous distention can decrease blood loss exponentially. With these techniques, the risk of postoperative renal
failure has not been shown to be significant, nor has the risk of
air embolism, which can be minimized, regardless, by keeping
the patient in about 15 of Trendelenberg (26,27). Normal
resuscitation is performed after the resection is completed and
hemostasis has been achieved.
basic techniques
Positioning, Skin Incision, and Exposure
The patient should be positioned supine with the arms
extended at right angles to the body. Any self-retaining retractor can be utilized, however, we prefer the Goligher retractor to
elevate the costal margin, and this crossbar can be fitted to the
table to form a 45 angle from top of the crossbar to the
xyphoid. The patient should be prepped from the mid-chest to
below the umbilicus, and draped to expose the right chest in
the event a right thoracotomy is necessary to gain additional
exposure. Though some groups routinely make a J-shaped thoracoabdominal incision, in our experience a thoracoabdominal
incision was rarely necessary in over 1800 cases (2). We employ
selective use of diagnostic laparoscopy based on the risk of
unresectable disease (28), and conform the type of incision to
the expected resection. For access to both lobes of the liver, a
bilateral subcostal incision can be used with or without vertical
midline extension. For the great majority of liver resections, we
employ a hockey stick incision, which includes a right subcostal incision with vertical midline extension to the xyphoid.
These incisions, when combined with the Goligher retractor,
provide good exposure of the suprahepatic IVC, even with large
right-sided tumors. We have found a higher rate of incisional
hernia with a Mercedes incision compared to a hockey stick
incision (29). For left-sided resections, a midline incision may
suffice. Occasionally, when there is severe right-sided hepatic
atrophy or exposure to the suprahepatic IVC is necessary for
safety, extension into the right chest can be helpful (Fig. 3.1).
Mobilization
The ligamentum teres is divided between clamps and ligated,
leaving a long secure ligature that is used as a handle to further
expose the porta hepatis. The thin veil of the falciform ligament is incised along its length to free it from the anterior
abdominal wall and expose the ligamentum teres. In obese
individuals, the area where the falciform is fused to the anterior abdominal wall may be invested within a large fat pad.
This fat pad can be removed with diathermy from beneath
25
Figure 3.1 Incisions for liver resection. B-D, initial upper midline exploration.
A-B-C, ideal for exposure of the whole liver (hockey stick). C-D-E, the classic
chevron incision with A-D (Mercedes) extension. C-D, right subcostal incision. F, thoracoabdominal extension. Source: Blumgart; Surgery of the Liver,
Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
the caudate and celiac axis, and providing access through the
foramen of Winslow to the porta hepatis. Intraoperative ultrasound is used at this point to define the extent of disease, vascular relationships, and to confirm resectability.
To mobilize the right liver, the leaf of the right coronary ligament is dissected from the falciform ligament and carefully
incised over the IVC and territory of the right hepatic vein.
This should be done sharply with downward traction on the
liver and superior traction on the diaphragm. Once the right
hepatic vein is identified, the right coronary ligament is taken
close to the liver surface to its furthest extent laterally and the
right triangular ligament is divided. To complete the mobilization, the right liver must be freed inferiorly. Omental and peritoneal attachments to the liver and gallbladder are divided to
expose the inferior extent of the right triangular ligament. The
retroperitoneal attachments are incised off the right adrenal
gland and the liver can then be rotated medially to expose the
retrohepatic IVC.
If the right liver is to be resected or control of the right
hepatic vein is needed, the multiple small venous branches
from the IVC to the posterior liver must be individually dissected, controlled, and divided. Large accessory inferior right
hepatic veins are common and may require division with a
vascular stapler or control with vascular clamps and ligatures.
It is critical for the surgeon on the left side of the table to
retract the right liver medially to expose these branches and
prevent injury to the cava. When all of these branches are
ligated and divided, all that is left to expose the right hepatic
vein will be a fibrous band of tissue that runs lateral to the
vein, encircles the IVC, and courses posteriorly to the left and
posterior border of the caudate, known as the caval ligament
(Fig. 3.3). A tunnel can be safely created medial to this ligament and lateral to the right hepatic vein with a Kelly clamp or
renal pedicle clamp in order to allow either a ligature or a
Figure 3.2 Mobilization of the liver begins with downward traction on the liver and division of the falciform ligament to the inferior vena cava. Source: Blumgart;
Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
26
HEPATIC RESECTION
vascular load endo-GIA staple fire. Once this is divided, the
right liver is mobile and the lateral aspect of the right hepatic
vein is exposed.
The left liver is mobilized similarly, however since it does not
lie on the vena cava, an extensive caval dissection is not necessary. Sharp and blunt dissection over the suprahepatic IVC will
expose the groove between the right vein and the common
trunk of the middle and left and middle hepatic veins. Downward traction on the liver and cephalad traction on the diaphragm help expose the left coronary ligament. The groove
between the left and middle hepatic veins can be exposed with
sharp dissection if there is no long intrahepatic common
channel (Fig. 3.4). Care must be taken here to identify the
phrenic vein as it courses on the underside of the diaphragm
to enter the IVC, as it can be inadvertently injured if the triangular ligament is not properly exposed or not divided close to
the liver surface (Fig. 3.5). As the left lateral segment is released
vascular isolation
Once the liver is mobilized, there are essentially three steps to
safely perform a hepatectomy. These involve vascular inflow
control, vascular outflow control, and parenchymal transection.
Inflow Control
All major hepatic resections require control of the vascular
inflow to be accomplished safely. Furthermore, adequate
Figure 3.3 Multiple small venous branches from the IVC to the posterior liver must be individually dissected and divided. When all of these branches are controlled,
all that is left to expose the right hepatic vein will be a fibrous band of tissue, the caval ligament. A tunnel can be safely created behind this ligament and above the
right hepatic vein with a Kelly clamp. Once this is divided, the entire right liver is mobile and the venous outflow can be encircled and controlled. Source: Blumgart;
Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
27
28
Figure 3.4 Sharp and blunt dissection over the suprahepatic IVC exposes the
right, middle and left hepatic veins. Source: Blumgart; Surgery of the Liver,
Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
Left phrenic
vein
Diaphragm
Left triangular
ligament
Diathermy
Figure 3.5 Downward traction on the liver and cephalad traction on the
diaphragm help expose the left coronary ligament. Care must be taken here
to identify the phrenic vein as it courses on the underside of the diaphragm
to enter the IVC, as it can be inadvertently injured if the triangular ligament
is not properly exposed or not divided close to the liver surface. Source:
Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition;
Chapter 80; copyright Elsevier.
HEPATIC RESECTION
major hepatectomy, extrahepatic control of these vessels is
preferred. Standard anatomy consists of a single right hepatic
vein entering the vena cava, and a left and middle hepatic vein
that is joined and entering the cava as a single trunk. Autopsy
studies of the left and middle hepatic venous trunk have elucidated at least five types of hepatic vein trunk variants (39).
The right hepatic vein is typically encircled after the dissection of the vena cava and caval ligament has been carried out
as described earlier. The base of the right hepatic vein should
be dissected sharply and once exposed, a clamp can be passed
between the right and middle hepatic veins. Exposure of the
left and middle hepatic vein extraheaptically can be challenging. The groove between the right and middle hepatic veins is
initially developed from above the liver. The left liver is mobilized and the ligamentum venosum is divided just before its
insertion into the left hepatic vein. Here a tunnel is carefully
developed underneath the middle and left hepatic vein and
they are encircled (Fig. 3.6). It is often difficult to individually
encircle the left or middle hepatic vein extrahepatically but
this depends on the anatomy of the common trunk. It is
important to identify the hepatic venous anatomy on preoperative imaging and recognize variations in the branching patterns,
since bleeding in this area can be difficult to control. Ligation
of the hepatic venous outflow of the liver can also be accomplished during parenchymal transection with careful exposure
of the cava and the origin of these veins once the liver has
been transected to expose them. The exposures for specific
resections are discussed later in the chapter.
Parenchymal Transection
Once vascular inflow and outflow to the lobe or segment has
been controlled, all that remains is division of the liver parenchyma. There are many techniques to accomplish this. The
instruments used are left to the surgeons preference, but it is
imperative that the vessels and ducts divided be identified
and dissected before division. Transection of the liver should
be a deliberate dissection of intrahepatic structures rather
than simply coagulation of liver tissue. In addition to the
ability to confidently ligate each branch on the transection
(A)
(B)
Figure 3.6 (A) Medial retraction of the left lateral segment exposes the ligamentum venosum. (B) The ligamentum venosum is divided sharply where it is tethered
to the left hepatic vein, releasing the vein and enabling a tunnel to be dissected under the middle and left hepatic veins and anterior to the IVC. Source: Blumgart;
Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
29
left of the IVC, and that the right hepatic vein is skeletonized
completely right at the liver surface. It is especially important
to gain extrahepatic control of the vein with large tumors near
the hepatic venous confluence or in the posterior sector near
the vena cava, where it can be difficult to obtain tumor clearance without excessive traction on the vein. Alternatively, the
right hepatic vein can also be controlled from within the liver
during parenchymal transection, however, this usually forces
the hepatic transection to the right of the true principal
midliver plane.
After inflow ligation, a line of demarcation becomes evident. Figure-of-eight stay sutures are placed to either side
of this line and parenchymal transection can begin safely.
The surgeons left hand lifts the left lobe from above the
IVC carefully as the transection plane is deepened. This
will expose the middle hepatic vein, and division of the
specimen can proceed to the right or left of the vein
depending on tumor clearance. As the dissection proceeds
superiorly, the segment V and then VIII hepatic veins are
divided along the middle hepatic vein. The main right portal pedicle is exposed and divided with the endo-GIA stapler. This will control the right hepatic duct if it was not
controlled extrahepatically.
Alternatively, an anterior approach can be used to resect
the right lobe of the liver. This approach is advantageous
when the right lobe cannot be mobilized due to a large
right-sided tumor, or there is a large mass adherent to the
diaphragm or IVC (46). In this approach, after extrahepatic
inflow division, the liver is transected without mobilization.
It is then freed from its venous and ligamentous attachments
to the IVC and peritoneum. The parenchyma is transected
from the anterior liver surface to the IVC along the line of
demarcation, and venous tributaries are controlled from the
front, including the right hepatic vein (47,48). To help control bleeding in the deeper parenchymal plane, the hanging
maneuver may be employed (49). In this maneuver, the
anterior plane of the IVC is dissected from the liver undersurface. The most inferior veins draining the caudate are
ligated and divided, and a tunnel is carefully created anterior to the IVC to the space between the right and middle
hepatic veins with a Kelly clamp. This is a blind tunnel of 4
to 6 cm. A tape is passed that can then be used to elevate the
liver away from the anterior surface of the IVC, helping to
define the plane of transection and facilitating exposure of
the deeper tissues. In this technique, the right portal pedicle
Brisbane
Segments resected
Right hepatectomy
Right lobectomya
Left hepatectomy
Extended left hepatectomya
Left lobectomy
Right hemihepatectomy
Right trisectionectomy
Left hemihepatectomy
Left trisectionectomy
Left lateral sectionectomy
30
HEPATIC RESECTION
is divided, parenchymal transection is completed to the
IVC, the lateral venous attachments to the IVC are ligated
and divided, the right hepatic vein is stapled, the coronary
and triangular ligaments are divided, and the specimen is
removed.
Right Trisectionectomy (Right Lobectomy, Extended Right
Lobectomy, Right Trisegmentectomy)
A right trisectionectomy is a right hemihepatectomy extended
to include segment IV. The liver is mobilized as described for a
right hepatectomy. To approach the inflow and outflow of segment IV, the ligamentum teres is elevated to expose the umbilical fissure. If a bridge of tissue between segments III and IV is
present concealing the fissure, this should be divided with
diathermy. Here, the ligamentum teres can be traced to its
embryologic origin at the left portal vein. Incising the fibrous
tissue that tethers the left main pedicle to the base of the
umbilical fissure releases the left-sided structures from the
(A)
(B)
(C)
(D)
(E)
Figure 3.7 The anatomy and classification of major hepatic resections. (A) right hepatectomy, (B) left hepatectomy, (C) left lobectomy, (D) extended left hepatectomy,
(E) right lobectomy.
31
Figure 3.9 To expose and control the portal pedicles to segment IV, the liver
tissue is divided to the right of the falciform ligament and the pedicles feeding
segments IVA and IVB are ligated and divided as they come off the main left
pedicle. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th
Edition; Chapter 80; copyright Elsevier.
Figure 3.8 During right hepatectomy, the right hepatic artery usually passes
posterior to the common bile duct and is sharply dissected, ligated, and
divided to the right of the duct. After cholecystectomy, retraction of the cystic
duct will expose the underlying artery. Source: Blumgart; Surgery of the Liver,
Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
32
described for a left hemihepatectomy. The inflow to segments V and VII can be addressed in a few ways. The anterior sectoral pedicle can be encircled intrahepatically either
through hepatotomies or after transection in the right scissura to the left of the right hepatic vein. The pedicle can be
encircled and clamped confirming flow the posterior sector.
Alternatively, an extensive hilar dissection can be carried
out to identify and divide the arterial and portal branches
to the right anterior sector. It is critical that preoperative
imaging is reviewed for anatomic variations in the inflow
and outflow to the right liver. Once the anterior sectoral
inflow is divided, a near horizontal line of demarcation
becomes evident anterior to the right hepatic vein and
dividing the right anterior and posterior sectors. Parenchymal transection continues anterior to the right hepatic vein
and the specimen is removed. The middle hepatic vein is
necessarily taken as part of this resection and is addressed
as described earlier. A left trisectionectomy is a challenging
operation that requires significant experience with major
hepatic resections.
Left Lateral Sectionectomy (Left Lobectomy, Left Lateral
Segmentectomy)
A left lateral sectionectomy involves removal of segments II
and III. The left lobe of the liver is mobilized and the hilar
plate is lowered as previously described. Just to the left of the
umbilical fissure, the portal pedicles to segments II and III are
identified and divided. These can be identified and controlled
through multiple hepatotomies or during parenchymal transaction in a plane just to the left of the falciform ligament. A
deliberate dissection in the umbilical fissure is usually not
necessary. The left hepatic vein is usually divided after parenchymal resection back to its origin but can also be controlled
extrahepatically as described in the outflow control section
of the chapter.
HEPATIC RESECTION
33
conclusion
Major hepatic resections for benign and malignant tumors can
be accomplished safely and efficaciously. Proper patient selection, precise preoperative imaging, specific anesthetic techniques,
and knowledge of the principal complications are essential.
Study of each patients segmental anatomy will allow inflow and
outflow control and the ability to tailor the resection needed for
each individual.
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34
2. Baer HU, Dennison AR, Mouton W, et al. Enucleation of giant hemangiomas of the liver: Technical and pathologic aspects of a neglected procedure. Ann Surg 1992;216(6):6736.
3. Gedaly R, Pomposelli JJ, Pomfret EA, Lewis WD, Jenkins RL. Cavernous
hemangioma of the liver: anatomic resection vs. enucleation. Arch Surg
1999 Apr;134(4):40711.
4. Yoon SS, Charny CK, Fong Y, et al. Diagnosis, management, and outcomes
of 115 patients with hepatic hemangioma. J Am Coll Surg 2003;197(3):
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5. Are C, Gonen M, Zazzali K, et al. The impact of margins on outcome after
hepatic resection for colorectal metastasis. Ann Surg 2007 Aug;246(2):
295300.
6. Cady B, Jenkins RL, Steele Jr GD, et al. Surgical margin in hepatic resection for colorectal metastasis: A critical and improvable determinant of
outcome. Ann Surg 1998;227(4):56671.
7. Cady B, Stone MD, McDermott Jr WV, et al. Technical and biological factors in disease-free survival after hepatic resection for colorectal cancer
metastases. Arch Surg 1992;127(5):5619.
8. Ekberg H, Tranberg KG, Andersson R. Determinants of survival in liver
resection for colorectal secondaries. Br J Surg 1986;73(9):72731.
9. Elias D, Cavalcanti A, Sabourin JC, et al. Resection of liver metastases
from colorectal cancer: The real impact of the surgical margin. Eur J Surg
Oncol 1998;24(3):1749.
10. Kato T, Yasui K, Hirai T, et al. Therapeutic results for hepatic metastasis of
colorectal cancer with special reference to effectiveness of hepatectomy:
Analysis of prognostic factors for 763 cases recorded at 18 institutions.
Dis Colon Rectum 2003;46:52231.
11. Ohlsson B, Stenram U, Tranberg KG. Resection of colorectal liver metastases: 25-year experience. World J Surg 1998;22(3):26877.
12. Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal
liver metastases. World J Surg 1995;19(1):5971.
13. Shirabe K, Takenaka K, Gion T, et al. Analysis of prognostic risk factors in
hepatic resection for metastatic colorectal carcinoma with special reference to the surgical margin. Br J Surg 1997;84(8):107780.
14. Hamady ZZR, Cameron IC, Wyatt J, et al. Resection margin in patients
undergoing hepatectomy for colorectal liver metastasis: A critical
appraisal of the 1 cm rule. Eur J Surg Oncol 2006;32(5):55763.
15. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on
survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005;241(5):71524.
16. Mimica Z, Pogorelic Z, Perko Z, et al. Effect of surgical incision on pain
and respiratory function after abdominal surgery: a randomized clinical
trial. Hepatogastroenterology 2007;54(80):221620.
17. Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging,
and treatment of hepatocellular carcinoma. Liver Transpl 2004;10
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18. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg. 2007;94(3):
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19. Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on perioperative
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21. Orlacchio A, Bolacchi F, Cadioli M, et al. Evaluation of the severity of
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22. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg
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23. Covey AM, Brown KT, Jarnagin WR, et al. Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases. Ann Surg 2008;247(3):4515.
24. Belghiti J. Arguments for a selective approach of preoperative portal vein
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25. Lamade W, Glombitza G, Fischer L, et al. The impact of 3-dimensional
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26. Cunningham JD, Fong Y, Shriver C, et al. One hundred consecutive
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hepatobiliary malignancy: prospective analysis of 401 cases. Ann Surg
Oncol 2003 Mar;10(2):1839.
29. DAngelica M, Maddineni S, Fong Y, et al. Optimal abdominal incision for
partial hepatectomy: increased late complications with Mercedes-type
incisions compared to extended right subcostal incisions. World J Surg
2006;30(3):4108.
30. Blumgart L. Hepatic resection. In: Dudley HAF, Rob C, Smith of Marlow
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31. Tung TT. Les Re?sections Majeures et Mineures du Foie. 1979.
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35. Delva E, Camus Y, Nordlinger B, et al. Vascular occlusions for liver resections. Operative management and tolerance to hepatic ischemia: 142
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36. Emond J, Wachs ME, Renz JF, et al. Total vascular exclusion for major
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37. Emre S, Schwartz ME, Katz E, Miller CM. Liver resection under total vascular isolation. Variations on a theme. Ann Surg 1993;217(1):1519.
38. Hannoun L, Borie D, Delva E, et al. Liver resection with normothermic
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39. Nakamura S, Tsuzuki T. Surgical anatomy of the hepatic veins and the
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40. Fong Y, Blumgart LH. Useful stapling techniques in liver surgery. J Am
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35
introduction
Ultrasound is the initial study of choice in most clinical situations due to the lack of ionizing radiation, relatively low cost,
and accessibility in varied settings such as at the bedside or in
the operating suite. Ultrasound differs from other crosssectional imaging techniques in that it uses sound propagation
and reflection from interfaces within tissue for imaging.
Images are generated by piezoelectric material within the
transducer that transmits and receives the sound signal. Higher
frequency transducers provide the best resolution, but high
frequencies are attenuated more rapidly in tissue. For that reason, transducer frequency is selected for the application.
Superficial structures are evaluated at frequencies in the range
of 6 to 18 MHz and transabdominal ultrasound, which
requires better penetration, typically uses frequencies ranging
from 3 to 6 MHz.
Doppler is a unique feature of ultrasound for imaging vessels and blood flow. When moving blood is insonated, the frequency of the returning signal is proportional to blood
velocity. A cursor is placed over a specific blood vessel and
images are obtained in both gray scale and Doppler (termed
Duplex scanning). The Doppler information can then be
displayed in three different formats: (1) spectral Doppler, (2)
color Doppler, and (3) power Doppler. Spectral Doppler shows
a waveform with velocity changes and flow direction over
time. Color Doppler displays mean velocities and direction of
flow within vessels. The color codes assigned for velocities are
usually displayed in the upper left aspect of the image. Power
Doppler gives the amplitude of the Doppler signal without
direction or frequency information; since it is not angledependent, it is very useful for imaging low flow and
tortuous vessels.
Ultrasound contrast agents further improve applications for
vascular imaging. Current contrast agents use microbubbles
encapsulated within thin lipid spheres. After intravenous
injection, the microbubbles remain intravascular and do not
diffuse into the interstitium as do MRI and CT contrast agents.
After a low-power ultrasound signal is applied, the microbubbles oscillate (expand and contract) at harmonic frequencies
that are detected by the transducer (1,2). With these ultrasound contrast agents, it is now possible to image tumor vasculature in exquisite detail (37) (Fig. 4.1).
Despite the versatility of ultrasound, there are limitations.
Sound is reflected at bone and air interfaces so scans are
obtained from different positions to avoid intestinal air or rib
artifact. This lack of standardized perspective compared to
axial imaging format of CT and MRI may present difficulty for
referring clinicians who are unfamiliar with the technique. To
lessen bowel gas interference, 6-hour fast is recommended to
improve visualization of the pancreas and liver and to provide
sufficient gallbladder distension. Another significant limitation
36
liver
Anatomically the liver is divided into sectors that are defined
by the scissurae that contain the hepatic veins; these sectors are
then subdivided into individual hepatic segments that each
contain intact portal and arterial inflow and hepatic venous
outflow and draining bile ducts (8,9). Ultrasound hepatic
anatomy is shown in Fig. 4.2.
Diffuse Liver Disease
Diffuse liver abnormalities include fatty infiltration, hepatitis,
and cirrhosis. Hepatic steatosis is present in 17% to 33% of the
general population and in 70% of overweight individuals (10).
On ultrasound, the liver has diffusely increased echogenicity
and in advanced cases significant sound beam attenuation
obscures the deep liver. Areas of focal sparring may be seen
anterior to the portal confluence and adjacent to the gallbladder. Hepatic steatosis impacts perioperative outcome and
accurate preoperative diagnosis would be useful (11). Fatty
infiltration increases liver stiffness, which can be measured by
tissue displacement in response to the transmitted ultrasound
wave. These elastography techniques hold promise for diagnosis of diffuse infiltrative liver diseases such as hepatic steatosis
and early-stage hepatic fibrosis (1214).
Focal Hepatic Lesions
Cystic lesions
Ultrasound is the best modality to differentiate cystic from
solid liver masses and to determine the internal architecture
of cystic lesions. Simple cysts, found in 2% to 3% of patients
(15), have thin wall, no internal echoes, and bright posterior
enhancement. Even if the cyst is lobulated or has thin septation, benign diagnosis can be made (16). Symptomatic large
simple cysts may be treated with ultrasound-guided aspiration and sclerosis (15,17), but it is extremely important to
assess the cyst wall. Mural nodularity, thick tumor rim, and
internal vascularity may indicate neoplasm such as biliary
cystadenoma and these lesions should not be unroofed or
aspirated since complete surgical resection is required. Cystic
liver metastases present as complex cysts often with solid or
(A)
(B)
Figure 4.1 Microbubble contrast enhanced ultrasound image of a hypervascular liver mass. (A) Contrast enhanced image shows the intense hypervascularity of
this liver lesion (arrow) that proved to be focal nodular hyperplasia. (B) The lesion (arrows) is subtle on the corresponding grayscale image. (Complements of
Siemens Medical Solutions, Ultrasound Division. Malvern, PA.)
irregular rim. These are typically from sarcoma, cystadenocarcinomas of the ovary and pancreas, and mucinous colon
carcinoma primaries (16,18). Ovarian metastases are characteristically peripheral implants. Squamous cell tumors with
necrosis appear as cystic masses and other metastases may
cavitate in response to chemotherapy.
The appearance of cyst contents on ultrasound can be used
for differential diagnosis. Pyogenic abscess initially may be
echogenic and later liquified with debris, fluid-fluid levels, and
irregular wall (Fig. 4.3). Echogenic reflections with reverberations, seen in 20% to 30% of cases, suggest air within the
abscess (18). The classic echinococcal cyst is a complex cyst
with well-defined wall, containing double echogenic lines.
Multiple, internal echogenic foci, snowstorm signs settle in
the dependent portions of the cyst. Localized splits in the cyst
wall, with floating, undulating membranes, are also characteristic and the cyst wall may calcify (19,20). Hematomas in the
acute stage may be echogenic and then they have layering lowlevel echoes from blood, and later become honeycombed with
septation. When a preexisting cyst becomes hemorrhagic,
internal septation may be thick and irregular, but they float
freely in real-time and are not rigid.
Solid Liver Lesions
Solid liver lesions are further characterized by lesion echogenicity, vascularity, and peripheral halo. Definitive diagnosis
of benignity can be made for hemangiomas, focal fatty infiltration, and focal fatty sparing because of their classic ultrasound
features. Benign focal nodular hyperplasia can also be identified when the characteristic spokewheel vascular pattern, tortuous feeding artery, and marked hypervascularity are seen on
contrast-enhanced ultrasound or Doppler images (Fig. 4.1).
Hypoechoic liver masses and lesions with a peripheral halo are
suspicious for malignancy. Although CT and MRI are used for
tumor staging, there can be added benefit from ultrasound to
37
(A)
(B)
(C)
(D)
(E)
Figure 4.2 Normal liver anatomy. (A) Transverse view of the right lobe. The middle hepatic vein separates the right from left hepatic lobes. The right hepatic vein
divides the right anterior sector (segments 8 and 5) and the right posterior sector (segments 7 and 6). R = right hepatic vein, M = middle hepatic vein, IVC =
inferior vena cava. (B) Longitudinal view of the right lobe reveals the right hepatic vein RHV and the hepatic segments. RK = right kidney. (C) Transverse view of
the portal vein bifurcation. Segments are numbered. R = right portal vein, L = left portal vein, RK = right kidney, IVC = inferior vena cava, A = aorta. (D) Longitudinal view of the left lobe. The left hepatic vein separates the posterior left sector segment 2 from the anterior sector (segments 3 and 4). The caudate, segment 1,
is demarcated anteriorly by the fissure for the ligamentum venosum (arrowhead) and the inferior vena cava posteriorly. IVC = inferior vena cava. RPV = right
portal vein. (E) Color Doppler sagittal image of the portal vein reveals hepatopetal flow.
38
thrombus (29). With ultrasound contrast agents, the hypervascularity and dysmorphic vessels in HCC are more apparent
and there is washout in the portal venous phase.
Hypoechoic liver masses are suspicious for malignancy.
Liver metastases that are hypoechoic are most commonly from
breast, lung, esophagus, stomach, pancreas, and non-Hodgkin
lymphoma.
(A)
(B)
Figure 4.4 Colorectal metastasis to left hepatic lobe was evident on ultrasound but not by CT done the same day. (A) The lateral left lobe was considered negative
on CT. (B) Longitudinal ultrasound revealed a segment II metastases with peripheral halo (calipers) consistent with malignant lesion.
(A)
(B)
Figure 4.5 Hemangioma. (A) Typical hemangioma (arrow) is uniformly echogenic with no surrounding halo. (B) An atypical hemangioma with a thin bright rim
(arrow) is shown in this longitudinal view of the right hepatic lobe. Another hemangioma (arrowhead) is noted peripherally.
39
(A)
(B)
(C)
Figure 4.6 Acute cholecystitis in a 56-year-old woman with abdominal pain. (A) Longitudinal view reveals a laminated appearance to the anterior gallbladder wall
(arrowheads) and gallstone (arrow) with posterior acoustic shadow. (B) Transverse view shows thickened wall at 6 mm (calipers). (C) Longitudinal color Doppler
image reveals vascular flow within the gallbladder wall.
(A)
(B)
Figure 4.7 Gallbladder carcinoma. (A) Longitudinal and (B) transverse sonogram of the gallbladder reveals a stone (arrowhead) with acoustic shadowing. The
anterior fundus is narrowed and surrounded by hypoechoic soft tissue that infiltrates the adjacent liver (arrows).
40
pancreas
The echotexture of the normal pancreas is uniform and slightly
higher echogenicity than liver. With aging and obesity, fatty
infiltration of the pancreas may further increase echogenicity.
The pancreatic duct is best seen transversely and is normally
less than 2 mm in the body and 3 mm in the head (39).
Diffuse Pancreatic Diseases
In acute pancreatitis, the pancreas may become enlarged and
hypoechoic with indistinct margins from edema. The edema
may involve the entire gland or only a portion, usually the
head. Peripancreatic fluid is a useful diagnostic feature; fluid
and vascular mural thickening may also be observed (40)
(Fig. 4.8). Pancreatic duct may be dilated. In the most acute
stage, ileus limits ultrasound visualization and CT is more useful, but ultrasound has a role to exclude biliary calculi as an
etiology for the pancreatitis (4144). Severe inflammation
progresses to inflammatory pancreatic mass or phlegmon with
fluid collection, hemorrhage, and necrosis. Fluid is commonly
seen within the lesser sac, anterior pararenal spaces, transverse
mesocolon, small bowel mesentery, and parapancreatic spaces
(45). Pseudocysts may persist for a minimum of 4 weeks after
the onset of pancreatitis (46). Identification of infected pseudocyst is limited, but the presence of echogenic foci corresponding to gas bubbles is suggestive of infection. If there is
clinical suspicion, ultrasound can provide image guidance for
fluid aspiration or drainage. Venous thrombosis and pseudoaneurysms that occur secondary to pancreatitis can also be
evaluated sonographically.
Ultrasound findings in chronic pancreatitis include alteration of texture, calcification, pancreatic duct, and/or bile duct
dilation, and chronic pseudocyst. The gland is usually atrophic
and heterogeneous. Calcification, either focal or diffuse, and
pancreatic duct dilation are the most classic sonographic features (47). When findings of chronic pancreatitis mimic neoplasm with ductal dilation, CT or MRI is needed to make the
distinction.
Pancreatic Neoplasms
Characterization of pancreatic masses, aspiration and biopsy
are increasingly being done with endoscopic ultrasound
(EUS). Miniature ultrasound transducers mounted on endoscopes display radial or linear images of the pancreas. EUS is
more sensitive for detection of small masses and biopsy can be
performed through the posterior gastric wall (48).
Adenocarcinoma appears on ultrasound as a focal mass with
atrophy and pancreatic duct dilation distal to the mass. Vascular invasion is frequent and bile ducts are dilated commonly
for masses in the pancreatic head. Ultrasound is considered
reliable for diagnosis of nonresectable tumors and in such
cases further imaging is not required; evaluation can proceed
directly to biopsy for tissue diagnosis (40,49) (Fig. 4.9). Staging of pancreatic adenocarcinoma by EUS and CT were compared in a prospective study by DeWitt (50). EUS had higher
sensitivity than CT for tumor detection (98% vs. 86%), better
staging accuracy (67% vs. 41%), and both techniques were
equivalent for nodal status. EUS is also useful for biopsy especially when CT-guided biopsy is negative. In a prospective
study of patients with negative CT-guided biopsy of pancreatic masses, EUS biopsy had 95% sensitivity and 100% specificity for diagnosis (51).
Neuroendocrine tumors such as insulinomas and gastrinomas usually have classical symptoms. When tumors are small,
abdominal ultrasound is limited, but laparoscopic ultrasound
and intraoperative ultrasound are extremely useful for tumor
detection (52,53). Approximately one-third of endocrine
tumors are nonfunctioning and these tumors are more likely
malignant.
Cystic pancreatic neoplasms (serous microcystic adenomas,
mucinous adenomas, and solid and cystic pseudopapillary
tumors) are best evaluated with EUS. Serous microcystic adenomas are benign tumors with multiple cysts ranging in size
from 1 mm to 2 cm. These tumors may appear solid on ultrasound because of numerous interfaces produced by the microscopic cyst walls (5457). Macrocystic mucinous tumors of the
pancreas are malignant or potentially malignant and have
cysts >2 cm. The cysts may have thick septation, mural nodules, and calcification may be present (47,56). It is not possible
to distinguish between benign and malignant mucinous
tumors, but in general, larger cysts and cystic masses with
41
(A)
(B)
(C)
Figure 4.9 Unresectable pancreatic adenocarcinoma. (A) Longitudinal ultrasound image of the pancreas shows an enlarged pancreatic head (m) and dilated common bile duct (arrow), PV = portal vein, IVC = inferior vena cava. (B) Transverse sonogram reveals the pancreatic head mass (m) and dilated pancreatic duct
(arrows) anterior to the splenic vein (SV). IVC = inferior vena cava, a = aorta. (C) Transverse sonogram reveals a left hepatic metastasis (arrows). R = right hepatic
vein, M = middle hepatic vein, IVC = inferior vena cava.
intraoperative ultrasound
Intraoperative ultrasound (IOUS) is an important tool for (1)
assessment of tumors at the time of resection, (2) vascular mapping during hepatic resection or live split liver donor transplantation, and (3) guidance during intraoperative tumor ablation
or biopsy (6064) (Fig. 4.10). During hepatic resection, IOUS is
used to characterize liver lesions that are indeterminate or occult
on preoperative imaging. IOUS can accurately assess tumor
extent relative to vascular structures and bile ducts (6568); this
is important since approximately 1 to 2 cm margin should be
available between the tumor and vessels for optimal surgical
outcome and vessel encasement or thrombosis may alter surgical approach (6972). A prospective study by Cerwenka et al.
(73) evaluated the role of IOUS in patients who had partial hepatectomy after standardized hepatic protocol preoperative MRI.
Small additional lesions with mean size of 1.5 cm were found by
IOUS in 7% of patients and in 5% of patients IOUS findings
altered surgical strategy (73,74). IOUS altered management in
20% of patients who had resection for primary or secondary
hepatic malignancies. Even with recent improvements in crosssectional imaging, there was no significant difference in resection
42
(A)
(B)
(C)
Figure 4.10 Intraoperative ultrasound reveals additional hepatic lesions. (A) A 2 cm segment 7 liver lesion (arrows) with peripheral halo and (B) an 8 mm
segment 6 lesion (arrow) were seen on preoperative imaging. (C) A nonpalpable 6 mm lesion (arrow) in segment 4A was not evident on preoperative imaging.
Lesions were resected with diagnosis of metastatic neuroendocrine carcinoma; primary site later identified in the pancreas. (Complements of Robert A. Kane,
M.D., Professor of Radiology, Harvard Medical School, Chief, Body and Abdominal Ultrasound Imaging, Beth Israel Deaconess Medical Center, Boston, MA.)
interventional procedures and better three-dimensional visualization of tumor and treatment zone during radiofrequency
ablation (63,8284).
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biliary obstruction. Surgery 2006; 140(5): 75663.
38. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;
234(4): 50717; discussion 1719.
39. Hadidi A. Pancreatic duct diameter: sonographic measurement in normal
subjects. J Clin Ultrasound 1983; 11: 1722.
40. Ralls PW, Wren SM, Radin R, et al. Color flow sonography in evaluating
the resectability of periampullary and pancreatic tumors. J Ultrasound
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CT in establishing prognosis. Radiology 1990; 174(2): 3316.
44. Clavien P, Hauser H, Meyer P, et al. Value of contrast-enhanced computerized tomography in the early diagnosis and prognosis of acute pancreatitis. Am J Surg 1988; 155: 45766.
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70711.
46. Donovan PJ, Sanders RC, Siegelman SS. Collections of fluid after pancreatitis: evaluation by computed tomography and ultrasonography. Radiol
Clin North Am 1982; 20(4): 65365.
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1998: 24156.
48. Catalano MF, Lahoti S, Geenen JE, et al. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and
secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc
1998; 48(1): 1117.
49. Yassa NA, Yang J, Stein S, et al. Gray-scale and color flow sonography
of pancreatic ductal adenocarcinoma. J Clin Ultrasound 1997; 25(9):
47380.
50. DeWitt J, Devereaux B, Chriswell M, et al. Comparison of endoscopic
ultrasonography and multidetector computed tomography for detecting
and staging pancreatic cancer. Ann Intern Med 2004; 141(10): 75363.
51. Gress F, Gottlieb K, Sherman S, et al. Endoscopic ultrasonography
Guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann
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52. Fendrich V, Bartsch DK, Langer P, et al. Diagnosis and surgical treatment
of insulinomaexperiences in 40 cases. Dtsch Med Wochenschr 2004;
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and intraoperative sonographics localization. AJR Am J Roentgenol 2003;
181: 78792.
54. Buck JL, Hayes WS. From the archives of the AFIP. Microcystic adenoma
of the pancreas. Radiographics 1990; 10(2): 31322.
55. Fugazzola C, Procacci C, Bergamo Andreis IA, et al. Cystic tumors of the
pancreas: evaluation by ultrasonography and computed tomography.
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56. Johnson CD, Stephens DH, Charboneau JW, et al. . Cystic pancreatic
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57. Friedman AC, Lichenstein JE, Dachman AH Cystic neoplasms of the pancreas. Radiology 1983; 149: 4550.
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patients. Ann Surg 2006; 244(4): 57282.
45
introduction
The recent increase in the geriatric population in society and
increased life span have raised the expectation from surgeons
to expand their operative indications to include geriatric
patients. In liver surgery, the indications for hepatectomy have
been expanded to include patients aged 70 and older, and several studies have demonstrated acceptable long-term survival
of elderly patients after such surgery (1,2). In 1937, Brooks
reported the results of surgery for 287 patients aged 70 and
older. The operative mortality rate was high (19%), and onethird of patients who had abdominal operations died in hospital. Nevertheless, the author emphasized that with the rapid
growth of the elderly population, and prolonged life expectancy, surgeons will increasingly be confronted with surgical
problems among the elderly and must therefore strive to
improve their results by studying physiologic processes in the
aged (2,3). In the seven decades since Brooks paper, advancements in anesthesiology and intensive care, an increased
knowledge of liver physiology, surgical hepatic anatomy, and
resection techniques have encouraged hepatic resection in
elderly patients, achieving improved surgical outcomes.
Because of the high prevalence of liver cancers and aging of
the world population, the elderly population considered for
liver resection has increased (4,5). Also an effective multidisciplinary approach and better selection of elderly patients leads
to reduced age-related perioperative morbidity and mortality
(6). Moreover, the definition of elderly patients has been better defined so avoiding unnecessary confusion that has generated over the past years.
Although advances in minimally invasive ablative techniques
have increased the treatment options for patients with malignant hepatobiliary disease, liver resection remains the only
treatment demonstrated to offer long-term survival (79). Also
the past three decades have seen a dramatic decline in the mortality rate after liver resection in selected elderly patients, which
is less than 5% in tertiary cancer care referral centers (2,6,10).
Colorectal cancer has become a major public health problem that increasingly affects older people (11), and because the
liver is the most common site of metastases, the number of
elderly so affected is increasing (12). Liver resection is also successfully performed in aged patient suffering primary malignancies such as hepatocellular carcinoma (HCC) with results
comparable to those seen in younger people.
In this chapter, we highlight the main advances performed
in liver surgery, taking into account all the issues that are still a
matter of debate for elderly patients with primary or metastatic liver disease.
of arbitrary definition of elderly, in liver surgery the common practice is to identify as elderly a patient older than
70 years (6,1318). This is due to the evidence of a rapid
decrease of liver mass and portal blood flow from 70 years
onward (17), which may affect liver function.
A limited life expectancy in the elderly might argue against
extending the indications for hepatectomy in these patients.
However, life expectancy for people aged between 80 and
85 years is still 8 years, and 6 years for those over 85 years old.
Moreover, the risk of cancer-related death diminishes with
increasing age; it is estimated to be 40% for those aged between
50 and 70 years, falling to 10% for those over 90 years old (19).
Recently, several studies reported comparable early and
long-term results between young and aged patients undergoing liver resection. These studies highlighted that an age limit
does not exist to contraindicate liver resection. After a careful
evaluation of the operative risk, a similar chance of long-term
survival can be offered also to well-selected elderly patients.
47
hepatocellular carcinoma
Primary tumors of the liver are among the most common
solid tumours worldwide (4).
48
49
financial cost
In the current climate of scarce health care resources, treatment for elderly patients has been under close scrutiny. Several
studies have shown that elderly patients have benefited from
liver resection for malignancy with results comparable to those
younger than 70 years of age. The use of health care resources
in terms of intensive care unit and in-hospital stays is no different than in the younger population, and some of this costsaving can be attributed to better support in terms of
anesthesia and community nursing (32). Therefore careful
selection of patients using the ASA grade and meticulous surgical technique are essential to achieve better outcomes after
hepatic resection in patients over the age of 70 years.
conclusions
Age alone should not be considered a contraindication for
liver resection: hepatectomy is safe, effective, and a curative
therapy in the elderly. Major hepatectomies are the feasible
procedure in patients older than 70 years who have preserved
liver function and controllable medical conditions, yielding
close to 0% operative mortality and low morbidity rates in
specialized tertiary centers.
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51
52
introduction
The management of patients with small hepatic metastases
from colorectal cancer and other histologies requires the consideration of many diverse patient- and tumor-related factors.
These factors include the natural history of the tumor type, the
expected cure rate after surgical treatment, effectiveness of
alternative treatments, and the morbidity of surgical resection.
In general, the indications for any major surgical procedure
include the potential for cure, prolongation of survival, and
palliation of symptoms. For metastatic tumors to the liver in
selected cases, the cure rate may be over 50% for colorectal
cancer (1), but will be exceedingly rare for other histologies
such as gastric cases, and melanoma and sarcoma. Small
metastases to the liver generally do not cause symptoms
(except for hormone secreting neuroendocrine tumors) and,
therefore, palliation of symptoms is not a common indication
for management of these lesions. Nevertheless, many issues
remain unresolved. Does resection of a small solitary hepatic
metastasis prolong survival in cases where the patient is likely
to develop widespread metastases in the future? Is there any
harm in allowing a tumor to go untreated for a period of time,
knowing that with close follow-up the resection option may
still be possible in the future? Do metastases metastasize such
that a delay in management may obviate the curative option?
Unfortunately, all of these difficult issues are only addressed by
sparse data in the literature.
The risk and extent of the surgical procedure plays a significant role in the decision making for management of small
hepatic metastases. It is more reasonable to excise an enlarged
subcutaneous lymph node for metastatic cancer than it is to
perform a hepatic lobectomy when the chance of benefit is
low in both cases. As other less invasive ablative options
become routine therapy, it may be reasonable to consider
these options in cases where surgical resection is unreasonable. These alternative options include percutaneous
approaches at ablation such as radiofrequency ablation and
percutaneous alcohol injection (2). Laparoscopic procedures
may also be an alternative for the management of small
hepatic metastases, including laparoscopic resection of
tumors and laparoscopically directed ablation such as cryotherapy. If the risks, discomfort, and hospital stay are truly
minimal, then it becomes reasonable to consider local treatment of these lesions, even with a small chance of overall
benefit to the patient.
This chapter will provide an overview of the data on survival
benefit after resection of hepatic metastases and the techniques
of surgical management. A brief discussion of minimally invasive and percutaneous procedures for management of small
solitary hepatic metastases will follow. In addition, a discussion of the role for adjuvant therapy after resection or ablation
of the hepatic metastases will be included.
53
Author
Date
Actuarial
5-year
survival
(%)
1988
1992
1995
1997
1997
509
185
180
A077
240
37
30
36a
47
47
Median
survival
(months)
45
54
Histology
Neuroendocrine
Neuroendocrine
Genitourinaryb
Sarcoma
Breast/melanoma/sarcoma
Breast
Breast
Gastric
Gastric
Gastrointestinale
4-year survival.
Includes renal (5), testicular (9), adrenal (7), ovary (7), uterine (4), cervix (2).
4 of 21 actual 5-year survivors.
d
1 of 7 actual 5-year survivors.
e
Includes gastric (5), pancreatic (2).
NR: not reached.
b
c
54
N
15
74
34
14
41
21
34
21
A07
A07
Actuarial 5-year
survival (%)
Median survival
(months)
73
73a
60
A00
26
A09
18
19c
14d
A00
NR
NR
NR
30
32
26
27
18
15
25
do metastases metastasize?
For small solitary hepatic metastases, where many months
of growth would still not preclude resection, the question is
whether a waiting period would allow for further spread of
the tumor from the metastatic deposit itself. If metastatic
tumors were unable to further metastasize, waiting for the
first sign of progression prior to initiating treatment and
allowing other metastatic disease to declare itself would
seem a reasonable approach. If, however, metastases are able
to spread during that waiting period, then the chance of
potential cure may be adversely affected by the delay in
definitive treatment. Unfortunately, it is clear that metastatic tumors do have the potential to metastasize themselves, and this must be considered when recommending
observation alone.
Experimental evidence suggests that cells from spontaneous
metastases are more likely to metastasize than cells populating
the parent neoplasm (29). Clinically, the most obvious examples of metastases from metastatic colorectal cancer deposits
are in the cases of perihepatic lymph node metastases (30) and
satellite-tumor formation (31).
Published data would indicate that metastases to periportal
lymph nodes occur in 10% to 20% of cases of hepatic colorectal
metastases (30). The presence of lymph node metastases portends a poor prognosis. Therefore, excision of liver tumors before
they spread to regional lymph nodes would be advantageous.
A recent paper examined the incidence of satellite micrometastasis in colorectal liver metastases by careful histologic
examination of resection specimens and found that 56% of
specimens had micrometastases as far as 3.8 cm away from
the tumor being resected (31). In some cases, these satellites
could be traced to the original metastasis by a trail of cells,
suggesting spread from the original metastasis. As discussed
previously, the presence of satellitosis is an important independent poor prognostic factor. It may be that a delay in
resection allows for the development of satellitosis, which
negatively impacts on prognosis. On the other hand, the
presence of satellitosis may be an indicator of biologic aggressiveness, which portends a poor prognosis regardless of when
the tumor is resected.
patient selection
Colorectal Metastases
In order to decide when surgical resection is reasonable for
small solitary hepatic metastases, it is important to review
prognostic factors that are independent of size and number,
which may influence the decision regarding management of
these tumors. Many studies have examined data on prognostic
factors for outcome after hepatic resection for colorectal
metastases. The time to development of liver tumor after
resection of the primary, pathologic margin, stage of the primary tumor, tumor number, carcinoembryonic antigen levels,
satellitosis, extrahepatic disease, and positive surgical margin
have all been shown to predict survival after hepatic resection
for colorectal metastases independent of size (7,8,10,32).
Extrahepatic disease is considered a contraindication to
hepatic resection. Even the presence of perihepatic lymph
nodes portends a poor prognosis and generally is felt to be a
contraindication to resection. Particularly in the cases of small
solitary hepatic metastases with extrahepatic disease, there
would be no advantage to resection or ablation of the liver
tumor because systemic disease will likely be the ultimate
cause of death regardless of what is done with the liver
metastases. Of the other various factors that are prognostic for
outcome, surgical margin, and satellitosis are the least useful in
patient selection. No one would subject a patient to surgical
resection expecting a positive margin. Satellitosis cannot be
easily assessed preoperatively and therefore is a poor selection
criterion for surgery.
55
Survival
0.8
0.6
0.4
0.2
0.0
0
12
24
36
48
60
Months
Figure 6.1 Prediction of long-term outcome for small (<3 cm) (N = 293)
metastatic deposits based on clinical risk score (CRS). CRS is based on the
following five criteria: (1) node positive primary cancer, (2) disease-free interval <12 months, (3) number of liver tumors >1, (4) size of liver tumor >5 cm
and (5) CEA > 200 ng/dl. For score = 02 (N = 236) (open box), the median
survival was 56 months and the 5-year survival 47%. For score = 34 (N = 57)
(filled triangles), the median survival was 32 months and the 5-year
survival 24%.
56
Neuroendocrine Tumors
Patients with symptomatic neuroendocrine tumors should be
considered for resection or ablation. For the small tumor,
symptoms are most likely derived from hormonal secretion by
the tumors, and such hormone levels will also provide a
marker for effectiveness of the ablation or resection. For
asymptomatic tumors, a period of observation to allow assessment of the pace and aggressiveness of the tumors is reasonable when the tumors are small. At the first signs of progression,
resection or ablation should be considered.
Noncolorectal, Nonneuroendocrine Tumors
Harrison et al. defined prognostic factors involved in the resection of noncolorectal, nonneuroendocrine hepatic metastases
(26). In this study, 96 patients underwent liver resection. The
prognostic factors of significance on multivariate analysis
included the disease-free interval (>36 months), curative
resection (versus palliative incomplete resection), and primary
tumor type. Their conclusions would suggest that regardless of
histology, with a long disease-free interval patients may benefit
from surgical resection.
resection techniques
For small solitary metastases to the liver, the goal of resection
is to completely excise the tumor while preserving the maximum normal hepatic parenchyma. Preserving parenchyma
facilitates postoperative recovery and also provides flexibility
for further resections should intrahepatic recurrences
occur (35). Small surface-oriented metastases can be excised
using a nonanatomic wedge resection, whereas deeper lesions
require formal segmentectomies or sectorectomies. A goal of
at least a 1 cm margin is reasonable (36). The use of intraoperative ultrasound is important to rule out other small hepatic
metastases, which may not be evident on preoperative scans
and in defining the intersegmental planes for designing the
approach to segmentectomy. Even for wedge resections, ultrasound is beneficial in defining the vascular anatomy around
the lesion, which may help minimize blood loss.
Wedge Resections
Wedge resections must be performed meticulously to avoid
inadvertently leaving a positive margin. Large chromic liver
sutures can be placed and used for retraction during dissection. The parenchymal dissection should be performed
along the lines used for other forms of liver resection. We
prefer the Kelly clamp technique where the clamp is used to
crush the normal parenchyma, exposing vessels that are then
clipped, tied, suture ligated, or stapled using a vascular stapling device (37). The Pringle maneuver is used intermittently for 5 minutes at a time followed by reperfusion of the
parenchyma, during which time the argon beam coagulator
is used to coagulate small bleeding vessels on the surface.
This technique is superior to the simple use of electrocautery for the dissection, which is often attempted for what
seems to be routine wedge resections. The char effect of the
electrocautery prevents adequate visualization of the anatomy, making it quite easy to stray into large vessels or into
the tumor.
Segmental Resections
For all but the most superficial lesions, we prefer a segmental
approach for the resection of tumor (39). Segmental resections have a significantly lower rate of pathologic positive
margins, and this translates into improved long-term
survival (40). Small, deep solitary metastases and surface
lesions adjacent to major vascular structures lend themselves
particularly well to segmentectomies or sectorectomies. The
intersegmental planes can be identified intraoperatively using
vascular landmarks with the aid of intraoperative ultrasound.
Using these planes for parenchymal dissection will minimize
blood loss and help ensure a safe margin.
Inflow occlusion for the segment can almost always be performed first, thereby producing demarcation of the segmental
planes to further enhance the dissection. The portal triad to
segments II, III, and IV can be identified and controlled within
the umbilical fissure with little parenchymal dissection (37).
The right posterior sectoral pedicle can be found by dividing
the parenchyma along a horizontal cleft (fissure of Gans) present on the inferior surface of the right lobe of the liver. The
pedicle can be traced to its bifurcation to segments VI and VII
for control of the individual segmental portal triads. The anterior sectoral pedicle can be dissected from an inferior or anterior approach.
The major hepatic veins lie within the intersegmental planes
and can be a source of significant blood loss during the
parenchymal transection phase of a segmentectomy. The use
of low central venous pressure (05 mmHg) during parenchymal dissection can decrease back bleeding in these veins (41).
Extrahepatic control of the left, middle, and right hepatic veins
can also be achieved and the vein of concern temporarily
57
(A)
(B)
(C)
(D)
Figure 6.2 An example of a small, solitary colorectal metastasis to segment VI. (A) MRI reveals subtle abnormality not seen on CT scan. (B) Intraoperative ultrasound reveals the tumor and adjacent segment VI portal vein. (C) Intersegmental planes have been marked on the liver capsule with electrocautery and parenchymal dissection begun. (D) Resected segment with tumor (microscopic negative margins). (Special thanks to Dr Peter Choyke for MRI scan.)
radiofrequency ablation (45). These techniques will be discussed further in chapter 8. They provide ideal alternatives to
laparotomy and major liver resection for the treatment of
small solitary hepatic metastases, since the small tumor is
the most likely to be completely treated by ablation techniques. Furthermore, treatment by ablative techniques does
not preclude future resection.
Percutaneous approaches to tumor ablation are even more
attractive than laparoscopic procedures. Local injection of
toxic agents such as ethanol has been shown to be effective
for hepatocellular cancers, however these agents have not
been proven for other histologies and are known to be
poorly effective for colorectal cancer (2). Radiofrequency
ablation can be performed percutaneously under ultrasound
guidance with local anesthesia. Figure 6.3 demonstrates a
case of a metastatic pancreatic cancer 2 years after a dramatic primary response to gemcitabine and radiation therapy. Because the patient will likely begin to fail in multiple
sites in the near future with limited survival potential, a laparotomy and hepatic resection was not considered reasonable. She was treated with percutaneous radiofrequency
ablation, achieving a good zone of necrosis encompassing
the mass, and she spent only one day in the hospital with
very minimal discomfort. How such procedures, which have
low morbidity and which maintain quality of life, will factor
58
adjuvant chemotherapy
The role for adjuvant systemic chemotherapy after the
removal of small solitary hepatic metastases is not well
defined. Even for hepatic colorectal metastases, which are
commonly treated with surgery, data on adjuvant chemotherapy after liver resection is sparse. Two retrospective studies
have suggested a benefit of adjuvant systemic chemotherapy
after metastasectomy, but others have not supported this
(6,4648). Use of systemic chemotherapy after resection of
hepatic colorectal metastases is based mainly on data demonstrating adjuvant 5-fluorouracil (5-FU) and levamisol or
5-FU and leucovorin to decrease recurrence rate and improve
survival when used after resection of the primary tumor (49).
It is hoped that a similar benefit will be seen when 5-FUbased chemotherapy is used after metastasectomy. Current
practice is to offer adjuvant 5-FU-based chemotherapy after
hepatic resection to patients who have had no previous chemotherapy. There are currently no data to support the use of
irinotecan and oxaliplatin in an adjuvant setting, although
studies are in progress.
(A)
(B)
(C)
Figure 6.3 An example of a small, solitary pancreatic cancer metastasis treated with percutaneous radiofrequency ablation. (A) Pretreatment CT scan reveals
hypodense 3 cm right lobe liver metastasis. (B) Ultrasound hoto with radiofrequency probe inserted into tumor. (C) Post-treatment scan (3 weeks) reveals large
zone of necrosis replacing prior tumor. (Special thanks to Dr Thomas Shawker for ultrasound photo.)
conclusions
Algorithms for the management of small solitary hepatic
metastases are shown in Figure 6.4. Both patient and tumor
characteristics must be considered in making management
decisions. The most important tumor-related characteristic is
59
High CRS
(34)
Low CRS
(02)
Observation
or
chemotherapy
Resection
No
extrahepatic
progression
Extrahepatic
progression
Resection
or ablation
Chemotherapy
Ablation
Resection
Adjuvant
therapy
protocol
Adjuvant
therapy
protocol
(A)
Neuroendocrine
metastases
Symptomatic
Non-colorectal
non-neuroendocrine
Asymptomatic
Long disease-free
interval
Resection
Ablation
Short disease-free
interval
Observation
Resection
Progression
No
progression
Resection
or ablation
Observation
(B)
Effective
chemotherapy
(>20% response)
No effective
chemotherapy
Trial of
chemotherapy
Ablation vs
observation
(C)
Figure 6.4 Algorithms for the management of small hepatic metastases. (A) Algorithm for colorectal metastases (CRS, clinical risk score). (B) Algorithm for
neuroendocrine metastases. (C) Algorithm for non-colorectal, non-neuroendocrine metastases.
60
repeat anatomic liver resections in the future for recurrent disease. Enucleation with positive margins is acceptable for treatment of this histology because resection is almost never
curative, and such cytoreduction can provide significant and
durable palliation with minimum risk.
For patients with small, solitary, noncolorectal nonneuroendocrine tumors, the most significant factor in terms of
prognosis seems to be the disease-free interval (Fig. 6.4C).
For patients with a long disease-free interval from primary
resection a curative surgical resection is indicated as the
most effective means of therapy. While it may be still unlikely
that these patients can be cured, they must be given the benefit of the doubt and the most optimal procedure performed.
The definition of long has been arbitrarily set at 36 months
by Harrison et al. (26), but in reality it must vary according
to histology. For gastric cancer, 1224 months would be
key points
Factors that determine management
Contraindications
Extrahepatic disease (except solitary pulmonary
metastases)
Positive hilar lymph nodes
Relative contraindications
Presentation within 12 months of resection of
primary tumor
CEA >200 ng/dl
>1 liver tumor
Tumor >5 cm in size
Positive resection margin
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Hepatectomy for liver metastases from breast cancer. Eur J Surg Oncol
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introduction
The safety of elective liver surgery has improved dramatically
in the past 30 years. A multicenter American series comprising
621 liver resections published in the late 1970s reported a 13%
mortality (1). By contrast, recent large published series
describe posthepatectomy mortality rates of 0% to 4.4%, with
19.6% to 45% morbidity (28) (Table 7.1). Furthermore, individual units have demonstrated a significant reduction in
morbidity and mortality over time, despite ever-widening the
indications for hepatectomy (6,8). This dramatic improvement in immediate postoperative outcome can be explained
by increased specialization of liver surgery in high-volume
centers (9), better selection of patients in terms of hepatic
functional reserve and comorbid conditions, advances in surgical technique, including greater understanding of hepatic
segmental anatomy and improved instrumentation for the
parenchymal transection. Furthermore, anesthesia and critical
care has improved enormously, the routine use of low central
venous pressure (CVP) anesthesia being a particular advance.
However, even a 20% complication rate remains significant,
particularly if the indication for hepatectomy is for livingdonor transplantation. Furthermore, postoperative morbidity
can also adversely affect disease-specific and disease-free survival (1012). Thus the short- and long-term consequences of
postoperative morbidity, coupled with increasing litigation,
and limited health care resources, has renewed the drive to further improve the immediate outcome from liver resection,
with emphasis on prevention of and improved management of
complications, when they occur. The precise definitions of the
specific complications such as bleeding, bile leak, and hepatic
insufficiency are still without consensus. Moreover, the stratification of the severity of each complication is still unclear.
Standardized definitions, grading, and reporting of the complications of hepatectomy are needed to allow an objective,
quality assessment of outcome data from different units and
further improve results. The system proposed and validated by
Clavien, focusing on the therapeutic consequences of complications in order to rank their severity, is currently the best
available (13). However, it is still not universally adopted
within the surgical community.
A number of studies have attempted to identify the risk factors associated with complications and death from hepatectomy, three of which are detailed in Table 7.2. From these
studies, there is consensus that the estimated blood loss or
blood transfusion rate, the extent of hepatic resection, and an
additional extrahepatic procedure are all independent predictors of morbidity and mortality. In addition, medical comorbidity, an elevated preoperative creatinine, preoperative
thrombocytopenia, or hypoalbuminemia also appear to
increase the operative risk. However, in the Hong Kong
study (8), while cirrhosis per se was associated with increased
bleeding
Incidence
Bleeding is the most feared complication of hepatectomy, both
on the operating table and in the immediate aftermath of surgery. In the 1960s and 1970s, it was the cause of major morbidity and mortality. The 1974 Liver Tumor Survey was a
multicenter series of 621 hepatic resections performed in 98
U.S. centers, published in 1977. It reported a 13% mortality,
with 15 of the 82 deaths (18%) due to exsanguinating hemorrhage in the operating room and bleeding being the documented primary cause of death in 26 of the 76 patients (34%),
where the cause of death could be determined (1). However,
bleeding is now relatively rare, with the median estimated
blood loss for an elective hepatectomy being 345 to 600 ml
(3,6) and the need for perioperative blood transfusion now
being the exception rather than the rule. Indeed, the incidence
of major hemorrhagic complications is rare, 0.7% (7/1005) in
our own series (3). Of these seven cases, there were no on-table
deaths, five patients were treated nonoperatively and two
underwent reexploration for bleeding from a hepaticojejunal
anastomosis and a left caudate branch of the portal vein
respectively. In the Sloan-Kettering series of 1803 patients, the
incidence is similar (1%) (6).
Prevention
Prevention remains the key to the management of bleeding. In
the preoperative assessment, a careful drug history should be
taken. If the patient is on drugs such as aspirin, clopidogrel, or
warfarin, the indication for the treatment should be reviewed,
and the drugs stopped where possible. Patients on warfarin as
prophylaxis for thromboembolic events can be managed with
an inferior vena cava (IVC) filter, placed preoperatively. It is
63
Years of study
No of centers
No of resections
Imamura
et al.
Rees et al.
Wei et al.
Malik et al.
Jarnagin et al.
19942002
1056
19872005
19922002
19932006
19912001
1
2
1
1
1005
423
687
1803
Belghiti et al.
19901997
747
Poon et al.
19892003
1222
Case-mix
50% HCC
29% cirrhotic
100% CRLM
100% CRLM
100% CRLM
62% CRLM
10% HCC
Elective & emergency.
35% benign 28% HCC
17% CRLM
32% cirrhotic
60% HCC
33% cirrhotic
Mortality
Morbidity
0%
39%
1.5%
1.7%
3.0%
3.1%
25.9%
19.6%
29.5%
45.0%
4.4% all
3.9% elective
8.7% cirrhotic
25.0% emergency
4.9%
22.0%
32.4%
Table 7.2 Three Studies Reporting the Independent Predictors of Morbidity and Mortality after Hepatic Resection
Reference
Jarnagin et al.
Years of study
19912001
No of resections
1803
Belghiti et al.
19901997
Poon et al.
19892003
1222
Predictors of morbidity
Estimated blood loss
Extent of resection
+ EH procedure
preoperative creatinine
Hypoalbuminemia
Medical comorbidity
Male gender
ASA score
Extent of resection
Steatosis
Blood transfusion
+ EH procedure
Thrombocytopenia
Blood transfusion
+ EH procedure
Predictors of mortality
Estimated blood loss
Extent of resection
+ EH procedure
preoperative bilirubin
Thrombocyt openia
Age
+ EH procedure (in patients with
malignancy)
Hypoalbuminemia
Thrombocytopenia
preoperative creatinine
Major resection
Blood transfusion
64
Late (weeks/
months)
Specific complications
Hypothermia
Bleeding
Respiratory
atelectasis, pleural
effusion, pneumonia
Cardiovascular
DVT, PE, MI,
arrhythmias, CVA
Renal failure
Wound infection
Pain
Incisional hernia
Bleeding
Bile leak
Hepatic insufficiency
Intra-abdominal
abscess
biliary complications
Biliary stricture
65
66
hepatic insufficiency
Definition and Incidence
There is currently no internationally accepted definition of
postoperative liver failure or hepatic insufficiency. Belghitis
group have proposed the 50-50 criteria, which are a prothrombin index <50% of normal (corresponding to an International Normalized Ratio (INR) of 1.7 or more) and a
serum bilirubin > 50 mol/L on postoperative day 5, as a
simple, accurate predictor of liver failure and death (47). On
the fifth postoperative day, both prothrombin time and bilirubin should have returned to normal values. They found
that the persistence of the 50-50 criteria at this time indicated a significant impairment of liver function and was
associated with a 59% risk of early postoperative mortality,
compared with a 1.2% risk if the criteria were not met. They
recently prospectively evaluated these criteria in a cohort of
436 elective hepatectomies and found that the 50-50 criteria on postoperative days 3 and 5 were accurate predictors of
death on multivariate analysis (48). The MD Anderson group
reviewed data from 1059 noncirrhotic patients who underwent a major hepatectomy and found that a peak bilirubin of
more than 120 mol/L (7.0 mg/d/L), accurately predicted
liver-related death and suggested that this be used as a definition (49). By this definition, the incidence of postoperative
liver failure with or without multiorgan failure resulting in
death in their series was 2.8%. In the French multicenter
series of 1568 hepatectomies, the incidence of liver failure
was 43/1568 (2.7%), however this was responsible for death
in 7/43 (16%) of those patients (50). In the Hong Kong series
(8), postoperative liver failure occurred in 47 out of the
1222 hepatic resections (3.8%), but again, it is not defined.
This series had a higher incidence of patients (59.2%) with
cirrhosis or chronic hepatitis compared to most Western case
series. Overall, the reported incidence in the literature ranges
from 0.7% to 9.1% (51).
67
intra-abdominal infection
Importance and Incidence
Posthepatectomy infections are important as they can precipitate liver failure and death, as discussed earlier. The incidence
of infected perihepatic collections ranges from 2.7% to 6.1% in
modern case series (6,8), but is higher (12.8%) in older series
(74). The incidence of infected ascites is less than 1% (8).
Factors Affecting the Incidence of Intra-abdominal Infection
The decreasing incidence of intra-abdominal infections over
time is a reflection of the evolution of liver surgery in the past
30 years. In Yanagas series of 149 liver resections performed
between 1973 and 1984, 19 patients (12.8%) developed intraperitoneal septic complications, of whom 13 patients died of
liver failure (74). They identified five risk factors for this,
which were: (1) right or extended right hepatectomy, (2) age >
65 years, (3) operation time > 5 hours, (4) blood loss > 3L, and
(5) postoperative bleeding, which required a laparotomy to
achieve hemostasis. A further Japanese case series of 535 hepatectomies performed between 1992 and 2005 reported that
advanced age, diabetes mellitus, the use of silk sutures, and bile
68
leakage were all associated with postoperative infective complications (75). They show a reduction in their postoperative
infection rate from 44.7% at the start of the study to 9.2% by
the end, with improvements in clinical practice such as early
enteral nutrition and aggressive management of bile leaks.
There is no evidence that the use of postoperative systemic
antibiotics reduces postoperative infective complications. In a
prospective randomized trial, Wu and coworkers showed that
postoperative systemic antibiotics after liver resection did not
influence the incidence of infective complications, which was
23% in each group (76). Another prospective randomized trial
investigated whether omentoplasty to the hepatic parenchymal transection surface reduced the incidence of deep abdominal complications (bleeding, hematoma, infection with or
without purulent discharge through drains, or bile leakage).
The authors found that while deep abdominal complications
were significantly associated with major hepatic resections,
omentoplasty did not reduce their incidence (77).
Abdominal Drainage
The use of routine drainage after liver resection and its role
in preventing complications remains controversial. A prospective randomized trial involving 186 patients compared
closed suction drainage with open drainage after elective
hepatectomy. The trial showed that the incidence of infected
subphrenic collections, postoperative ascites, and pleural
effusion was significantly lower in the closed suction drainage group. However, both groups showed similar rates of
subphrenic hematoma and biloma formation (78). In contrast, another trial prospectively randomized 120 patients
undergoing elective hepatectomy to closed suction drainage
or no drainage (79). This showed no difference in overall
complication rate between the two groups. However, 18% of
patients in the no drainage group subsequently required a
percutaneous drain, compared to 8% in the drained group,
but this was not statistically significant. The authors concluded that routine drainage was unnecessary after elective
hepatectomy and adopted a selective drainage policy. A trial
from Hong Kong, which randomized 104 patients with
chronic liver disease to closed suction drainage or no
drainage, showed that there was significantly higher morbidity in the drainage group (73%) compared to the no drainage
group (38%) (80). Further, specifically there was a higher
incidence of wound complications in the drainage group and
a trend towards more septic complications.
In conclusion, elective closed suction drainage in patients
with chronic liver disease is not recommended. For all other
patients, there is no evidence that routine abdominal drainage
prevents postoperative abdominal septic complications. However, for patients at high risk of bile leakage (as outlined earlier
in this chapter), routine drainage is recommended.
cardiac complications
In our own series, the Sloan-Kettering and the Hong-Kong
series, the most common cardiac complication of hepatectomy
is arrhythmia, with an incidence of 2% to 5% (6,8). Myocardial
infarction and heart failure will also occur in about 1% of
patients. At-risk patients should be identified preoperatively
and undergo a cardiac assessment with exercise or pharmacological stress echocardiography and coronary angiography. Cardiac function should be optimized preoperatively with medical
therapy, coronary stenting, and coronary artery bypass grafting
as required. We have also used a perioperative intra-aortic
balloon pump (86).
renal failure
Definition and Incidence
Renal failure is defined as the need for renal replacement therapy. Studies have shown that 3% to 7% of patients require
renal replacement therapy after liver resection (21,87). In our
own case series, the incidence is 0.9% (unpublished data).
Etiology of Renal Failure After Hepatic Resection
There are three main factors which may contribute to the
development of renal failure following liver resection. Elderly
patients and those with conditions such as hypertension,
atherosclerosis, or chronic kidney disease are at risk (88).
These patients have a reduced capacity for neurohumoral
autoregulation of glomerular blood flow during surgery and
thus an increased risk of acute tubular necrosis (ATN) (88).
Perioperative use of NSAIDs may also impair normal autoregulation of glomerular perfusion through inhibition of
arteriolar dilatory prostaglandins (88) and should be avoided
in patients with preoperative renal impairment. The second
factor relates to the hit of surgery. Two key factors in the
pathogenesis of ATN are hypovolemia and renal damage by
inflammatory mediators (87). Both these events are predictable in every hepatic resection that employs low CVP anesthesia and portal inflow occlusion. Obstruction of the portal
blood flow with the Pringle maneuver causes splanchnic
venous congestion and, in combination with warm ischemic
liver injury, results in a flush of anerobic metabolites and
cytokines into the systemic circulation on release of the
hepatic inflow clamp (23). Low CVP anesthesia relies on
patients being maintained in a hypovolemic state until liver
resection has been completed (20,21). This is in contrast to
most other major surgical procedures, where patients are
given significant volumes of crystalloid and colloid in the
perioperative period. Moreover, vasodilators are often used
to further reduce the CVP, leading to distributive changes in
blood flow (20). Certainly, low CVP anesthesia with or without hepatic inflow occlusion can produce major circulatory
changes, potentially resulting in ATN and subsequent renal
impairment or failure (87). Another factor, which contributes to the etiology of renal failure following liver resection is
a low perfusion state either secondary to cardiac dysfunction
or distributive circulatory changes, such as sepsis or hepatorenal failure (87,88). Postoperative renal dysfunction is
often multifactorial.
Consequences of Postoperative Renal Failure
The potential consequences of acute kidney injury include
increased risk of mortality and may contribute to the
development of chronic kidney disease (89).
69
wound complications
The incidence of wound infection was 5.2% in the SloanKettering series, with a further 10 patients (0.5%) having a
wound dehiscence (6). The Hong Kong series of 1222 liver resections reports double these complication rateswith 115 patients
(9.4%) developing a wound infection and 16 patients (1.3%)
suffering wound dehiscence (8). An explanation of the higher
incidence of wound complications in the Hong Kong series may
be their higher percentage of cirrhotic patients (33% vs. 9%).
A study from Japan of 626 liver resections, with a 7.7% incidence of incisional hernias, examined the risk factors for this
(90). Risk factors included the type of incision, with a reversed
T incision having a significantly higher incidence of an incisional hernia (21.7%) compared to midline (6.3%), J-shaped
(4.7%), or a right transverse incision with long midline extension (5.4%). Furthermore, postoperative ascites, body mass
index, repeat hepatectomy, and steroid use were also significant risk factors. The incidence of reported incisional hernia
was 0.2% in our own series, with the two known patients who
developed incisional hernias undergoing repair of these at the
time of repeat liver resection. We believe this low incidence is
related to the method of closure of the J-shaped wound, with
a tension-free, 2-layer closure, using a 6:1 suture (looped
0-nylon) to woundlength ratio, as opposed to the traditional
4:1 ratio (85).
conclusions
The safety of elective liver surgery has improved dramatically
in the past 30 years, despite ever-widening indications for
hepatectomy. However, complications still happen and prevention is the key to minimizing their incidence. When complications do occur, they should be aggressively managed, in a
high-dependency environment, by a multidisciplinary team.
International consensus regarding definitions of complications and a severity classification is still required.
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Pancreatic resection
Thilo Hackert, Moritz Wente, and Markus W. Bchler
background
Pancreatic cancer remainswith an overall long-term survival rate of less than 1%one of the most difficult cancers to
treat. It is the fourth leading cause of cancer-related mortality
in the Western world and is responsible for around 30,000
deaths per year in the United States and 65,000 per year in
Europe (1,2). In only 10% to 20% of pancreatic cancer patients
potentially curative surgery is possible, and even in these
patients, the median survival is only 10 to 18 months with
5-year survival rates of approximately 20% to 25% (3,4).
Nonetheless, surgery remains the only treatment option with
the chance of cure. Pancreatic surgery has significantly changed
during the past few years. Irrespectively, pancreas resections
remain an intervention of particular significance, often technically challenging and with high logistic demands for preoperative diagnostics and perioperative management. Recently, the
value of centralization of pancreatic surgery in high volume
institutions has been demonstrated. The current mortality
rates following pancreatic resections are well below 5% in specialized surgical centers (5,6).
standard resections
Whipple Resection
Partial Pancreaticoduodenectomy (Whipple resection) with or
without distal stomach resection is the surgical option for
tumors of the pancreatic head, which account for the majority
of pancreatic cancers (Fig. 8.1). Pylorus-preserving pancreaticoduodenectomy has been proven to be equal to the classical
pancreaticoduodenectomy in terms of tumor recurrence or
long-term survival, and should therefore be considered the standard procedure for tumors of the pancreatic head (7). Key steps
of the surgical procedure are the postpyloric division of the duodenum, which is usually carried out by use of a stapling device
andmeanwhile common in many centersthe supracolic
division of the ascending duodenum as soon as this portion is
reached during resection. This modification facilitates the resection procedure and allows manual control of the pancreatic head
without switching positions between the supra- and infracolic
department. Division of the pancreas is done sharply above the
superior mesenteric vein after this has been tunneled to make
sure that the vein is not injured during resection and that the dissection can be done without vein replacement (see below).
After removing the specimen, tumor-free resection margins
should be confirmed intraoperatively by frozen sections of the
cut end of the bile duct and the cut end of the pancreatic remnant. Bleeding control along the pancreatic dissection margin
is achieves by carefully stitching single bleeding sites with
monofilament and nonabsorbable sutures. The pancreatic
duct must be seen and protected during this procedure. During pancreaticoduodenectomy, a standardized lymphadenectomy needs to be carried out. This includes the complete
73
Figure 8.1 Partial pancreaticoduodenectomy. Classical Whipple resection (left) and pylorus-preserving modification (right).
Figure 8.2 Intraoperative situs after partial pancreaticoduodenectomy. Pancreatic remnant with probe introduced, dissected portal vein and hepatic
artery. A jejunal loop is prepared for the pancreaticojejunostomy.
mesenteric vein are suitably located for this procedure. Dissection of the pancreas is performed above the vein after tunneling and lifting up the body of the gland. The dissection
itself can be done sharply or by using a stapling device, preferably with a thickness-adopted adjustment of the stapler. To
date, there are no high-power studies to support either procedure. In case of sharp dissection, we prefer a V-shaped transection line. As in other resections, tumor-free resection margins
should be examined by intraoperative frozen section. The pancreatic duct is separately closed by a monofilament Z-shaped
nonabsorbable suture and the transection line can afterward
be closed by single stitches covering the complete margin by
pancreatic capsular tissue. There is no need or evidence for any
further covering of the resection margin by sealants or
patches (18). This procedure implies a certain limitation concerning the extent of distal resection toward the head of the
74
pancreas. The larger the tissue area of the transected parenchyma gets, the more difficult it gets to close the parenchyma,
which is associated with increased fistula rates. Therefore, the
right margin of the superior mesenteric vein represents the
limit to which a safe surgical closure of the pancreatic remnant
can be performed. In case of transection by a stapling device,
this limitation is technically implied by the length of the stapler line. No additional sutures are necessary after stapler dissection. Despite all approaches, fistula development after distal
pancreatectomy remains an unsolved problem. Fistula rates
range from 12% to 40% (8,19). To address this clinical problem, remnant closure by sutures after sharp dissection is currently compared to stapler dissection in a randomized
controlled study (DISPACT trial) in a multicenter approach
including 21 European centers and 360 patients by February
2009 (20). A spleen-preserving distal pancreatectomy can be
performed in benign lesions or intraductal papillary mucinous neoplasias (IPMNs), if the splenic vessels are not involved
in the tumor or cystic process. However, there are no clear
advantages in preserving the spleen in adult patients (21). Possible advantages could be infection prophylaxis, less operative
blood loss, fistula rates as well as fewer thromboembolic complications (22,23). By contrast, the risk of splenic infarction
and portal hypertension has to be regarded whenever the
spleen is preserved. From the currently available literature
mainly retrospective studiesnone of these parameters is
clearly proven, further studies have to address this topic in the
future. By contrast, there is growing evidence that distal pancreatectomy can be performed with good results laparoscopically. This approach is usually performed using 5 trocars and
stapler dissection of the pancreas. It is routinely performed in
several centers with results comparable to the open approach
in terms of operative morbidity and outcome (23). The possible advantages of laparoscopic operations, with faster patient
recovery, less pain medication, and better cosmetic results are
currently evaluated in larger series.
Total Pancreatectomy
The concept of total pancreatectomy has to be divided into the
rescue procedure in not conservatively managed postoperative
PANCREATIC RESECTION
Figure 8.3 Pancreatico-jejunostomy. Preparation of duct sutures (upper left), position of the jejunal loop (upper right), anterior wall sutures (lower left), and
completed anastomosis (lower right).
75
Figure 8.4 Pylorus-preserving pancreatic head resection (Berne modification). Note the incision and fixation of the bile duct in the resection cavity.
Figure 8.5 Pylorus-preserving pancreatic head resection (Berne modification). Resection cavity with first layer of the posterior wall of the pancreaticojejunostomy
(left), completed anastomosis (right).
76
PANCREATIC RESECTION
achieve surgical cure. Limited resections represent a tissuesparing treatment option to minimize the risk of exocrine
or endocrine pancreatic insufficiency postoperatively (42)
and to reduce surgical morbidity and mortality by reduced
operative trauma. One of the most important aspects to
perform an enucleation successfully is the accurate localization of the tumor or cystic lesion. Besides preoperative
localization by CT or MRI scan, the most important tool
for tumor location is the experience of the surgeon performing the exploration (4346). Mobilization of the pancreas is essential when tumors or cystic lesions have to be
located to enable a careful digital examination of the suspected lesion. This should be supplemented by intraoperative ultrasound to exclude multifocal tumorous lesions
especially in endocrine tumors or IPMNs. In addition, a
possible relation to the pancreatic duct can only be clarified
by ultrasound examination, if there is any doubt about it
intraoperatively (47).
A tumor size of 2.5 cm in diameter can be regarded as the
limit for a safely performed enucleation. Tumors measuring
more than 2.5 cm in size show malignant histological changes
significantly more frequently, making a local surgical approach
impossible. Besides, tissue trauma and wound surface following an enucleation reach a critical size for development of fistulas or other complications including bleeding or postoperative
pancreatitis (47). Enucleation itself is performed by careful
dissection along the tumor under clip ligation or stitching of
vessels supplying the lesion (Fig. 8.6). There is no evidence for
any sealant or glue application after completing of the enucleation. Drain placement is essential as currently fistula rates of
approximately 20% are reported (48), most of them, however,
clinically uncomplicated.
exceptional indications
Vessel Resections
A common problem in pancreatic head resections is tumor
adherence to the superior mesenteric or portal vein. Today,
portal vein resection has become an established procedure and
can be carried out with morbidity rates of that are comparable
to standard Whipple procedures (4956). Portal vein resection
can be performed as a tangential resection with a direct suture
or a patch reconstruction. In cases where a segmental resection
is required due to a more extensive tumor adherence, either a
direct anastomosis or the interposition of an autologous venous
graft such as the saphenous vein or an allograft, e.g., a gore-tex
tube. In case of a primary anastomosis, it is essential to mobilize the mesenteric root completely, which implies the complete
mobilization of the right hemicolon. After this preparation, a
tension-free reconstruction of defects up to 3 cm length is usually possible. The anastomosis is performed as a running suture
of the posterior and anterior vessel wall with two 5-0 or 6-0
nonabsorbable sutures. When defects cannot be reconstructed
by the patients vein alone, a size-adopted graft should be
inserted in a similar end-to-end manner (52). Kinking of any
venous anastomosis must be avoided to prevent intra- and
postoperative vein or graft thrombosis with consecutive failure
of the bowel circulation. In certain situations, it may be helpful
not only to minimize the time of intraoperative occlusion of
the mesenteric/portal vein but also to clamp the superior mesenteric artery for this period to avoid venous congestion and
swelling of the small bowel and the right hemicolon (Fig. 8.7).
Arterial resection is a rather uncommon surgical procedure during pancreatic cancer resection. If the superior mesenteric artery is involved in the tumor process, this is a
general exclusion criterion for resection and has only been
reported in few patients (56). By contrast, tumor adherence
or infiltration along the celiac axis must not be considered as
generally irresectable (43,53). In selected patients, the celiac
trunk might be resected down to its aortic orifice in Whipple
as well as in left resection or total pancreatectomies (5456).
As long as the proper hepatic artery can be preserved, a
reconstruction is possible. The left gastric and splenic artery
can usually be cut without reconstruction, a consecutive
Figure 8.7 Examples of portal vein resections. Direct end-to-end anastomosis (left) and graft implantation (right).
77
oncological outcome, making multivisceral resections an individually tailored approach that requires careful patient selection and surgical experience.
Recurrence Resections
Localized recurrence in pancreatic cancer may be an indication for relaparotomy and resection in selected patients.
Although a large number of recurrences are located close to
the arterial vessels, and therefore not resectable, recent studies
support the concept of surgical exploration and resection
whenever possible (6163). This approach can be combined
with intraoperative radiotherapy and radiation of the tumor
bed to reduce the risk of another recurrence at the site of resection (Fig. 8.8). In case of local irresectability, intraoperative
radiation can be performed with a palliative intention in terms
of tumor reduction and pain control. An extended resection of
the recurrent tumor with arterial vessels does not seem to be
justified as the chance for a radical tumor removal is poor and
patients do not seem to benefit from R1 or R2 resections. The
available studies report successful resection rates of approximately 50% with acceptable surgical morbidity and suggest a
survival benefit for those patients, especially in situations with
a long time interval (>912 months) between the initial tumor
diagnosis and the recurrence manifestation (63). As these are
observational studies, there is no proven evidence for this
approach today and larger controlled trials are required to
evaluate long-term oncological value.
Metastasis Resections
Resection for metastatic pancreatic cancer is clearly restricted
to exceptional indication and has only been reported anecdotally so far (64,65). Most commonly, the indication for metastasis resection arises in young patients with the accidental
finding of a synchronous single liver lesion intraoperatively,
which can be removed without increasing operative
morbidity (64). Apart from this individual indication, metastasis resection can be performed in long-term survivors with
Figure 8.8 Pancreatic cancer recurrence resection. Intraoperative finding of the recurrence located in the interaortocaval space (left), situs after resection (right)
prior to intraoperative radiation.
78
PANCREATIC RESECTION
localized metastastic disease, indicating favorable tumor biology and justifying the aggressive operative approach. This has
to be embedded in a global oncological concept, must be
decided highly individually and cannot be regarded as a
standard procedure (65).
conclusion
Pancreatic surgery has undergone a remarkable development
during the last decades. Appropriate surgical approaches have
been established and can be used in differential indications
today. In pancreatic cancer, standard resections include the
classical Whipple operation and the pylorus-preserving modification, which should be preferred whenever possible as well
as a distal or total pancreatectomy in extended tumors of the
gland. All of these procedures can be carried out safely with
surgical mortality rates well below 5% in specialized centers
due to a high grade of standardization and experience. Modern
tissue-sparing procedures such as the duodenum-preserving
pancreatic head resection in chronic pancreatitis or tumor
enucleations offer limited approaches for circumscribed nonmalignant pancreatic pathologies. Furthermore, extended
resections for the treatment of pancreatic malignancies
including multivisceral and recurrence resectionsare technically feasible although the oncological outcome of these
procedures has to be further evaluated and pancreatic cancer
treatment must always be embedded in an interdisciplinary
concept of surgery and adjuvant therapy to ensure best
possible outcome.
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specific complications
Pancreatic Anastomotic Leak and Pancreatic Fistula
Pancreatic leak occurs in 7% to 29% of patients following pancreatic resection (Tables 9.1 and 9.2) (5,7,1014). The wide
range in incidence is due in part to variability in defining the
manifestations of pancreatic leaks and several classification
systems have been proposed (9,15,16). Given similarity in
management and clinical manifestations, pancreatic leak,
fistula, fluid collection, and abscess will be considered
together (12).
Parenchymal consistency and the extent of operation are
associated with pancreatic leak following right or left pancreatectomy (Table 9.3) (17). Small pancreatic duct diameter is a
predictor of leak following PD (7,18). Management of fluid
collections resulting from a pancreatic leak may involve operative drains, placement of postoperative drains, or reoperation
(Fig. 9.1). Vin et al. reported that prolonged drainage was predicted by volume collected during the first 48 hours, fluid
amylase >1000, or distal pancreatectomy (12). The magnitude
of the pancreatic leak may also depend on whether the source
is the main duct or parenchyma (19). Those patients who do
develop pancreatic leaks are more likely to suffer from other
complications or death, and this risk is exacerbated by superimposed infection (12). Numerous strategies have been
attempted to minimize the chances of pancreatic leakage and
these are discussed below.
81
Pancreatic
Fistula or Leak
Delayed Gastric
Emptying
Hemorrhage
Bile Leak
Overall
Complications
223
228
300
489
300
1423
680
356
440
13%
8%
7%
13%
17%
9%
18%
15%
16%
NR
NR
29%
12%
NR
15%
NR
4%
7%
9%
NR
5%
NR
6%
NR
NR
NR
2%
NR
<1%
2%
2%
<1%
2%
NR
NR
2%
41%
26%
48%
39%
39%
38%
NR
38%
36%
Death
9%
6.1%
10.1%
11%
2%
2.0%*
1.7%
1.6%
Fistula or Leak
Hemorrhage
Overall Complications
72
190
175
132
64
302
462
220
13%
13%
23%
14%
22%
12%
29%
13%
NR
NR
2%
4%
3%
3%
NR
NR
27%
26%
42%
57%
37%
35%
NR
NR
Death
1.7%
1.5%
0
5.0%
1.5%
2.0%
0.8%
2.0%*
82
Morbidity %
Mortality %
LOS (days)
OR TIME
(minutes)
EBL
Author
PD
PPPD
PD
PPPD
PD
PPPD
PD
PPPD
PD
PPPD
PD
PPPD
Van Berge
Henegouwen (25)
200
34
37
48
44
20
18*
1580
1247*
360
288*
Lin (23)
31
38
50
56
687
451
237
215
Jimenez (106)
62
12
33
45
44
12
15*
723
707
114
45
32
72
57*
24
25
2096
1453*
476
404*
Seiler (24)
*p < 0.05, DGE = delayed gastric emptying, PD = standard pancreaticoduodenectomy, PPPD = pylorus-preserving pancreaticoduodenectomy,
LOS = length of stay, EBL = estimated blood loss.
Figure 9.1 The patient presented with fever and abdominal pain 2 weeks after a pancreaticoduodenectomy. A CT scan revealed a fluid collection in the RUQ (long
arrow), which was managed with CT-guided percutaneous drainage (catheter indicated by short arrow). The amylase level in the aspirated fluid was consistent with
a pancreatic leak (11,320 U/L).
Death
Long-term survival following pancreatic resection is a function of the underlying disease, while perioperative mortality is
related to the occurrence of complications, in addition to
patient, institutional, and technical factors. Fortunately, the
perioperative mortality rate following pancreatic resection has
been reported to be less than 2% in the most recent large series
(1214,47,49,50). Pancreatic leak (11) and PPH (40,51,52) are
the complications most frequently associated with perioperative mortality. As noted above, the improved mortality rates
following pancreatic resection are due in large part to better
management of complications. The vast majority of complications can be managed percutaneously, thereby reducing their
severity and the risk of death (47).
Figure 9.2 Following a pancreaticoduodenectomy and hemodynamic instability, metallic coils were placed in the gastroduodenal artery stump (long
arrow) to treat a suspected pseudoaneurysm. The catheter is positioned within
the common hepatic artery (short arrow).
83
Mortality %
Placebo
Octreotide
Placebo
Octreotide
Placebo
Octreotide
246
252
218
247
110
211
38
19
20
22
6
11
18^
9
9*
10*
12
9
55
29
36
30
25
34
32*
16*
22*
16*
30
40
5.8
3.8
5.6
0.8
0
0
3.2
1.6
8.1
1.6
2
1
*p < 0.05 versus the control group, ^statistical significance not indicated.
84
Morbidity %
85
Evidence Category
Recommendation
Strength Category
Ib
Ib
Ib
Ib
III
Ib
Ia
Recommended grading of categories of evidence: Ia, evidence from meta-analysis of randomised controlled trials; Ib, evidence from at least one randomised
controlled trial; IIa, evidence from at least one controlled study without randomisation; IIb, evidence from at least one other type of quasi-experimental study;
III, evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies and case-control studies; IV, evidence from expert
committee reports or opinions and/or clinical experience of respected authorities. Recommended strengths of management recommendation: A, directly based
on category I evidence; B, directly based on category II evidence or extrapolated recommendation from category I evidence; C, directly based on category III
evidence or extrapolated recommendation from category I or II evidence; D, directly based on category IV evidence or extrapolated recommendation from
category I, II, or III evidence.
summary
While the mortality rates following pancreatic resection
have improved dramatically, the incidence of complications remains high. Based upon the available literature,
several recommendations have been proposed ( Table 9.6).
Refinements in our abilities to detect and manage complications following pancreatectomy account, in large part,
for improved perioperative mortality statistics. Further
progress in enhancing the safety of pancreatic resection
will depend upon the development of more effective measures to prevent and treat postpancreatectomy complications. Better understanding of the biology of the diseases
we subject to pancreatic resection will allow for more precise patient selection and improve both perioperative and
long-term outcomes.
references
1. Kausch W. Das carcinoma der papilla duodeni und seine radikale entfernung. Beitr Klin Chir 1912; 78: 43951.
2. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the
ampulla of vater. Ann Surg 1935; 102(4): 76379.
3. Stojadinovic A, Brooks A, Hoos A, et al. An evidence-based approach to
the surgical management of resectable pancreatic adenocarcinoma. J
Am Coll Surg 2003; 196(6): 95464.
4. Wente MN, Veit JA, Bassi C, et al. Postpancreatectomy hemorrhage
(PPH): an International Study Group of Pancreatic Surgery (ISGPS)
definition. Surgery 2007;142(1): 205.
5. Balcom JH, Rattner DW, Warshaw AL, et al. Ten-year experience with
733 pancreatic resections: changing indications, older patients, and
decreasing length of hospitalization. Arch Surg 2001; 136(4): 3918.
6. Buchler MW, Wagner M, Schmied BM, et al. Changes in morbidity after
pancreatic resection: toward the end of completion pancreatectomy.
Arch Surg 2003; 138(12): 13104; discussion 1315.
86
7. Muscari F, Suc B, Kirzin S, et al. Risk factors for mortality and intraabdominal complications after pancreatoduodenectomy: multivariate
analysis in 300 patients. Surgery 2006; 139(5): 5918.
8. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and
outcomes. Ann Surg 1997; 226(3): 24857; discussion 257.
9. Grobmyer SR, Pieracci FM, Allen PJ, et al. Defining morbidity after pancreaticoduodenectomy: use of a prospective complication grading system. J Am Coll Surg 2007; 204(3): 35664.
10. Bottger TC, Engelmann R, Junginger T. Is age a risk factor for major
pancreatic surgery? An analysis of 300 resections. Hepatogastroenterology 1999; 46(28): 258998.
11. Gouma DJ, van Geenen RC, van Gulik TM, et al. Rates of complications
and death after pancreaticoduodenectomy: risk factors and the impact
of hospital volume. Ann Surg 2000; 232(6): 78695.
12. Vin Y, Sima CS, Gertrajdmen GI, et al. Management and outcomes of
postpancreatectomy fistula, leak, and abscess: results of 908 patients
resected at a single institution between 2000 and 2005. J Am Coll Surg
2008; 207(4): 490.
13. Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J Gastrointest Surg 2006; 10(9): 1199210; discussion 12101.
14. Ferrone CR, Warshaw AL, Rattner DW, et al. Pancreatic fistula rates after
462 distal pancreatectomies: staplers do not decrease fistula rates. J Gastrointest Surg 2008; 12(10): 16917; discussion 16978.
15. Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery 1992; 111(5): 51826.
16. DeOliveira ML, Winter JM, Schafer M, et al. Assessment of complications after pancreatic surgery: A novel grading system applied to
633 patients undergoing pancreaticoduodenectomy. Ann Surg 2006;
244(6): 9317; discussion 9379.
17. Bartoli FG, Arnone GB, Ravera G, Bachi V. Pancreatic fistula and relative
mortality in malignant disease after pancreaticoduodenectomy. Review
and statistical meta-analysis regarding 15 years of literature. Anticancer
Res 1991; 11(5): 183148.
87
88
10
introduction
Laparoscopy offers great advantages to the patient with HPB
disease. Although described in the early part of the 20th century, crude instrumentation limited its use. Progress seemed
slow until the 1960s saw widespread uptake in the gynecologic
community, with the Hopkins rod lens system greatly improving the optics.
Sporadic reports of laparoscopic staging for HPB cancer
soon followed, but it was not until the handheld camera development in the 1980s that the minimal access explosion began.
Now surgeons could view the image on a monitor, and use two
hands to operate instruments, while an assistant held the camera. Even the gall bladder could be removed using tiny incisions. The next 10 years saw almost every abdominal operation
attempted, such that the interest now is not in what can be
done, but in what should be done, and how best to do it.
laparoscopic cholecystectomy
Cholecystectomy was the first general surgical procedure to be
widely performed laparoscopically. Following the first reports
in 1985 and 1988 (1), the technique was rapidly popularized
(25). Despite a possible increase in the incidence of severe
bile duct injuries, the benefits of the laparoscopic approach
have subsequently been confirmed by meta-analysis (6), demonstrating shorter hospital stay and faster convalescence with
no difference in operating time or complications.
There are various techniques in common usage, with the
surgeon standing either on the patients right or left or between
the legs, with the choice of technique depending on local
teaching and personal preference. There are, however, fundamental principles to safely performing a laparoscopic cholecystectomy.
Correct identification of the anatomy is fundamental. Most
bile duct injuries are due to misperception rather than technical errors (7). It is important to understand the normal variations in biliary anatomy and how pathological changes may
alter the relationships between the structures. The 30 telescope permits better visualization of Calots triangle.
Hartmanns pouch is retracted laterally and inferiorly so that
the angle between the cystic and common hepatic ducts is
increased rather than closed. Calots triangle is dissected high,
just beneath the edge of the gall bladder, on both its anterior
and posterior surfaces, to clearly identify the cystic duct and
cystic artery as the only structures passing to the gall bladder
(the critical view (8)). Dissection is never carried below the
plane of Rouvires sulcus (9).
Routine intraoperative cholangiography is recommended.
This has been shown to decrease the risk and severity of biliary
injury (10). It is essential that the full complement of upper
duct anatomy is visualized to be certain that the common bile
duct or an aberrant right hepatic duct is not being excised. It
Transcystic flushing
Transcystic stone extraction
Choledochotomy
Transampullary stenting
Choledochoduodenostomy
Flushing
Small filling defects in the bile duct may be air bubbles, and
only the dynamic image of fluoroscopy may allow visible distortion or coalescence of these bubbles. Small stones low in the
bile duct may be flushed or pushed into the duodenum using
the cholangiogram catheter, with intravenous glucagon occasionally helping by relaxing the sphincter.
Transcystic Stone Extraction
Formal duct exploration is performed, where possible (in
about two-thirds of cases), via a transcystic approach. We prefer to use a purpose-built Nathanson CBD exploration catheter (Cook). This allows manipulation of a basket under
contrast-assisted fluoroscopy. The cystic duct is dissected
lower, close to the common bile duct. Balloon dilatation of the
89
Figure 10.1 Laparoscopic transcystic cholangiography demonstrating calculus in the distal common bile duct.
Figure 10.2 The calculus from Figure 10.1 after transcystic extraction utilizing
the Nathanson basket. Inset: completion cholangiography.
90
Choledochotomy
In certain circumstances, a transcystic approach is unlikely to
be successful, and if the CBD is of sufficient diameter, then it is
reasonable to proceed straight to a laparoscopic choledochotomy. These circumstances include large stones (>10mm),
multiple stones (>3) or stones above the cystic duct
confluence.
To perform laparoscopic choledochotomy, the anterior surface of the common bile duct is dissected just sufficiently to
confidently identify the anatomy. A 1.5-cm vertical incision is
made in the common bile duct below the cystic duct confluence. Filling of the duct system with saline via the transcystic
catheter distends the collapsed duct and helps prevent injury
to the posterior duct wall when the anterior wall is incised.
Another method is to gently lift up the anterior wall with a
suitable small atraumatic grasper (such as a dolphin-nose)
introduced via the right subcostal port. This will create a small
transverse ridge of the anterior duct wall, which can then be
cut using scissors introduced via the epigastric port, thus creating a vertical incision that can then be extended with the
scissors. A similar effect can also be created using stay sutures.
Initial flushing via the choledochotomy with the suckeraspirator and massaging of the duct may remove the stones. A
choledochoscope can be introduced, this time from the epigastric port. A 3 or 5 mm flexible scope may be employed, or
even a rigid ureteroscope if the orientation is suitable. (On the
rare occasions that a rigid ureteroscope is required, it can
pancreatic pseudocyst
Pancreatic pseudocysts can be managed endoscopically with
gastrotomy and stenting (perhaps the only current valid indication for NOTES [Natural Orifice Transabdominal Endoscopic Surgery]). Pancreatic pseudocysts can also be drained
internally via a laparoscopic approach (3846). Most commonly the pseudocyst is located in the lesser sac and the appropriate procedure is a cyst-gastrostomy. An anterior gastrotomy
is made. The cyst can be seen bulging forward, adherent to the
posterior stomach wall, which is incised with diathermy or the
harmonic scalpel to enter the cyst. Cyst fluid will come flowing
out under pressure at this point, and is important to have an
instrument ready to pass into the cyst so that the point of
communication is not lost. The cyst fluid is aspirated with the
sucker and the cyst emptied. A linear stapler is then introduced into the small cyst-gastrotomy to create a wide cystgastrostomy, and the residual unstapled edges are sutured
together. The pseudocyst can be entered with the laparoscope
and inspected, and any debris removed. The anterior gastrotomy is then closed with sutures or a stapling device. In some
cases, the position of the pseudocyst will require a side-to-side
cyst-gastrostomy or Roux-en-Y cyst-enterostomy.
Published reports suggest that laparoscopic cyst-gastrostomy
has a higher initial success rate and lower recurrence rate than
endoscopic cyst-gastrostomy (42,47). As the cyst-gastrostomy
created via the endoscopic approach is only small, any large
debris is unable to exit the cyst. However, endoscopic
approaches can be improved with using balloon dilatation and
multiple stents to maintain better drainage, endoscopic ultrasound to guide the procedure and avoid vessels (48,49), and
with the development of stapling instrumentation for natural
orifice surgery (50).
laparoscopic staging
A proportion of patients with hepatobiliary and pancreatic
malignancies will appear to be resectable on noninvasive
91
92
gastric outlet obstruction, it is not necessary to perform a palliative biliary or gastric bypass (101). In many instances, the
endoscopic approach is effective to relieve obstruction. Duodenal stenting is safer and provides a better quality of life than
laparoscopic gastrojejunostomy in the short term (102),
although laparoscopic gastrojejunostomy may provide a more
durable result for patients with a longer life expectancy (103).
ERCP with placement of a plastic biliary stent has a lower
morbidity than traditional open surgical bypass, although
plastic biliary stents have a tendency to occlude, resulting in
recurrent biliary obstruction requiring a repeat procedure
(104). Metallic stents, however, have a much higher patency
rate in the longer term, and can serve many patients for the
remainder of their survival (104106).
In some cases, however, stenting fails for technical reasons or
due to inability to access the ampulla. In these cases, a laparoscopic bypass is a useful option (107116), with the potential
for lower morbidity and shorter hospital stay than an open surgical procedure (113,115). A laparoscopic biliary bypass is most
easily performed as a stapled or sutured side-to-side cholecystojejunostomy. The main limitation of this approach is that the
confluence of the cystic and common hepatic ducts must
be well above the tumor to prevent recurrent biliary
obstruction (117). This can be confirmed at the procedure by
cholangiography via the fundus of the Gall bladdera Verres
needle with large syringe attached is used to empty the gall
bladder of bile, which is then filled with contrast to confirm
that the cystic duct confluence is more than 1 cm above the
level of the tumor. If this is not the case, an hepaticojejunostomy is constructed. A gastrojejunostomy is typically fashioned
in an antecolic, isoperistaltic stapled side-to-side manner.
laparoscopic pancreatectomy
Distal pancreatectomy is well suited to a laparoscopic approach.
The usual indication is a solid or cystic tumor of the tail of the
pancreas that is not clearly benign on preoperative imaging.
The procedure may involve en-bloc resection of the spleen and
splenic vessels; preservation of the spleen with preservation of
the splenic vessels; or preservation of the spleen without preservation of the splenic vessels with the spleen supplied from
the short gastric and gastroepiploic vessels (the Warshaw technique (118)).
For lesions close to the spleen, when splenectomy is necessary, the approach can be similar to laparoscopic splenectomy,
with the patient left side up, and the spleen and distal pancreas
mobilized from lateral to medial. After division of the short
gastric vessels and the gastrocolic omentum, the pancreas
can be divided en bloc with the splenic vessels using a
linear stapler.
For a medial to lateral approach, the pancreatic neck is
divided, either with a stapling device or with the harmonic
scalpel with subsequent suture closure of the pancreatic
stump. Where the splenic vessels are being resected, the
splenic vein is divided with a stapling device and the splenic
artery divided with a stapling device or locking clips. If the
splenic vessels are to be preserved, then the tail of the pancreas is dissected carefully from them with control of the
small vessels with clips and/or the harmonic scalpel or
Kentucky in November 2008. Agreed definitions of laparoscopic liver surgery include the following:
Pure laparoscopic: where the liver resection is completed laparoscopically and the specimen removed
via a remote incision;
Hand assisted: where the surgeon operates with his
nondominant hand inside the abdomen, placed via
an airtight device, through which the specimen is
removed;
Hybrid liver resection (145): where the liver is mobilized laparoscopically and most of the resection is
done through a smaller than usual right upper quadrant incision;
Conversion: where the surgeon changes to an open
operation from one of the above. One can also convert from pure laparoscopic to hand assist or hybrid.
The most suitable cases for a laparoscopic approach are solitary small (<5 cm) lesions located in the peripheral segments
(26) of the liver. Larger lesions are acceptable if they are
pedunculated or located in the left lateral section. Multiple
lesions may be suitable if they can be resected with a single anatomic hepatectomy with a clear margin, but not where multiple
complicated or bilobar procedures are required. Hemihepatectomies can be considered for a laparoscopic approach where
the plane of transection and major structures (pedicles, hepatic
veins and inferior vena cava) are well clear of any lesions.
Lesions located in segments 7 and 8 are difficult to approach
laparoscopically for a tumorectomy as the costal margin limits
the approach angles of the instruments, and there is a real risk
of compromising the deep margin for fear of causing difficultto-control bleedingthey should only be considered for a
laparoscopic tumorectomy if they are particularly small and
superficial, otherwise they need to be considered for an open
procedure or a laparoscopic right hemihepatectomy.
The procedures are usually performed in the supine position, often with the surgeon standing between the legs. The
left lateral decubitus position is useful for lesions in segments
6 and 7, which enables better exposure of the right posterior
section of the liver. Hand ports may be used. These are most
useful in right sided resections where mobilization is difficult, either in nonanatomical resections with a posterior
tumor in the right lobe, or right hemihepatectomies with a
bulky right lobe. Good quality laparoscopic equipment is
vital. A good 10-mm laparoscopic right angle is also a very
important tool.
An initial laparoscopy is performed, and laparoscopic ultrasound is used to identify the lesions and their relationships to
the appropriate anatomy (Fig. 10.4). A tape can be placed
around the hepatic pedicle in readiness for a Pringle maneuver
if required; this is usually reserved for situations where bleeding is encountered rather than used routinely, and uses an
intermittent protocol (as the time of transection tends to be
longer than in open surgery). The gall bladder is resected
where indicated, but after division of the cystic duct and artery,
it may be left attached to the liver until later in the procedure
to help maneuver the liver, such that the gall bladder and
round ligament become the two handles of the liver. It is a
93
Figure 10.4 Laparoscopic ultrasound used to mark out resection line for a
tumor in segment 6.
useful point to divide the round ligament flush with the anterior abdominal wall such that there is not dangling tissue
irritatingly obstructing the view and dirtying the camera
through the whole procedure.
There are many methods of parenchymal transection: harmonic scalpel (Ethicon), Ligasure device (Covidien), Gyrus
(Gyrus ACMI), CUSA (Integra), TissueLink (Salient Surgical
Technologies), stapling devices, water jet, and metal clips. Each
have their advantages and disadvantages, and used appropriately each can have their place. Personal preference and experience as well as local teaching and availability determine the
choice. The various energy-delivery devices will not control
the large venous structures; these must be identified intraparenchymally and controlled with clips or stapling devices. It is
also prudent to individually control the large pedicular
branches. Stapling devices can be used en-masse across portions of the parenchyma to control the larger structures within,
but a degree of finesse is lost and unexpected bleeding can be
encountered. The combination of the harmonic scalpel for the
superficial 2 cm of dissection with the CUSA for the deeper
dissection is a good technique (147). A good alternative is the
Ligasure device, which when used with a modified technique
(closing while activating, using the cutting blade sparingly,
with gentle saline irrigation to prevent charring) can be used
to dissect out the larger intraparenchymal structures (148).
Left lateral sectionectomy begins with mobilization of the
falciform ligament, left coronary ligament, and lesser omentum to mobilize the left lobe. The parenchyma is divided so as
to expose the upper surface of the segments 2 and 3 pedicles
intrahepatically. The pedicles are then divided with a stapler.
The parenchymal transection is then completed to expose the
left hepatic vein intrahepatically, which is divided with a stapler. An alternative to this technique is mass stapling of the left
lateral section (149,150). Left lateral sectionectomy is particularly suitable to a laparoscopic approach and arguments have
been made that the laparoscopic approach should be used routinely for this resection (149,151).
94
Figure 10.5 Laparoscopic dissection of the right portal vein. The right hepatic
artery has been divided. The cystic duct has been divided and is used to retract
the bile duct. The right portal vein has been looped. The left portal vein is
clearly demonstrated and the right portal vein can be seen dividing into its
anterior and posterior branches.
references
Figure 10.6 Mobilization of the right liver from the inferior vena cava.
conclusion
Laparoscopic approaches for the simplest of HPB procedures,
cholecystectomy, have literally exploded around the world.
More complex operations have been reported in small series,
but have not been taken up with the same enthusiasm. As technology improves, and the skill set of surgeons increases, it
seems inevitable to us that more and more will be done. As
long as basic oncologic principles are adhered to, and the surgical maxim of conversion if concerned is followed, patients
will continue to benefit from this exciting surgery.
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11
overview
The maturation of surgery of the liver, biliary tract, and
pancreas as field unto itself has happened concomitantly
with, and partly as a result of, advances in cross-sectional
imaging. Rather than relying on expected anatomy based on
textbooks, surgeons can now plan operations based on the
precise anatomical details of each individual patient. The
ability to predict anatomical variations, which are present in
nearly one-half of the patients, has taken the element of
surprise out of the operating room and can help reduce
operative morbidity (1).
In this chapter, we briefly discuss the application of computed tomography (CT) and magnetic resonance imaging
(MRI) to the surgical management of disease of the liver, biliary tract, and pancreas. We begin by reviewing the relevant
cross-sectional anatomy of the organs being studied. Next, we
discuss the various techniques used to obtain high-quality
CT and MRI images of the liver, biliary tract, and pancreas.
Finally, we review the cross-sectional imaging characteristics
of important pathological entities commonly encountered by
surgeons caring for patients with diseases of the liver, biliary
tract, and pancreas.
cross-sectional anatomy
The effective use of cross-sectional imaging in the diagnosis
and treatment of disorders of the liver, biliary tract, and
pancreas mandates a strong understanding of anatomy. Developing this understanding of the complex three-dimensional
structures and being able to extrapolate from two-dimensional
representations requires a structured approach. A more
detailed description of relevant anatomy can be reviewed in
the previous chapters and elsewhere, therefore we will here
focus on the interpretation of cross-sectional anatomy and its
relation to in situ anatomy (2).
Liver and Biliary Tract
Segmental liver anatomy is the basis for modern liver surgery;
therefore, we provide a framework with which to define this
anatomy for each patient based upon cross-sectional imaging.
Cantlies plane, also known as the main portal fissure, is an
imaginary plane drawn from the gallbladder fossa toward the
inferior vena cava (IVC) that divides the anatomical right and
left lobes of the liver. The course of the middle hepatic vein
(MHV) is fairly constant and lies in this otherwise potentially
avascular plane; therefore, it can be used to delineate the two
lobes on cross-sectional imaging (3). The right hepatic vein
(RHV) defines the plane separating the anterior (segments 5
and 8) and posterior sectors (segments 6 and 7) of the right
lobe. While the plane of the left hepatic vein (LHV) separates
the anterior and posterior sectors of the left lobe, its anatomy
is highly variable, making it a less useful landmark.
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In contrast to hepatic veins, which course between liver segments, portal veins and their accompanying artery and bileduct branches define the center of each segment. The main
portal vein (PV) typically branches extrahepatically into the
left and right portal veins (LPV and RPV, respectively); the
RPV divides into the anterior and posterior sectoral branches,
while the LPV enters the umbilical fissure and provides
branches to the left lobe. While this describes standard anatomy, approximately one-third of patients have variant portal
venous anatomy (Table 11.1) (4).
In standard arterial anatomy the common hepatic artery
arises from the celiac axis and divides into the gastroduodenal
artery and the proper hepatic artery. The proper hepatic artery
then gives rise to the right and left hepatic arteries. However,
nearly one-half of patients have variations in their hepatic
arterial system. A list of arterial variants demonstrated in a
recent study is shown in Table 11.2 (1).
Pancreas
The pancreas is divided into the head, uncinate process, neck,
body, and tail. These divisions are based upon external landmarks such as the superior mesenteric vein (SMV), which lies
under the neck of the gland and defines the separation between
the head and the body. The pancreas has a long course through
the retroperitoneum and is intimately associated with multiple organs including the transverse colon, stomach, duodenum, and spleen. Additionally, it has a close relationship with
the portal venous system that, in part, defines the resectability
of pancreatic masses. The pancreas has a rich arterial supply
that comes from multiple branches of the celiac and superior
mesenteric arteries. As in hepatic surgery, preoperative determination of variations in peripancreatic vascular anatomy can
greatly aid in operative planning.
technique
Liver and Biliary Tract
CT is commonly used as the primary modality to detect, characterize, and follow hepatic or biliary pathology. Modern
multislice helical CT scanners allow for the rapid acquisition
of large volumes of data in a single patient breath-hold, thereby
allowing for the construction of high-resolution axial, coronal,
sagittal, and three-dimensional images.
Noncontrast CT allows us to make determinations about the
character of the liver parenchyma based on changes in density.
This is useful for detecting global hepatic abnormalities;
however, it does not allow for the precise delineation of hepatic
vascular structures nor the detection and characterization of
subtle hepatic masses. CT examination of the liver, therefore,
relies on iodinated contrast enhancement. Accurate CT imaging
requires achieving maximal differences in attenuation between
tissues, therefore understanding the contrast enhancement
No.
1
2
3(Z)
Standard anatomy
Trifurcation
Right posterior portal vein as first
branch of main portal vein
Segment VII branch as separate
branch of right portal vein
Segment VI branch as separate
branch of right portal vein
Other
130
18
26
65
9
13
12
12
4
5
Table 11.2 Frequency of Different Arterial Variants Seen at CT Angiography in 371 Patients
Type of finding
Classic celiac arterial anatomy
Replaced RHA off SMA
Replaced LHA off LGA
Artery to segments 2 and 3 off LGA
Artery to segments 4A and 4B off RHA
Trifurcation of CHA into GDA, RHA, and LHA
RHA off celiac axis
Accessory LHA off LGA
LGA directly oft abdominal aorta
CHA off SMA
CHA directly off the aorta
RHA off GDA
Accessory RHA
Common trunk of celiac axis and SMA
Medial and lateral branches separate off CHA
LHA off CHA
GDA off RHA
SMA gives rise to GDA
LHA off celiac axis
RHA off aorta
Segment 4 branch off GDA
Extrahepatic branching of RHA into anterior and posterior with
artery to segment 4 off anterior division of RHA
% of patients (n = 371)
51
15
8
5
5
4
4
4
3
2
2
1
1
<1
<1
<1
<1
<1
<1
<1
<1
<1
Note: Twenty patients had two variants seen at CT and one patient had four variants.
Abbreviations: LHA, left hepatic artery; RHA, right hepatic artery; LGA, left gastric artery; SMA, superior mesenteric artery; CHA, common hepatic artery;
GDA, gastroduodenal artery. Source: Reprinted with permission from Ref. 4.
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(A)
Hepatic Hemangioma
Hepatic hemangiomata are common vascular lesions of the
liver that receive their blood supply from the hepatic artery.
Hemangiomata rarely cause symptoms; however, giant ones
can be associated with abdominal pain or other compressive
symptoms (7). Hemangiomata are diagnosed based on their
nodular, clump-like pattern of early arterial enhancement on
CT (Fig. 11.2). Although small ones are fairly homogeneous in
appearance, large hemangiomata may have a heterogeneous
appearance due to areas of thrombosis. MRI is the most accurate imaging modality for diagnosing hepatic hemangiomata.
On T2-weighted imaging, they are hyperintense and have a
lobulated appearance. Administration of gadolinium again
shows early peripheral nodular enhancement.
Focal Nodular Hyperplasia
Focal nodular hyperplasia (FNH) is a common benign liver
tumor made up of all elements of the hepatic parenchyma.
FNH are completely benign and rarely, if ever, lead to symptoms. However, the fibrolamellar variant of hepatocellular carcinoma may be mistaken for FNH based on similar imaging
characteristics (8). Therefore, accurate identification of FNH
is of paramount importance.
On pathological examination, FNH typically have a central
scar that may be demonstrated on cross-sectional imaging.
Contrast-enhanced CT show rapid homogeneous enhancement during the arterial phase with reduced attenuation during the portal venous phase (Fig. 11.3). MRI imaging of FNH
reveals isointensity or slight T1 hypointensity or T2 hyperintensity, with a central scar that has even less T1 intensity or
more T2 intensity (9). Contrast administration shows early
enhancement with delayed enhancement of the central scar.
Hepatocellular Adenoma
Hepatocellular adenomas are benign proliferations of hepatocytes with a dramatically increased prevalence in patients with
a history of oral contraceptive use. Although they are benign
lesions, resection of hepatocellular adenomas is recommended
because of their propensity for hemorrhage and, albeit rare,
risk of malignant transformation. Adenomas are recognized
(B)
Figure 11.1 Biliary cystadenoma. (A) T2- and (B) postcontrast T1-weighted images of a biliary cystadenoma hanging off the inferior portion of the right lobe of
the liver. Arrows indicate solid enhancing component of mass distinguishing this from a simple cyst.
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(A)
(B)
Figure 11.2 Hemangioma. (A) T1-weighted postcontrast imaging reveals a nodular peripheral enhancement (black arrow) pattern in the early arterial phase that
is characteristic of hemangiomas. (B) T2-weighted imaging reveals a hyperintense, lobulated lesion.
(A)
(B)
(C)
(D)
Figure 11.3 Focal Nodular Hyperplasia (A) T1-weighted precontrast image is isointense to hepatic parenchyma (B) T2-weighted image is also isointense to hepatic
parenchyma except the central scar (arrow), which is bright (C) T1-weighted postcontrast image in the arterial phase demonstrates homogenous, hyperintense
enhancement with the central scar enhancing on (D) delayed postcontrast images.
103
104
(A)
(B)
Figure 11.4 Hepatocellular carcinoma. (A) Arterial phase CT image demonstrating a dominate right-lobe mass. (B) Note the change in enhancement on the portal
venous phase of imaging.
(A)
(B)
Figure 11.5 Gallbladder carcinoma. T2-weighted MRI (A) axial and (B) coronal images demonstrate a solid mass in the gallbladder with hyperintense surrounding
liver parenchyma consistent with local extension of the tumor into the liver parenchyma.
differentiation is necessary. The presence on MRI of dependent debris within a cystic pancreatic lesion has been found to
be highly suggestive of the diagnosis of pseudocyst (20).
Serous cystadenoma (SCA) are the most common benign
neoplasm of the pancreas and are typically asymptomatic
findings, however a proportion of patients do present with
symptoms due to mass effect (21). SCA are comprised of multiple smaller cysts and may have a variable appearance based
on the size of the cysts that comprise them. In fact, microcystic
tumors may have an appearance on CT more consistent with
that of a solid tumor. MRI and ultrasound may be helpful in
defining the cystic nature of such tumors. Since asymptomatic
SCA do not require treatment, differentiating them from other
malignant or premalignant lesions is critical. In the event that
imaging characteristics are nondiagnostic, biopsy or resection
may be indicated.
Intraductal papillary mucinous neoplasms (IPMN) are premalignant tumors arising from the main pancreatic duct or its
105
(A)
(B)
Figure 11.7 Neuroendocrine metastases. (A) Innumerable hypodense neuroendocrine metastatic nodules with variable levels of rim-enhancement on portal
venous phase contrast-enhanced CT. (B) Coronal slice demonstrates direct extension of tumor into the portal vein (arrow).
(A)
(B)
Figure 11.8 Intraductal papillary mucinous neoplasm (IPMN). (A) T1-weighted postcontrast imaging reveals a low-intensity multilocular lesion in the head and
uncinate process of the pancreas suspicious for a side-branch IPMN. (B) T2-weighted images demonstrate high signal intensity.
branches. IPMN contain epithelium ranging from benign adenoma to invasive adenocarcinoma. IPMN are differentiated
based on whether they arise from side-branches or from the
main pancreatic duct, with the latter having a higher potential
for progressing to invasive malignancy. Cross-sectional imaging
reveals a cystic region within or adjacent to the pancreatic
parenchyma that may demonstrate continuity with the pancreatic ductal system. Factors that influence the decision to perform pancreatectomy for IPMN include size, growth, and the
presence of fibrous septations or solid components. Mucinous
cystic neoplasms (MCN) are less common lesions, typically seen
in women, which are characterized by ovarian-type stroma.
MCN are also felt to be premalignant lesions, therefore their
resection is recommended. MCN have imaging characteristics
similar to those of IPMN, with the absence of a definable connection to the main pancreatic ductal system (Fig. 11.8).
Pancreatic Neuroendocrine Tumors
Pancreatic neuroendocrine tumors (PNET), also known as islet
cell tumors, are rare malignant neoplasms that have a relatively
slow growth rate. While most PNET are nonfunctional, they
106
may secrete hormones that lead to clinical symptoms, especially in the setting of metastatic disease to the pancreas. PNET
are typically hypervascular lesions that show early arterial
phase enhancement on CT, but may be isodense on portal
venous phase. Small functional tumors may prove difficult to
identify on cross-sectional imaging studies, therefore accurate
timing of imaging to the arterial phase of enhancement is
important. Similarly, MRI imaging of PNET usually demonstrate high signal intensity on T2-weighted images and low
intensity on T1-weighted images with significant contrast
enhancement (22) (Fig. 11.9).
Solid Pseudopapillary Tumor
Solid pseudopapillary tumor (SPT) of the pancreas is a rare,
indolent tumor that most commonly affects women in the
first three decades of life. Although it has metastatic potential,
malignant behavior is uncommon, therefore resection is considered curative. CT imaging is varied and may demonstrate a
large lesion with internal hemorrhage or cystic degeneration.
While vascular encasement, pancreatic ductal dilatation, and
hepatic metastases are seen only in the carcinomatous variant
pancreas is intimately associated with the portal venous system and in close proximity to the celiac artery and superior
mesenteric artery (SMA). High-quality cross-sectional imaging clearly defines these relationships and predicts the likelihood of successful resection.
Metastatic Cancer to the Pancreas
In contrast to the liver, the pancreas is a rare site of metastatic
disease. Although multiple types of cancer have been reported
to metastasize to the pancreas, renal cell carcinoma, nonsmall
cell lung carcinoma, and lymphoma are the most common
sources of isolated pancreatic metastases. Renal cell carcinoma
metastases to the pancreas are typically well-circumscribed,
arterial-enhancing lesions, while other histologies tend to be
more diffuse and variable in enhancement patterns.
conclusions
CT and MRI have become essential components in the diagnosis, perioperative management, and follow-up of hepatic,
biliary, and pancreatic pathology. Therefore, the ability to
appropriately order and interpret these studies, in consultation with radiologists, is a prerequisite to the surgical management of patients with such diseases.
references
1. Winston CB, Lee NA, Jarnagin WR, et al. CT angiography for delineation
of celiac and superior mesenteric artery variants in patients undergoing
hepatobiliary and pancreatic surgery. AJR Am J Roentgenol 2007; 189(1):
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2. Blumgart LH. Surgery of the Liver, Biliary Tract, and Pancreas, 4th edn.
Philadelphia, PA: Saunders Elsevier, 2007.
3. Kamel IR, Lawler LP, Fishman EK. Variations in anatomy of the middle
hepatic vein and their impact on formal right hepatectomy. Abdom Imaging 2003; 28(5): 66874.
4. Covey AM, Brody LA, Getrajdman GI, Sofocleous CT, Brown KT. Incidence, patterns, and clinical relevance of variant portal vein anatomy. AJR
Am J Roentgenol Oct 2004; 183(4): 105564.
107
108
12
imaging techniques
computed tomography
Ultrasound
Liver metastases are generally multiple, spherical, and have
well-defined margins. Most lesions are hypoechoic. The most
common hyperechoic metastases are observed in patients with
CRC or neuroendocrine tumors. Large lesions often have
more central hypoechogenicity related to areas of necrosis. A
hypoechoic halo is seen surrounding the lesions in 40% of
cases (8). More rarely, liver metastases may appear as diffuse
infiltration.
contrast-enhanced ultrasound
109
(A)
(B)
(C)
Figure 12.1 (AC) Portal-phase CT shows a small liver tumor that is not characteristic of liver metastasis. This lesion is homogeneous and hyperechoic on
ultrasound (B). Portal-phase contrast-enhanced ultrasound demonstrates washout, which is highly suggestive of liver malignancy (C).
110
(A)
(B)
(C)
(D)
Figure 12.3 (AD) MR imaging of a colorectal metastasis. The tumor is hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note the peripheral
halo on portal-phase T1-weighted imaging and the delayed enhancement due to fibrous stroma (C and D).
111
(A)
(B)
(C)
(D)
Figure 12.4 (AD) MR imaging of endocrine metastases. The tumors are strongly hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note
the strong hypervascularity on arterial-phase T1-weighted imaging and the washout on portal-phase imaging (C and D).
(A)
(B)
Figure 12.5 MR imaging of liver metastases. Multiple tumors are seen on T2-weighted imaging (A). Conspicuity of small tumors is more evident on diffusionweighted imaging (B).
112
perfusion imaging
Liver metastases induce changes in liver perfusion and have
been shown to increase arterial blood flow and the arterial
portal flow ratio (hepatic perfusion index) compared to normal liver. Interestingly, animal studies have demonstrated that
those changes may be detected at an early stage when liver
metastases are occult on other imaging modalities (18).
Hepatic perfusion index can be obtained using various techniques: nuclear medicine, US, CT, or MR imaging. Early results
in patients were promising but lack of standardization in utilization, lack of consensus regarding the imaging modality, and
the presence of multiple mathematical models have meant
that perfusion has not been adopted in routine practice.
(A)
(B)
Figure 12.6 (A and B) Liver metastases before and after chemotherapy. Note the significant decrease in size of the tumors. Furthermore, the tumors present diffuse
calcifications after chemotherapy.
113
(A)
(B)
(C)
Figure 12.7 (AC) Liver metastases developed on a fatty liver. The tumor located in the posterior part of the segment 4 is barely visible on portal-phase CT (A) and
is better seen on pre- and postcontrast T1-weighted imaging (B and C).
114
Based on the existing evidence, it is difficult to provide highstrength management recommendations. Our policy at our
institution is to perform systematically a multidetector CT in
patients with liver metastases. PET/CT is indicated for the
detection of extrahepatic tumor before liver surgery. MR
imaging is not routinely performed and is reserved for characterization of small liver lesions, in fatty livers, and in difficult
cases after multidetector CT. For lesion characterization, we
use nonspecific contrast MR agents, while for tumor detection
and preoperative staging, we use liver-specific contrast agents.
In both cases, our protocol includes diffusion-weighted MR
sequences. Intraoperative US is routinely performed in our
institution and intraoperative contrast-enhanced US is under
investigation.
preoperative staging
Due to their biological properties, most liver metastases that
are resected are secondary to CRC. Selected isolated liver
metastases from breast cancer, sarcoma, renal cell cancer
115
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9. Albrecht T, Hoffmann CW, Schmitz SA, et al. Phase-inversion sonography during the liver-specific late phase of contrast enhancement:
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38.
117
13
introduction
Colorectal cancer (CRC) is a common malignancy with a very
high incidence in Western countries. Approximately 150,000
new cases of CRC occur each year in the United States,
accounting for more than 55,000 cancer-related deaths (1).
Over half the patients diagnosed with CRC will develop liver
metastases (CRLM) during the course of their disease (2), of
which 15% to 25% will have liver metastases at the time of the
diagnosis (3,4). In the absence of surgical treatment, 5-year
survival is exceptional (5) and even with the best chemo- and
bio-therapies, to date, median survival of unresected disease
does not exceed two years (6,7). On the other hand, long-term
survival and potential cure after surgical resection for CRLM
has been demonstrated by numerous studies. Surgery is therefore considered as the treatment of choice for patients with
resectable CRLM, yielding a 5-year survival between 35% and
52% (8,9). As a result, hepatic resection has evolved from a
rare procedure associated with considerable mortality to a
routine surgery with an operative mortality risk of around 2%
(10,11). At present, the low operative mortality along with survival improvement has led to an expansion of more extensive
liver surgery and to a clear change in surgical indications to a
point where virtually no tumor should be considered unresectable provided that resection can be complete. These
advances combined with novel systemic and regional ablative
therapies have modified the course of the disease, transforming it from a uniformly fatal to increasingly curable for a
majority of patients.
118
Although long-term survival and potential cure after surgical resection has not been demonstrated by randomized controlled trials, the evidence (uniformly poor results observed in
untreated patients in contrast to extensive data documenting
long-term survival after hepatectomy) supports a significant
survival benefit from resection and has provided the rationale
for increasing indications for liver surgery as the most effective
treatment of CRLM.
patient evaluation
Patient Selection for Surgery
In deciding which patient will tolerate liver resection, a number of factors will need to be considered, including patient
comorbidities. Age per se is not an independent factor for
increased operative risk (15). This is a very important fact,
considering that an increasing proportion of patients being
evaluated for surgery for malignant disease, are elderly. On the
other hand, scores like the American Society of Anaesthesiology (ASA) (16) or the preoperative Acute Physiology and
Chronic Health Evaluation score do significantly influence the
incidence of postoperative complications. Patients with an
ASA score > 1 have been shown to have more than three times
the mortality and twice the morbidity compared to those
patients with an ASA of 1 (16). Therefore, a major goal of the
preoperative evaluation is to identify patients who are at high
operative risk so those who have a prohibitive risk can be
excluded from surgery whereas those with manageable comorbidities can have these conditions addressed preoperatively in
an attempt to reduce their operative risk.
Definition of Tumor Resectability
The earlier definition of the resectability (based on factors
such as number of lesions, size, distribution, etc.) has been
progressively challenged resulting on a concept shift, which
now focuses on whether a macroscopic and microscopic complete (R0) resection of the liver lesion as well as complete
resection of any extrahepatic diseases can be performed. At
present, CRLM are defined as resectable if two aspects are fulfilled: (1) oncological anticipation that the disease can be completely resected without any residual hepatic or extrahepatic
disease; (2) maintenance of an adequate volume of the future
remnant liver with preserved vascular inflow, outflow, and
biliary drainage. In general, at least 25% of the total liver is the
minimum safe volume that can be left after liver resection in
patients with normal liver parenchyma (17).
Preoperative Imaging
The complex decision to determine resectability requires
detailed anatomic imaging to determine tumor location,
exclude unresectable extrahepatic metastases, and assess the
adequacy of the liver parenchyma after surgery. There are a
surgery). When resecting 4 liver metastases, the limiting factor is not the number of metastases but
whether it is possible to remove all of them (2932).
Similarly, the distribution (bilobar metastatic disease)
is no longer considered as a prohibitive prognostic
factor. Ercolani et al. (33) reported that the total tumor
volume of liver metastases had a stronger influence on
survival than did number and location. Also, data
from LiverMetSurvey concerning patients with bilobar metastatic disease have demonstrated a 1-, 5-, and
10-year survival of 90%, 44%, and 22%, respectively
(34). In general, if a complete resection of the metastases can be achieved with safe margins (R0 resection)
while maintaining a sufficient volume of the residual
liver, the number and location should not be considered as a contraindication to resection.
Whereas achieving a negative resection margin is well
established, the extent of this margin clearance
remains controversial. Increasingly, studies are demonstrating that there is no significant difference in
survival or recurrence related to the width of margin
achieved. Elias et al. (35) demonstrated that the overall survival of patients with resection margins less
than 1 cm was 27.8%, comparable to those with resection margins of 1 cm. Fong et al. (36), in his series of
426 patients undergoing hepatectomy for CRLM,
reported an identical 5-year survival in the group
with a clear margin of <1 cm compared to the group
with a margin of 1 cm or greater. Similarly, Figueras
et al. (37) reported that subcentimeter nonpositive
surgical margin did not influence hepatic recurrence
rates after hepatectomy for CLM. Kokudo et al. (38),
in his study, went further on by demonstrating that a
margin of 2 mm is clinically the minimum acceptable
requirement, which carries approximately a 6% risk of
margin-related recurrence. A recently published study
from our center showed that despite a higher recurrence rate in patients with R1 resection (complete macroscopic resection with 0 mm free margin) compared
to patients with R0 resection, the two groups had a
similar overall and disease-free survival (61% vs. 57%
and 28% vs. 17%) and recurrences were intrahepatic
rather than being localized at the surgical margin (39).
119
is the impossibility to remove all metastatic disease, while leaving sufficient functional hepatic parenchyma, regardless of the
location, distribution, number and size of the metastases.
Clinical Risk Scores
Over 10 years ago, Nordlinger (48) introduced the first scoring
system for patients with CRLM, based on a multicenter data
from 1568 patients who accepted potentially curative resections. In this large series, they identified three groups of
patients with low, intermediate and high risk for poor prognosis based on seven high risk factors (see Table 13.1A). Since
then, at least six more scoring systems have been developed
among which the proposal from Fong et al. (49) based on a
single institution series of 1001 patients attracted the most
attention. Seven parameters were found to be independent
predictors of prognosis. These include presence of extrahepatic disease; positive resection margin; nodal metastases
from primary cancer; short disease free interval; largest tumor
greater than 5 cm; more than 1 liver metastases; CEA greater
than 200 ng/ml (see Table 13.1A). The data for the first two
parameters are not available preoperatively. However, using
the last five criteria, a preoperative clinical risk score system
was created with each positive criterion counting as 1 point.
The total score out of 5 is highly predictive of a poor outcome
(5-year survival 14%). Patients with a score of 0, 1, and 2 have
a highly favorable outcome (5-year survival 60%, 44%, and
40%, respectively). Table 13.1B demonstrates the survival
rates for each score grade.
Nordlingers score*
120
Nordlingers score
1 year
3 years
5 years
Median (mo)
93
91
89
86
70
71
72
66
60
42
38
27
60
44
40
20
25
14
74
51
47
33
20
22
Risk groups
Risk factors
2 years
Low risk
02
79
Intermediate risk
34
60
High risk
57
43
after the surgery (58). The preoperative cycles induced a complete response in 3.8% of patients and a partial response in
40.1% with a decrease in the diameter of the nodules of 29.5%.
At 3 years, the disease-free survival was 28.1% in the group
treated with surgery alone and 35.4% in the group that received
perioperative chemotherapy (p = 0.058). The reduction of the
size of the nodules could modify and facilitate the liver resection
with a minor hepatectomy instead of a major liver resection.
In patients presenting with five or more bilobar metastases,
Tanaka et al. (59) showed that the 5-year survival rate was 38.9%
in the group receiving neoadjuvant chemotherapy compared to
20.7% of the group treated with hepatectomy alone. In addition, multivariate analysis revealed neoadjuvant chemotherapy
to be an independent predictive factor for survival. These results
suggest a survival benefit of neoadjuvant chemotherapy in
patients with resectable metastases. Whether the use of adjuvant chemotherapy would translate as the gold standard practice is still a matter of debate. Obviously, multinodular
metastases are very likely to benefit from neoadjuvant chemotherapy owing to the potential of missing small metastases.
Approaches to Surgery
Assessment of Functional Hepatic Reserve
The functional hepatic reserve can be assessed by ChildPugh
score and hepatic biological blood tests, however, to date the
only test which has proven to have a good predictive value is
the indocyanine green (ICG) clearance test (60). In candidates
for liver resection with retention of less than 20% of ICG at
15 minutes, up to 60% of the volume of the parenchyma can
be resected. Although liver metastases rarely develop in cirrhotic liver, with the ever increasing use of more efficient chemotherapy regimens and targeted agents, a rising number of
patients are expected to present with damaged livers as a result
of chemotherapy given before resection. Specific pathologic
changes of the liver parenchyma (vascular changes and/or chemotherapy associated steatohepatitis) influencing the liver
regeneration and function as well as the ability of the patient
to recover have been observed, following administration of
preoperative chemotherapy. Hence in this new context, evaluation of the functional reserve of the liver is becoming critical.
Preoperative management
Neoadjuvant Chemotherapy
Conventional first-line chemotherapeutic regimens for resectable colorectal liver metastases (CRLM) contain fluorouracil
(5-FU) in addition to leucovorin. Using a bolus administration regimen for patients treated with 5-FU and leucovorin
response rates ranging from 20% to 30% and a median survival of 11.5 months has been reported (52,53). No significant
difference in median survival has been observed when the
5-FU was delivered by continuous infusion, despite improvement of the response rate and reduction of the toxicity.
Combination of 5-FU with newer drugs such as irinotecan
(topoisomerase I inhibitor) resulted in a higher response rate
(39%), longer progression free and overall survival time
(14.8) compared to 5-FU and leucovorin alone (54). In addition, it has been shown that irinotecan in combination with
continuous infusion of 5-FU/ leucovorin (FOLFIRI) produces
better response rates and longer progression free and overall
survival compared to 5-FU/leucovorin alone (55). More
recently, the combination of infusional 5-FU/leucovorin with
oxaliplatin (cisplatin derivative) has been found to be less
toxic and more efficacious than the bolus irinotecan/5-FU/
leucovorin regimen (56,57). Whether the combination of
infusional 5-FU/leucovorin with oxaliplatin (FOLFOX) or
FOLFIRI is better as first-line chemotherapy remains controversial as they have comparable response rates. What may be
more persuasive is that when these regimens are used sequentially when progression or toxicity occurs, regardless the order,
survival is prolonged.
For patients with up to four liver metastases, a prospective
trial conducted by the European Organization for the Research
and Treatment of Cancer compared surgery alone versus
surgery with perioperative chemotherapy (FOLFOX
4 oxaliplatin/5-FU/leucovorin), six cycles before and six cycles
Preoperative Biopsies
Currently routine biopsy of liver lesions as part of the diagnostic process for patients who are thought to have potentially
resectable lesions is not recommended. Although the seeding
along the needle track has been believed to be very rare (incidence 0.0030.07%) (61,62), it appears that it has been greatly
underestimated. An incidence of needle track metastases ranging from 10% to 19% has recently been reported (63,64).
Therefore, the potential benefits of liver biopsy in suspected
patients are outweighted by the risk of these serious complications as well as the risk of deriving false reassurance from a
false-negative result.
Role of Laparoscopy and Laparoscopic Ultrasound (LUS)
Evaluation
In the recent years, many surgeons have advocated the use of
laparoscopy for evaluation of CRLM preoperatively in order to
121
122
Figure 13.1 Picture showing multiple metastasectomies with maximal preservation of the liver parenchyma.
postoperative management
Adjuvant Systemic Chemotherapy
At present, despite several chemotherapy regimens, data would
support the use of 5-FU and leucovorin as adjuvant chemotherapy after liver resection if patients have not previously
failed this regimen. Portier et al., in a multicenter trial that randomized 173 patients after hepatectomy for CRLM to surgery
alone or to surgery followed by chemotherapy (5-FU/ Leucovorin), demonstrated that patients who received adjuvant chemotherapy had a significantly better disease-free survival compared
to that of patients treated with surgery alone (34% vs. 27%; p =
0.03) (71). A year later, Park et al., in a large two-center study
comparing 518 patients treated with no chemotherapy (379
American, 139 European) to 274 patients treated (240 American, 34 European) with 5-FU-based adjuvant chemotherapy,
demonstrated that systemic adjuvant chemotherapy prolongs
survival after hepatic resection for colorectal metastases (72).
Patients subjected to adjuvant chemotherapy had improved
survival (p = 0.007) even after stratification by clinical risk
score (p = 0.001). In every clinical risk score category, patients
subjected to adjuvant chemotherapy had a higher chance of
survival (range 1.32.0 times).
Meanwhile, for those who have previously failed this regimen, an oxaliplatin- or irinotecan-based regimen should
be considered. Despite that there has not been a clear demonstration of efficacy of any regimen, the higher response
rate observed in patients treated with FOLFOX or FOLFIRI
over the 5-FU/leucovorin has resulted in many groups to
preferentially use these regimens in adjuvant settings.
Author
Year
No. of
patients
Postoperative
morbidity (%)
1 year
3 years
5 years
10 years
Nordlinger
et al.
Fong et al.
Minagawa
et al.
Suzuki et al.
Choti et al.
Adam et al.
Kato et al.
Abdalla et al.
Tanaka et al.
Fernandez
et al.
Pawlik et al.
Wei et al.
1995
1568
28
1999
2000
1001
235
2.8
0.8
89
57
51
36
38
22
38
2001
2002
2003
2003
2004
2004
2005
26
226
615
585
190
193
100
1
1
0
18.6
18
26
1
93
91
69
86
62
57
61
73
46
66
32
40
41
33
58
43
58
26
2005
2006
557
423
1
2
19.6
97
93
74
58
47
28
which explain the fact why the operative mortality and longterm survival have plateaued.
In contrast, the perioperative morbidity rate is reported to
be greater than 20% (28,77). The major morbidity associated with liver resection includes hemorrhage (13%), bile
leak and/or fistula (4%), pleural effusion/pneumonia
(510%/520%), and hepatic failure (38%). Of the nonliver-related complications, intra-abdominal sepsis is found
to be the most frequent major complication, and pulmonary
infection is the most frequent minor complication. Among
liver-related complications, liver failure is the most serious
and occurs in 3% to 8% of all major liver resections often
being lethal. Similarly, intraoperative hemorrhage, although
rare, is another major complication with a mortality as high
as 17% (78).
Long-term Survival Results
Large series have reported a 5-year survival after hepatectomy
for CRLM of 35% to 52% with a 33- to 46-month median survival (8,9,46,79) (see Table 13.2). However, recent data have
shown an improved 5-year survival rate of 58% after complete
resection of CRLM (35). Also, a number of series with sufficiently long-term follow-up indicate that the 10-year survival
after resection can be expected in 20% to 30% of patients
(12,46,80) (see Table 13.2 and Fig. 13.1). Similarly the International Registry of Hepatic Metastases of Colorectal Cancer
(LiverMetSurvey), which to date includes more than
8000 patients, has demonstrated a 5- and 10-year survival of
41% and 26%, respectively.
An important oncologic question is whether the recently
improved systemic therapies can achieve the same results as
resection for CRLM? This seems unlikely considering that longterm survival beyond 5-years is rare without liver resection (5)
(Fig. 13.2). Indeed, the survival results can be questioned if
considering that the patients who undergo resection are selected
and may have better outcomes due to less aggressive disease.
123
Patient survival after a 1st liver operation for colorectal metastases: 8179 patients
Log rank p = <0.0001
100
90
80
70
60
50
41%
40
30
20
10
7%
0
0
2
Resected
5
Resected
10
Nonresected
Figure 13.2 Five- and ten-year survival following hepatectomy for colorectal liver metastases. Source: www.livermetsurvey.org.
124
91%
Resectable: 335
Initially non-resectable: 138
No surgery
80
Survival (%)
66%
p = 0.01
60
48%
40
30%
52%
33%
20
23%
No surgery
0
0
5
6
Years
10
Figure 13.3 Curves demonstrating 5- and 10-year survival for initially resectable patients and for patients who underwent rescue surgery. Source : From
Ref. (82).
(A)
(C)
(B)
(D)
Figure 13.4 Unresectable colorectal liver metastases downsized by chemotherapy.
125
RFA is currently the most commonly applied ablation method. RFA involves localized application of
conductive thermal energy to destroy tumor cells.
Specifically alternating electric current in the range
of radiofrequency waves (460 kHz) is applied from a
generator through a needle electrode placed directly
into the tumor.
126
embolization has taken place. Finally a second stage hepatectomy will be carried out to completely remove the liver
harboring the remaining metastases (Fig. 13.5). The success of this method relies on the liver regeneration between
the two interventions, allowing the second hepatectomy to
be performed with a lower risk of complications, including
liver failure.
Our experience, as well as that of others, has demonstrated
that this strategy can be carried safely and effectively in
selected patients with initially nonresectable multiple bilobar
CRLM (104107) (Table 13.3). In our latest study, the 3- and
5-year survival rates were 60% and 42%. It should be mentioned that during the first stage performing nonanatomic
(A)
(B)
(C)
(D)
Figure 13.5 Radiological follow-up of a patient treated with combination of neoadjuvant chemotherapy and two-stage hepatectomy. 1A, hepatic metastases before
chemotherapy treatment. 1B, planning of surgery after tumor downstaging (before the first hepatectomy). 1C, first hepatectomy. 1D, liver remnant following the
second hepatectomy (segments IV and I).
Table 13.3 Reported Survival Outcomes after Two-Stage Hepatectomy for Colorectal Liver Metastases
Patient survival (%)
Author/Institution
No of
patients
Success rate
(%)
Mortality rate
(%)
Morbidity rate
(%)
Median
(months)
3 years
5 years
16
33
12
11
45
81
76
100
100
69
15
0
0
0
6.5
45
56
NA
18
48
31
18
35
35
54
45
47
28
127
No residual tumor should be left in the future remnant liver at the first intervention.
If the resection alone cannot remove all lesions, one
of the ablative methods (RFA, cryotherapy) has to be
used for local tumor destruction in order to prevent
tumor progression during the regeneration of the
remnant liver.
At the first intervention, portal dissection and mobilization of the lobe that is to be resected during the
second intervention should be avoided.
Patients with unilobar multinodular metastases requiring resection of more than 60% to 70% of the functional liver parenchyma should undergo preoperative
portal vein embolization. Following PVE, the induced
hypertrophy of the future remnant liver allows for a
curative resection while minimizing the risk of postoperative hepatic insufficiency (Fig. 13.6A).
Patients with bilobar multinodular metastases for
which a planned resection would leave no more than
three nodules and none larger than 3 cm in the
remnant liver are preferentially treated with a
multimodal approach consisting of hepatic resection combined with RFA or cryotherapy of the
unresectable nodules (Fig. 13.6B).
Right lobectomy
Remnant liver <30%
Right hepatectomy
3 Metastases 30 mm (remnant liver)
Right hepatectomy
>3 Metastases > 3 mm (remnant liver)
Figure 13.6 Diagrammatic illustration of the surgical strategies used when treating patients with nonresectable multimodal metastatic disease. (A) Multifocal
unilobar metastases. (B) Multifocal bilobar metastatases. (C) Multifocal bilobar metastases. RFA, radio frequency ablation; Cryo, cryotherapy.
128
Table 13.4 Reported Survival Outcomes after Repeat Liver Resection for Recurrent Colorectal Metastases
Patient survival (%)
Author/Institution
Year
Fernandez et al.
Adam et al.
Yamamoto
Muratore et al.
Suzuke et al.
Petrowsky et al.
Adam et al.
Shaw et al.
1995
1997
1999
2001
2001
2002
2003
2006
No of patients
170
64
75
29
26
126
199
66
1 years
3 years
5 years
87
48
86
89
45
60
31
35
62
51
46
32
41
32
34
32
44
(%)
100
89%
First hepatectomy
Second hepatectomy
88%
80
Third hepatectomy
82%
54%
60
40
46%
36%
42%
32%
28%
20
0
0
Patients at risk
First hepatectomy
Second hepatectomy
Third hepatectomy
2
No
416
139
6
3
1 yr
267
80
49
2 yrs
169
37
31
4
3 yrs
120
27
15
4 yrs
83
19
10
5 Year
5 yrs
60
13
6
Figure 13.7 Survival after 1st, 2nd, and 3rd hepatectomy from the time of the index operation. Source: From Ref. (112).
129
130
conclusions
The surgical treatment of colorectal hepatic metastases represents the only potentially curative therapeutic option able
to achieve long-term survival and a hope for cure. Newer
treatment strategies have shifted from the traditional concept
of successive lines of medical therapy to that of a continuum
of care in which medical and surgical treatment combinations are tailored to the clinical settings. To optimize the
treatment of CRLM, management by a multidisciplinary
team consisting of oncologists, surgeons, and radiologists is
of the utmost importance.
Advances in body and hepatic imaging has allowed for more
accurate selection of patients with colorectal liver metastases.
Imaging modalities are now able to detect minimal metastatic,
which not very long ago would have been very difficult to do so.
The significance of the prognostic factors has changed,
although helpful in stratifying patients with regards to prognosis, should not be used to exclude otherwise resectable
patients from surgery.
Data on the use of neoadjuvant and adjuvant therapy to
decrease recurrence risk and improve survival in patients with
initially resectable metastases are encouraging, while further
evidence and assessment is needed.
With newer chemotherapy regimens, a significant proportion of unresectable patients are currently switched to resectable, opening the way to a survival benefit, which is not very
different to that of initially resectable patients.
The use of modern surgical techniques has resulted in
a reduction of perioperative mortality and morbidity,
whereas tumor ablation techniques, PVE, and radical liver
131
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3. Blumgart LH, Allison DJ. Resection and embolization in the management of secondary hepatic tumors. World J Surg 1982; 6: 3245.
4. Jatzko G, Wette V, Muller M, et al. Simultaneous resection of colorectal
carcinoma and synchronous liver metastases in a district hospital. Int J
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5. Wagner JS, Adson MA, Van Heerden JA, et al. The natural history of
hepatic metastases from colorectal cancer a comparison with respective
treatment. Ann Surg 1984; 199: 5028.
6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leukovorin for metastatic colorectal cancer. N
Eng J Med 2004; 350: 233542.
7. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and
cetuximab plus irinotecan in irinotecan refractory metastatic colorectal
cancer. N Eng J Med 2004; 351: 33745.
8. Ambiru S, Miyazaki M, Isono T, et al. Hepatic resection for colorectal metastasesanalysis of prognostic factors. Dis Colon Rectum 1999; 42: 6329.
9. Yazaki M, Ito H, Nakagava K, et al. Aggressive surgical resection for
hepatic metastases involving the inferior vena cava. Am J Surg 1999;
177: 2948.
10. Kato K, Yasui K, Hirai T, et al. Therapeutic results for hepatic metastasis
of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded in 18 institutions. Dis Colon Rectum 2003; 46: S2231.
11. Mutsaerts EL, van RS, Zoetmulder FA, et al. Prognostic factors and
evaluation of surgical management of hepatic metastases from
colorectal origin: a 10 year single institute experience. J Gastrointest
Surg 2005; 9: 17886.
12. Wood CB, Gillis CR, Blumgart LH. A retrospective study of the natural
history of patients with liver metastases from colorectal cancer. Clin
Oncol 1976; 2: 2858.
13. Wilson SM, Adson MA. Surgical treatment of hepatic metastases from
colorectal cancer. Arch Surg 1976; 111: 3304.
14. Scheele J, Strangl R, Altendorf-Hofmann A, Gall FP. Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 1991;
110: 1329.
15. Mentha G, Huber O, Robert J, et al. Elective hepatic resection in the
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16. 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 Col Surg 2000; 191: 3846.
17. Vauthey JN, Pawlik TM, Abdalla EK, et al. Is extended hepatectomy for
hepatobiliary malignancy justified? Ann Surg 2004; 239: 72230.
18. Sica GT, Ji H, Ross PR. CT and MR imaging of hepatic metastases. AJR
Am J Roentgenol 2000; 174: 6918.
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133
134
14
introduction
Colorectal cancer (CRC) is a major cause of cancer-related
mortality worldwide and in Western countries, and it is the
second most frequent cause of cancer-related death (1). The
United States has the highest annual incidence of invasive
CRC, and in 2008 an estimated 148,810 cases of CRC were
diagnosed and 49,960 people died from the disease (2). At
diagnosis, 20% to 25% of all patients will have synchronous
liver metastases and at least another 60% of patients who
develop metastatic disease will have metachronous liver metastases (3,4). The liver is the only metastatic site in about onethird of patients and this can be explained by the portal venous
drainage of the colon and rectum to liver (5). Overall liver
metastases are seen in approximately 20% to 70% of patients
with CRC and lung metastases are seen in 10% to 20%. (6) For
many years, the approach to patients with metastatic CRC was
minimalist with fluorouracil-based chemotherapy being the
only palliative option and median survival rarely exceeding
one year (7).
Surgical developments over the last 10 years in resection of
liver metastases have resulted in improved long-term survival.
Several large surgical series have shown 5-year survival rates
averaging 30% to 40%, and in some patients a chance of cure,
with 20% survival at 10 years after hepatic resection (810).
Developments in chemotherapy, both systemic and regional,
have resulted in a radically changed landscape for patients
with metastatic CRC. Those patients who present with initially
unresectable liver metastases, 80% to 85% of cases, may now
have the chance of hepatic resection after chemotherapy
downstaging. Even if liver resection is not possible, median
survival has increased with modern chemotherapies (3,11).
This review will focus on developments in chemotherapy
and biologic therapy for the treatment of metastatic CRC and
highlight how a true multidisciplinary approach has resulted
in improved survival for this common disease.
135
First-line
Rothenberg (22)
Rothenberg (32)
IFL
FOLFIRI
Tournigand (25)
FOLFIRI
Souglakos (33)
Park (137)
Oxaliplatin
Irinotecan
Second-line
RR (%)
mTTP
FOLFOX4
FOLFOX4
XELOX
FOLFOX6
FOLFOX6
FOLFIRI
FOLFOX
9.9
12.4
15.3
15
FOLFIRI
18
15
4.6
4.8
4.7
4.2
4
7.5
2
mOS
12.6
11.9
2.5
14
5
136
Catheter in
artery
Codman
3000
Pump
137
138
survival 14.5 vs. 11.4 months, respectively) (78). The randomized phase III PACCE study investigated the addition of Pmab
to a combination of bevacizumab and chemotherapy (either
oxaliplatin or irinotecan-based regimens) in the first-line setting demonstrated a decreased PFS for the Pmab/bevacizumab
plus oxaliplatin versus bevacizumab/chemotherapy combination (10 vs. 11.4 months, respectively, p = 0.044). In the irinotecan-based chemotherapy group, median PFS was 10.1 months
for those the received two antibodies versus 11.7 months for
those receiving one (79). A trend toward worse OS was observed
with Pmab/Bev plus systemic chemotherapy vs Bev plus chemotherapy in the KRAS wt group, 20.7 versus 24.5 months,
respectively. Additional toxicity was also seen in the Pmab/
bevacizumab/chemotherapy group. The CAIRO-2 study compared the combination of Cmab with bevacizumab and
XELOX in the first-line treatment and showed that the Cmab/
bevacizumab/XELOX resulted in a decreased median PFS
compared with XELOX/bevacizumab (9.4 vs. 10.7 months, p =
0.018) (80). KRAS analysis was performed retrospectively and
when compared to patients with KRAS mutations in the chemotherapy/bevacizumab group, cetuximab-treated patients
with KRAS mutated tumors had significantly shorter PFS (8.1
vs. 12.5 months, p = 0.003) and OS (17.2 vs. 24.9 months, p =
0.03). In those patients with KRAS wild-type tumors, there was
no difference in either PFS or OS with the addition of cetuximab. Thus the addition of VEGF/EGFR antibody combinations to chemotherapy suggests a lack of benefit. The SWOG/
CALGB 80405 trial looking at FOLFIRI or FOLFOX in combination with Cmab or bevacizumab or both may help to answer
this question (60). To date, therefore, dual biologic therapy
with bevacizumab and an anti-EGFR antibody should not be
used in combination with chemotherapy in the first-line treatment of metastatic CRC outside of a clinical trial.
Study
Regimen
Giacchetti (83)
5FU/LV/
Oxaliplatin
38
5 years, 50%
Bismuth (82)
16
Med, 48m
5years, 54%
Pozzo (138)
5FU/LV/
Oxaliplatin
FOLFIRI
Alberts (139)
Masai (140)
FOLFOX4
FOLFOXIRI
33.3
26
32.5
OS
All alive
19m f/u
Med, 26m
4 years, 37%
Med, 37m
139
140
for >10 days] (8% vs. 4%), hepatic failure [bilirubin >100 mg/
day for >3 days] (6% vs. 3%), and wound infection (3% vs.
2%). The clinical impact of these complications was not significant (120). Survival data are not yet available and the longterm benefit of neoadjuvant chemotherapy in those patients
with initially resectable liver metastases is still not clear, especially since both pre- and postchemotherapy was given. At present, the EORTC 40051 BOS (Biologics, Oxaliplatin and
Surgery) trial is assessing perioperative chemotherapy with
FOLFOX6 and cetuximab with or without bevacizumab in
patients with resectable hepatic metastases form CRC.
Our advice, in clearly resectable lesions, is resection should
be preformed first or if systemic chemotherapy is given, it
should be for a short a period as possible (no more than six
treatments at two-weekly intervals) to avoid liver toxicity, and
liver lesions should be resected as soon as possible if the patient
is a suitable surgical candidate. Consideration should then be
given to adjuvant systemic chemotherapy in combination
with HAI (see below).
141
HAI
Tono (141)
MSKCC (124)
ECOG (126)
Lorenz (128)
Lygidakis (129)
No. Patients
IV
FU
FUDR+IV FU/LV
FUDR+IVFU/LV
FU/LV
Multidrug**
po FU
FU/LV
FU
None
None
2-year OS(%)
MS (Mths)
HAI
IV
HAI
IV
HAI
IV
HAI
IV
9
74
45
113
20
10
82
30
113
20
78
90
67
67
30
60
43
63
78^
86
62
62
50^
72
53
65
63
72
64
44.8
20!
40
59
50
39.7
11!
If held,restart when:
Ref value (ref) *
Current value$
If held,restart when:
Ref value (ref)*
Current value$
50 U/L
0 to <3 X ref
3 to <4 X ref
4 to <5 X ref
5 X ref
<4 X ref
Alk Phos
90 U/L
0 to <1.5 X ref
1.5 to >2 X ref
2 X ref
<1.5 X ref
Total Bilirubin
1.2 mg/dl
0 to <1.5 X ref
1.5 to <2 X ref
2 X ref
<1.5 X ref
FUDR dose
>50 U/L
0 to <2 X ref
2 to <3 X ref
3 to <4 X ref
4 X ref
<3 X ref
>90 U/L
0 to <1.2 X ref
1.2 to 1.5 X ref
1.5 X ref
<1.2 X ref
>1.2 md/dl
0 to <1.2 X ref
1.2 to <1.5 X ref
1.5 X ref
<1.2 X ref
Reference value is the value obtained on the day patient received the last FUDR dose.
Current value is that obtained at pump emptying or on the day of planned treatment (whichever is higher).
142
100%
80%
50%
HOLD
50% off last dose
FUDR
100%
80%
HOLD
25% off last dose
FUDR
100%
50%
HOLD
25% off last dose
conclusions
Liver resection should now be considered in all patients with liverconfined metastatic disease from CRC. Modern systemic chemotherapy with irinotecan- and oxaliplatin-based regimens can
increase resection rates is a significant number of patients. The
addition of biologic agents in patients with the appropriate molecular signature may increase repose rates and resectability rates
even further. Long-term cures are possible in patients who undergo
liver resection and series with 10-year survivors have been reported
(10). In those patients in whom resection is not possible, overall
survival has increased from less than 1 year with fluorouracil regimens to over 2 years with chemobiologic regimens (74). Hepatic
arterial infusion with FUDR has consistently demonstrated
increased response rates and hepatic progression-free survival
compared to systemic chemotherapy. The combination of HAI
FUDR with modern chemotherapy and perhaps chemobiologic
therapy can result in increased resection rates of initially unresectable liver disease and also has a role to play after liver resection.
references
1. Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and
mortality in Europe in 2006. Ann Oncol 2007; 18: 58192.
2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin
2008; 58: 7196.
3. Kemeny N. Presurgical chemotherapy in patients being considered for
liver resection. Oncologist 2007; 12: 82539.
4. Rees M, Tekkis PP, Welsh FK, et al: Evaluation of long-term survival
after hepatic resection for metastatic colorectal cancer: a multifactorial
model of 929 patients. Ann Surg 2008; 247: 12535.
5. Kemeny N. Management of liver metastases from colorectal cancer.
Oncology (Williston Park). Oncology (Williston Park) 2006; 20:
116176.
6. Penna C, Nordlinger B. Colorectal metastasis (liver and lung). Surg Clin
North Am 2002; 82: 107590, xxi.
7. Meyerhardt JA, Mayer RJ. Drug therapy: Systemic therapy for colorectal
cancer. N Engl J Med 2005; 352: 47687.
8. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes
following hepatic resection, radiofrequency ablation, and combined
resection/ablation for colorectal liver metastases. Ann Surg 2004; 239:
81827.
9. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after
resection of hepatic metastases from colorectal cancer in patients
screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 2004; 240: 43850.
10. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival
after resection of colorectal liver metastases defines cure. J Clin Oncol
2007; 25: 457580.
11. Alberts SR, Wagman LD: Chemotherapy for colorectal cancer liver
metastases. Oncologist 2008; 13: 106373.
12. Hoff PM, Cassidy J, Schmoll HJ. The evolution of fluoropyrimidine
therapy: from intravenous to oral. Oncologist 2001; 6 Suppl 4: 311.
13. Meta-Analysis Group in Cancer. Toxicity of fluorouracil in patients with
advanced colorectal cancer: effect of administration schedule and
prognostic factors. J Clin Oncol 1998; 16: 353741.
14. Meta-Analysis Group in Cancer. Efficacy of intravenous continuous
infusion of fluorouracil compared with bolus administration in
advanced colorectal cancer. J Clin Oncol 1998; 16: 3018.
15. Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by
leucovorin in patients with advanced colorectal cancer: an updated
meta-analysis. J Clin Oncol 2004; 22: 376675.
16. de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing
monthly low-dose leucovorin and fluorouracil bolus with bimonthly
high-dose leucovorin and fluorouracil bolus plus continuous infusion
for advanced colorectal cancer: a French intergroup study. J Clin Oncol
1997; 15: 80815.
17. Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;
352: 14138.
18. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with
fluorouracil compared with fluorouracil alone as first-line treatment for
metastatic colorectal cancer: a multicentre randomised trial. Lancet
2000; 355: 10417.
19. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 90514.
20. Maiello E, Gebbia V, Giuliani F, et al. FOLFIRI regimen in advanced
colorectal cancer: the experience of the Gruppo Oncologico dellItalia
Meridionale (GOIM). Ann Oncol 2005; 16 Suppl 4: iv5660.
21. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of
irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line
treatment of metastatic colorectal cancer: results from the BICC-C
Study. J Clin Oncol 2007; 25: 477986.
143
144
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
145
146
147
15
148
building an effective
multidisciplinary team
An effective MDT needs to be built around a designated core
membership. Once this core group is established, then other
professionals from many disciplines can attend and become
involved. For the management of patients with CRLM, the key
disciplines of the core group include hepatobiliary surgery,
medical oncology, diagnostic radiology, interventional radiology, and palliative care. It is essential that there is a designated
team member from each of these disciplines. Other disciplines
that we have found helpful in support of our CRLM MDT
include gastroenterology/hepatology, our specialist nursing
colleagues, and histopathology. However, having a dedicated
clerical coordinator who can pull together all the relevant correspondence, documentation and investigations for each and
every patient to be discussed is absolutely essential for the successful operation of such an MDT. With regard to diagnostic
radiology, it is our experience that the radiologist presenting
the images to the MDT will require at least 3 hours preparation time for every 20 patients to be discussed. This requirement for radiology time has major cost implications for the
running of a busy radiology department.
computeed tomography
Recent advances in computed tomography (CT) technology
(helical CT and multidetector row helical CT) have improved
performance in speed of acquisition, resolution, and ability to
image the liver during various phases of contrast enhancement
with greater precision (9,12). Using intravenous iodinated contrast media these techniques characterize liver lesions based on
their enhancement patterns during the various phases of contrast circulation in the liver (12). CT has limitations, including
surgery
There are many substantial prospective and retrospective series
of surgical resection of CRLM consistently show 5-year survival
rates following liver resection of 30% to 50%, depending on
selection criteria (15). The problem encountered when attempting to interpret these reports is that although there are more
than 600 in the literature, barely 30 series are prospective studies, reporting more than 100 patients from reliable high-volume
centers, and with median follow-up of >24 months (15).
However, from these reports nearly all patients who survive for
more than 5 years can usually be considered cured of the disease.
resection margins
Historically, resection was only considered if the hepatobiliary
surgeon believed that the metastasis could be resected with a
margin of healthy surrounding liver that was >1 cm. The new
standards challenge the 1 cm rule. More recent studies show
that size of the resection margin has no effect on survival, as
long as the margin is microscopically clear of disease (20,21).
149
90
80
70
+9.2%
At 3 years
Periop CT
60
50
42.4%
40
Surgery only
30
33.2%
20
10
(years)
0
0
O
N
104 152
93 151
24
10
23
118
76
45
Figure 15.1 Three-year progression-free survival comparing surgery alone to surgery with perioperative chemotherapy in the EORTC 40983 (EPOC) trial (30).
secondary CRLM resection rates) when compared to conventional chemotherapy alone. Therefore, even more patients with
initially unresectable CRLM may respond to treatment with
combinations of systemic treatments in the future (2729).
Recent data from the German Phase II CELIM study have suggested that as many as 40% of patients with unresectable kras
wild type colorectal cancer metastases confined to the liver may
now be brought to liver resection with curative intent using
combinations of cetuximab with either oxaliplatin-based or
irinotecan-based chemotherapy regimens (30).
Recent data have suggested that the addition of perioperative (both neoadjuvant with adjuvant) chemotherapy
using FOLFOX to surgical resection confers improved disease-free survival when compared to surgery alone (31).
These data need to be interpreted with caution since the
study did not demonstrate its primary endpoint (3-year
disease-free survival on intention to treat at the point of
initial randomization), and only achieved significance on
the analysis of operated patients, when ineligible patients
were excluded (Fig. 15.1).
150
are often too close to major vascular structures to be considered resectable with a clear margin. Just as a surgical margin
would be likely to be compromised, high blood flow immediately adjacent to the tumor will conduct away heat, leading to
incomplete ablation and tumor recurrence (2).
The efficacy of RFA in unresectable CRLM has been established by several large cohort studies with median survivals of
28.9 to 36 months being achieved (32,33). Presently the dearth
of prospective randomized controlled trials comparing RFA
with chemotherapy over chemotherapy alone in unresectable
CRLM is being addressed by the EORTC CLOCC trial (EORTC
40004). Early progression-free survival data from this study
have suggested that the addition of RFA to FOLFOX-based
chemotherapy confers a statistically significant improved progression-free survival of 17 months compared to 10 months
for FOLFOX alone (T Ruers, personal communication).
Microwave ablation therapy is now becoming commercially
available. The major advantage of microwave ablation over
RFA is speed. Whereas it may take 20 to 30 minutes to achieve
an adequate ablation of a 3-cm metastasis using RFA, microwave can achieve the same degree of tumor destruction in only
3 to 4 minutes.
Extrahepatic disease
Determine if patient is
candidate for
hepatic resection or
HR and RFA or
RFA alone
Consider chemotherapy
No response
Consider chemotherapy
Hepatic resection
Response
All tumor(s)
resectable
HR and RFA
Some tumor(s) resectable
and some ablatable
(Laparotomy HR and RFA)
RFA alone
All tumor(s) ablatable
but not resectable
Lapartomy, Laparoscopic
or Percutaneous)
No response
Incomplete ablation or
new metastases
Consider
repeat or serial RFA
and/or
repeat HR
Figure 15.2 The possible treatment strategy algorithm for patients with colorectal liver metastases (40).
synchronous CRLM should have immediate definitive lifesaving treatment (endoscopic stenting, resection with either a
stoma or immediate reconstruction).
Most surgical oncologists would recommend that in situations where resection of the primary tumor may be more
demanding (T2T3 rectal carcinoma), or when the management strategy for the primary tumor requires neoadjuvant
treatment (chemoradiotherapy for T3T4 rectal carcinoma),
or the liver disease (albeit technically resectable) is of such an
extent that it requires at least a hemi-hepatectomy or more,
then planned sequential staged procedures carry lower perioperative risk (36,37).
However, when considering staged sequential treatment
strategies, concerned must remain about the risk of tumor
progression at both sites during treatment (31,3840). For
151
conclusions
If feasible, surgical resection remains the gold standard of
treatment for CRLM. Unfortunately, patients still present
with advanced colorectal cancer. Modern chemotherapy regimens offer increasing numbers of patients with initially
unresectable CRLM the chance of being brought to potentially curative liver surgery (Fig. 15.2) (41). The remaining
controversies in this field are the timing of such surgery and
the strategic decisions of which operation (bowel first, liver
first, or synchronous combined surgery) is now the first procedure of choice?
The role of the MDT in the management of colorectal cancer liver metastases is to collate all the available data that can
lead to an accurate assessment of disease spread and stage,
then using these data, to plan an effective treatment strategy
that ideally is focused on possible cure, but in any event is
aimed at gaining maximal survival advantage for our patients.
references
1. Poston GJ. Surgical strategies for colorectal liver metastases. Surg Oncol
2004; 13: 12536.
2. Primrose JN. Treatment of colorectal metastases: Surgery, cryotherapy or
radiofrequency ablation. Gut 2002; 50: 15.
3. Weiss L, Grundmann E, Torhorst J, et al. Hematogenous metastatic patterns in colonic carcinoma: An analysis of 1541 necropsies. J Pathol 1986;
150: 195203.
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153
16
introduction
Neuroendocrine tumors (NET), including both carcinoid
tumors and islet tumors, are derived from primitive neuroectodermal cells that are distributed throughout the body during embryonic development (14). Therefore, NETs originate
from various organs but most commonly involve the lungs,
bronchi, and gastrointestinal tract (2,5). NETs were traditionally classified into foregut, midgut, and hindgut derivatives
based on their presumed origin of gut. Currently, it is replaced
by the WHO classification system of 2000 according to the
histological differentiation (6). Clinical presentations widely
differ depending on both their organ and excess hormone
production (e.g., serotonin, histamine, tachykinins, and prostaglandins) (3,5). The overall incidence of NET has been
reported to be 1 to 2 cases per 100,000 people (5) (Tables 16.1
and 16.2).
Hepatic metastasis is the second common metastasis following lymph node metastasis in NETs (3) (Fig. 16.1). Up to 45%
of patients with abdominal carcinoid will present with bowel
obstruction and more than half of patients who were explored
for bowel obstruction due to NETs are found to have hepatic
metastases. Despite of the fact that liver is the common metastatic site of NETs, primary hepatic NET is extremely rare
(0.6% of all NETs) (2). In this chapter, we describe specifically
about the management of hepatic metastases of NETs.
diagnosis
Clinical Features
Hepatic metastases of NET could be diagnosed preoperatively
following investigation of a specific hormonal syndrome or
following the incidental finding of hepatomegaly or an abdominal mass. Or it could be discovered at the abdominal exploration for primary gastrointestinal NETs. Besides hormonal
symptoms, patients will complain local symptoms due to
tumor bulk (pain, early satiety, or palpable mass). Subclinical
hepatic metastasis does not require treatments, however,
lifestyle-altering symptoms or biologically aggressive tumors
require treatment (7). Demographics, presentation, symptoms,
tumor histology, and primary tumor location of patients with
NET-hepatic metastasis are summarized in Table 16.3 (8).
The most representative symptom of patients with NETs is
carcinoid syndrome. It is caused by systemic circulation of
hormonal products from bulky metastatic NETs. This syndrome is a manifestation of late stage of NET and 5% to 10%
of all NET patients present with this syndrome (1,5,9,10). In
patients with NET-hepatic metastasis, carcinoid syndrome is
frequently evident, at least biochemically (1). Common
symptoms and signs include cutaneous flushing (7180%),
diarrhea (7680%), hepatomegaly (71%), carcinoid heart disease (4170%), asthma (925%), pellagra (2%) (3,1115).
154
Pancreas
28
5
3
2
15
5
4
5
14
6
Diagnostic Imaging
Somatostatin Receptor (SSTR) Scintigraphy
Given the clinical presentation and biochemical confirmation
of NETs, topographical localization of primary tumor and
metastases should be pursued. SSTR scintigraphy utilizing
111
In-labelled SST analog (octreotide) can detect NETs that
express SSTRs. Sensitivity of this test is reported as 84% (57
93%) (1,34,35) (Fig. 16.2). The simultaneous use of single
positron emission computed tomography (SPECT) can
enhance the sensitivity. This is the first choice of diagnostic
imaging test to find the primary site of carcinoid tumors
(Grade III. Recommendation C).
Computed Tomography (CT) and Magnetic Resonance
Imaging (MRI)
CT and MRI are utilized to obtain more precise image of local
extent of tumor if surgery is contemplated, but not to look for
155
Figure 16.1 Macroscopic (A) and microscopic (B) views of large resected hepatic neuroendocrine liver metastasis (stained for chromogranin-A). Note the hypervascularity of the metastasis compared to the background liver and comparable colorectal liver metastases.
%
40
60
52 years
%
74
26
%
55
55
36
15
5
4
1
%
48
31
21
%
49
25
9
16
treatment
Treatment of NET-hepatic metastasis is required for patients
with lifestyle-altering symptoms, or biologically aggressive
tumors. The principal requirements are to remove the primary and metastatic sites in order to reduce levels of bioactive
agents (27,4446). Therefore, surgical resection is the first
choice as long as patients fit to surgery. Treatment options
include hepatic resection, hepatic artery occlusion, radiofrequency ablation, cryoablation, liver transplantation, and
medical therapy. Indications and timing of therapy are still
controversial.
156
Hepatic Resection
Surgical resection of NET-hepatic metastasis is categorized
into curative intent resection or palliation intent resection
(debulking/cytoreductive surgery). Both of approaches contribute to the improvement of symptoms and the prolonged
survival.
Curative intent resection is indicated for patients with solitary or localized hepatic metastasis. Only 10% to 25% of
NET-hepatic metastasis is found in this category. Palliation
intent resection is applied to patients with considerable
symptom due to multiple, bulky extended tumor. The removal
of more than 90% of the tumor bulk allows a significant palliation. Concurrent resection of extrahepatic tumors is often
performed. Regional lymphadenectomy should be done
because lymph node metastasis is common in NETs.
Administration of SST analogs will be required for patients
with residual tumors. Curative resection is associated with
longer survival than noncurative resection (91% vs. 76% at
5 years; median 3050 vs. 1632 months, respectively).
Summary of literature review regarding postoperative
outcomes is shown in Table 16.5 (8,4758). Postoperative morbidity and mortality rates are 22% (3-26%) and 3% (06%).
Although perioperative carcinoid crisis is not very frequent
(03%), precaution should be always taken. Relief of symptom
was achieved in 92% (46100) of patients. Disease-free survival
is 17 to 60 months (median 41 months) and 36% (1642%) at
5 years. Hepatic recurrence is reported in 82% of patients (52).
Survivals have an estimated median of 67 (5281) months.
Five-year survival rate extends up to 73% (3185%). Ten-year
survival is reported as 35% (Grade III. Recommendation C).
Description
Description
No symptoms
Mild symptoms
Symptoms impact
daily living
Sever symptoms
Disabling symptoms
Symptoms: None
Frequency: None
Lifestyle effects: None
Symptoms: Diarrhea, flushing, or wheezing
Frequency: Up to 4 times daily
Lifestyle effects: None to minimal
Symptoms: Diarrhea, flushing, or wheezing
Frequency: 57 times weekly
Lifestyle effects: Restricts patient from leaving home for prolonged periods of time.
Symptoms: Diarrhea, flushing, or wheezing
Frequency: Multiple daily episode
Lifestyle effects: Symptoms require significant recognization of daily activities to accommodate for these
symptoms; patients rarely leave home, must be close to bathroom facilities and medical supplies.
Symptoms: Diarrhea, flushing, or wheezing (severe) or of sufficient severity to warrant hospitalization for
treatment of dehydration, electrolyte imbalance, refractory hypertension, or asthma
Frequency: Numerous (>4) daily
Lifestyle effects: Symptoms are disabling; patients are unable to leave home or require hospitalization.
A diagnostic angiography should be obtained from a femoral approach to confirm the anatomy of artery and the
patency of portal vein before the administration of the therapeutic agents (Fig. 16.4). Patients should receive SST
analogs before the procedure to prevent hormonal adverse
events (59).
There are no definitive data to support the agents for embolization such as Gelfoam, Ivalon, starch particles, lipidol, or
radio isotope-loaded spheres. Selection of chemotherapeutic
agents is also still inconclusive. Cisplatin, doxorubicin, and
mitomycin are most commonly utilized.
Almost all of patients experience postprocedural abdominal
pain, nausea, vomiting, and fever. Transaminase levels will
shoot up dramatically, and then followed by the elevation of
157
Relief of
symptoms
(%)
Disease
free
survival
(%)
Disease
free
survival
(months)
Disease
specific
survival
(%)
Disease
specific
survival
(months)
Year
No. of
patients
Dousset (Paris,
France) (47)
1996
17
6108
24
100
36% at
5 years
17
46% at
5 years
NA
1998
15
27
NA
NA
NA
21
2000
34
27
NA
86100
NA
NA
2001
13
42
NA
46
NA
not
reached
not
reached
NA
2001
16
30
12
100
2001
31
26
26
90
69% at
3 years
42% at
5 years
NA
2003
170
NA
14
96
46
2004
17
NA
24
82
16% at
5 years
NA
Mazzaferro (Milan,
Italy) (54)
Osborne (FL, USA)
(55)
Musunuru (WI, USA)
(56)
Landry (KT, USA)
(112)
Eriksson (Uppsala,
Sweden) (58)
Median
2007
36
NA
NA
NA
2006
61
NA
73% at
5 years
76% at
5 years
68% at
6 years
73% at
5 years
31% at
5 years
61% at
5 years
85% at
5 years
59% at
10 years
NA
2006
13
20
NA
NA
2008
23
NA
2008
42
83% at
3 years
75% at
5 years
NA
73% at
5 years
67
60
9104
NA
92
19% at
10 years
NA
NA
100
NA
50
26
NA
NA
NA
18
20
71
NA
NA
27
22
92
36% at
5 years
41
35
not
reached
NA
81
135
NA
43
52
NA
158
NA
17
0
5
0
NA
2008
Median
2006
2005
2007
Median
HAE and HACE
Gupta (TX, USA) (66)
2003
2007
18
123
59
122
14
46
24
15
Median
Combination with chemotherapeutic agents (HACE)
Ruszniewski (Paris, France) (114) 1993
Drougas (TN, USA) (60)
1998
Doxorubicin, Lipiodol
Doxorubicin, cisplatin,
mitomycin C +5FU
Doxorubicin, Lipiodol
Cisplatin, doxorubicin,
mitomycin, Lipiodol
Cisplatin, doxorubicin,
mitomycin, ioxaglate
sodium, Lipiodol
Cisplatin, doxorubicin,
mitomycin
NA
NA
0
4
0
0
5
9
0
6
0
0
0
Mortality
(%)
20
NA
23
14
20
8
60
12
12
NA
111
23
1994
2003
Gelfoam
Polyvinyl alcohol particles
Lipiodol/Gelfoam
Polyvinyl alcohol particles
Trisacryl gelatin microsphere
(embosphere)
Gelfoam
Morbidity
(%)
55
35
24
59
15
Agent(s) used
1998
1999
2002
2006
2007
1989
No. of
patients
Median
Year
83
83
NA
75
61
92
64
78
NA
75
98
98.0
NA
49
3852
89100
64
59
33
38
Relief of
symptoms
(%)
31% at
3 years
31% at
3 years
NA
5% at 5 years
NA
5% at
5 years
NA
NA
NA
NA
NA
NA
NA
38% at 1
year
38% at 1
year
NA
NA
NA
NA
NA
Disease free
survival (%)
24
25
23
14
19
10
17
14
13
NA
NA
NA
NA
15
8
15
NA
37
NA
NA
Disease free
survival
(months)
NA
NA
NA
29% at 5 years
27% at 5 years
28% at 5 years
83% at 5 years
29% at 5 years
NA
NA
65% at 5 years
NA
65% at 5 years
72
13% died in
5 months
83% at 5 years
54% at 5 years
72% at 5 years
NA
NA
Disease specific
survival (%)
34
NA
34
33
39
33
48
33
NA
25
44
49
39
24
80120
24
NA
24
NA
NA
Disease
specific
survival
(months)
159
This treatment is suitable for relatively small tumors. Indications for RFA include (i) fewer than 4 in number, (ii) smaller
than 5 cm, (iii) accessible location in liver, and (iv) not in contiguity to vascular structures, bowel, or the gall bladder (46).
Complications include bleeding, sepsis, and intrahepatic
biliary duct damage. Morbidity rate is around 5%. No RFArelated mortality has been reported (58,69).
RFA is associated with the high incidence of the recurrence
at previously ablated sites (58,70,71). Local recurrence rate is
reported to be 5 to 6% (69,70,72). The assessment of outcome
of this procedure is somewhat difficult to be specific because
many of RFA are combined with surgical resection. A large
160
study by Mazzaglia et al. (69) detailed the outcomes of 80 laparoscopic RFA sessions in 63 patients who underwent RFA
alone for NET-hepatic metastasis (54). Relief of symptoms
was achieved more than 90% of the patients. Median diseasefree survival was 11 months. Median disease-specific survival
was close to 4 years. Five-year survival rate was 48% (Grade III.
Recommendation C).
Hepatic Cryoablation
Cryoablation can be applied for patients with unresectable
refractory NETs. Intraoperative approach combined with
hepatic resection is common rather than cryoablation alone.
The cryoprobe is inserted into tumor under ultrasound guidance. The freezing temperature of cryoprobe is maintained
liquid nitrogen perfusing in the uninsulated tip. Tumor is
monitored until the ice ball enveloped the tumor with a
1-cm margin of normal tissue. Multiple freezingthaw cycles
lead to tumor destruction (73). Indications for this procedure
are still unclear.
Complications include coagulopathy, bleeding, acute renal
failure, and pulmonary embolism. Morbidity rate is reported
variously but at a minimum of 23%. Mortality rate is 0% to
2% (7476).
Of note, this procedure is usually combined with hepatic
resection; therefore, the outcomes of reported studies are not
specific for cryoablation. Almost all patients experienced the
relief of symptoms and biochemical response. Local recurrence at the ablated site is reported as 17% in a study from
Seifert et al. (75). Median recurrence-free survival is
10 months. Median disease-specific survival is 20 to 49 months.
Three-year survival rate is up to 91% (7476) (Grade III.
Recommendation C).
Liver Transplantation
Liver transplantation is a therapeutic alternative of hepatic
resection for unresectable NET-HM patients. Whereas the
results of liver transplantation for other metastatic tumors are
poor (77), patients with NET-hepatic metastasis have been
more likely benefit from liver transplantation (57,7885).
Although this approach is still controversial, Milan criteria
for indication to liver transplantation in patients with NEThepatic metastasis are widely referred (Table 16.7) (54).
Patients will receive a full graft, a split graft or a domino
graft from deceased or living donor (78). The general principle
of complete resection of both primary and metastatic tumor
has to be pursued in the setting of this treatment. Therefore,
transplantation could be performed with concurrent resection
of extrahepatic tumor including lymphadenectomy of hepatic
pedicle and hepato-duodenal ligament (54,78,86). Standard
immunosuppression should be administered postoperatively.
Adjuvant chemotherapy or long-acting SST analogs will be
applied as appropriately (54).
Table 16.8 shows the summary of literature review. Postoperative morbidity includes acute rejection episodes, acute
cholangitis, and bacteremia. Overall morbidity rate are
reported as 56% (3275%). Mortality rate is 10% (544%).
Recent studies report that 5-year survival of 21% (3690%),
with symptomatic relief occurring in all of the patients.
Dousset (Paris,
France) (47)
Lang (Gottingen,
Germany) (57)
Lehnert(Heidelberg,
Germany) (87)
Rosenau (Hannover,
Germany) (88)
Florman (NY, USA)
(89)
V.Vilsteren (MN,
USA) (86)
Mazzaferro (Milan,
Italy) (54)
Olausson (Goteborg,
Sweden) (90)
Marin (Murcia,
Spain) (91)
Le Treut (Marseille,
France) (78)
Median
Year
1996
No. of
patients
9
1997
12
1998
103
2002
19
2004
11
2006
19
2007
24
2007
15
2007
10
2008
85
FollowDiseaseup
Relief of
free
period
Morbidity Mortality symptoms survival
(months)
(%)
(%)
(%)
(%)
NA
NA
44
NA
Rec rate
11%
NA
NA
8
100
Rec rate
57.1%
60
NA
14
NA
24% at
5 years
60
NA
5
NA
21% at
5 years
34
NA
27
NA
9% at
5 years
22
32
5
NA
80% at
1 years
60
NA
NA
NA
77% at
5 years
54
NA
7
NA
Rec rate
33.3%
36
75
10
NA
57% at
3 years
46
NA
14
NA
20% at
5 years
50
56
10
100
21% at
5 years
43.795 pt
58
6 weeks to
48 months
NA
11
NA
NA
NA
25
NA
NA
25
Disease
specific
survival
(%)
NA
Disease
specific
survival
(months)
24
NA
55
47% at
5 years
80% at
5 years
36% at
5 years
87% at
1 years
90% at
5 years
NA
NA
57% at
3 years
47% at
5 years
47% at
5 years
NA
NA
NA
NA
NA
NA
56
55
summary
Summary of treatment for NET-hepatic metastasis is shown in
Table 16.9.
161
Indication
Hepatic resection
(8,4756,58,112)
Hepatic artery
occlusion
HAE (17,55,
6365,113)
HACE (60,114118)
Hepatic cryotherapy
(7476)
Liver transplantation
(47,54,57,78,8691)
92
36% at
5 years
41
73% at
5 years
67
49
15
75
72% at
5 years
29% at
5 years
24
20
38% at
1 year
5% at
5 years
82
NA
11
NA
48
23
95
32% at
3 years
10
91% at
3 years
45
56
10
100
21% at
5 years
25
47% at
5 years
55
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18. Debas HT, Mulvihill SJ. Neuroendocrine gut neoplasms. Important lessons
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19. Kinney MA, Warner ME, Nagorney DM, et al. Perianaesthetic risks and
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47. Dousset B, Saint-Marc O, Pitre J, et al. Metastatic endocrine tumors: medical treatment, surgical resection, or liver transplantation. World J Surg
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48. Chen H, Hardacre JM, Uzar A, et al. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival? J Am Coll Surg 1998;
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49. Jaeck D, Oussoultzoglou E, Bachellier P, et al. Hepatic metastases of gastroenteropancreatic neuroendocrine tumors: safe hepatic surgery. World J
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163
164
165
17
introduction
gynecological tumors
Approximately 90% of malignant hepatic lesions are metastases of extrahepatic primary tumors. Despite enormous
progress of multimodal therapeutical options, surgical
resection remains the only option for curative treatment in
most of these cases. However, in contrast to colorectal or
neuroendocrine hepatic metastases, the surgical approach
for noncolorectal and nonneuroendocrine hepatic metastases is highly controversial. From a critical point of view, it is
argued that noncolorectal, nonneuroendocrine liver metastases often belong to very aggressive types of cancer. In addition, they partly derive from extraabdominal primary
tumors. In contrast to intraabdominal tumors metastasizing
through the portal vein with the liver theoretically being the
first filter organ, liver metastases of extraabdominal primary
tumors imply a simultaneous systemic spread of tumor cells.
However, resection of hepatic tumors can be accomplished
safely with an appropriate risk of perioperative mortality
and morbidity, and patients with favorable tumor biology
might benefit from a surgical approach. Therefore, proper
selected patients should be offered resection of noncolorectal, nonneuroendocrine liver metastases. Since noncolorectal, nonneuroendocrine hepatic metastases encompass a
heterogeneous group of primary tumors, the management
of these metastases needs to be discussed individually for
each primary tumor type.
breast cancer
Breast cancer is the most frequent malignant tumor and the
second most common cause of cancer death in women (1).
Patients with breast cancer rarely present with isolated liver
metastases, in only 10% to 20% of metastatic breast cancer,
metastases are restricted solely to the liver (2,3) (Fig. 17.1).
Therefore, the risk of systemic tumor relapse after removal of
liver metastases is high and ought to be accounted before a
surgical liver resection is contemplated. Retrospective studies
report a median survival between 36 and 63 months (46)
( Table 17.1) when patients underwent surgical treatment in
addition to systemic chemotherapy. In contrast, in patients
treated with chemotherapy alone, the median overall survival will rarely exceed two years (7). Predictive risk factors,
which should be considered for selecting appropriate
patients, are lymph node status, extensive hepatic lesions
requiring a major resection (8), recurrence of liver metastases within one year after resection of the primary tumor (9),
R2 resection, and failure to respond to preoperative chemotherapy (4).
Applying these criteria on patients with breast cancer and
isolated hepatic metastases enables to select a subset of patients
where liver resection may improve progression-free and overall
survival compared to systemic treatment alone.
166
Author
Year
Number
of patients
included
2008
2006
2004
12
454
31
Median
overall
survival
(months)
5-year
survival
35.9
45
63
33%
41%
61%
overall survival in metastatic disease remains still unsatisfactory. Even by introduction of immunotherapy and targeted
therapy, median overall survival reaches approximately only
two years (21), making systemic therapy a merely palliative
approach.
Resection of isolated liver metastases (4,22) (Fig.17.2) as
well as other distant metastases of renal cell cancer (23,24)
resulted in 5-year survival rates between 38% and 88%.
Though the results of these retrospective studies are certainly
influenced by a selection bias, they should be used to evaluate
carefully whether in patients with metastatic renal cancer a
complete surgical resection of the distant disease is possible.
These patients will most likely benefit from a surgical approach
if all disease can be resected. Whether the results of surgical
resection can be further improved by a multimodal therapeutic
regimen including immunotherapy and moleculary targeted
therapy needs to be further evaluated.
pancreatic cancer
Pancreatic cancer is one of the most aggressive tumors. It is the
fourth leading cause of cancer death in females and the fifth
leading cause in males worldwide (1). When pancreatic cancer
is first diagnosed, the majority of patients are not amenable to
surgical treatment according to the established standard criteria. Approximately only 15% to 25% of patients are eligible to
curative operation procedures. One of the most frequent
exclusion criteria for a curative surgical intervention is the
presence of distant metastases, namely, liver metastases. In
metastasized pancreatic cancer, palliative systemic chemotherapy is considered to provide the best therapeutical option. Yet,
in many cases, R0 resection of liver metastases in addition to
resection of the primary tumor would be technically feasible.
By palliative systemic chemotherapy, median overall survival
reaches approximately 6 months (2527). The impact of a
curative-intent surgical intervention is still unanswered. In
several retrospective studies of resection of liver metastases of
pancreatic cancer, the median overall survival ranges from
6 months to 20 months (4,19,2837) (Table 17.2). In single
cases, single patients have even survived longer than 5 years
(30). Though, despite some encouraging results, the decision
for the resection of pancreatic cancer liver metastases should
be made on an individual basis where the patient is aware of a
nonstandard treatment approach. Currently, resection of liver
metastases is highly controversial and certainly far from being
accepted by the medical community.
gastric cancer
Table 17.2 Selected Retrospective Studies Reporting About
Clinical Outcome in Patients after Resection of Liver
Metastases from Pancreatic Cancer
Author
Year
Number
of patients
included
Median
overall
survival
5-year
survival
17
10
40
5.9
11.4
20
Not published
Not published
25%
167
sarcoma
Author
Year
2007
2006
2001
Number
Median
of patients overall
included survival
42
64
40
34
15
12
5-year
survival
Not published
27%
18%
168
Year
2006
2006
2001
Histological type
Number of patients
included
Median overall
survival (months)
33
125
54
12
34
22
Not reached
32
Not reached
37
70%
31%
Ca. 50%
No survivor after 5 years
39*
30%*
GIST
Non-GIST sarcoma
GIST and leiomyosarcoma
Non-GIST sarcoma
GIST
Non-GIST sarcoma
5-year survival
melanoma
Melanomas belong to the most frequent types of tumors with
an increasing incidence over the last 30 years. Of the melanomas, 90% derive from the skin, 5% have an ocular origin, and
5% develop at other sites (58). Noteworthy, depending on the
primary site, melanomas display a different metastasizing pattern. Cutaneous melanomas disseminate to the liver only in
15% to 20% of patients with metastatic disease (Fig. 17.5).
This often happens with simultaneous metastatic decay of
other organs (59). By contrast, in 40% of patients with liver
metastases from uveal melanoma, the liver is the only site of
the disease (60). Therefore, the number of liver metastases
resected from uveal melanoma is nearly equivalent to that of
cutaneous melanoma.
While excision of early stage melanoma results in an excellent prognosis, chemotherapy achieves barely a median overall
survival of 12 months in disseminated tumor stage (60,61).
Hence, surgical resection of metastases offers the only chance
for cure. However, patients amenable to a surgical intervention
at the liver account for approximately only 2% to 3% of all
patients representing with liver metastases of melanoma
(62,63). In these cases, the median overall survival is estimated
to be between 19 and 28 months and the median 5-year survival reaches 20% (4,49,62) (Table 17.5). This may justify the
169
Year
Site of melanoma
Number of
patients included
Median overall
survival (months)
5-year survival
2006
2001
Cutaneous
Ocular
Cutaneous
24
16
5
24
29
22*
No survivor
20%
70%
Gender
Age (years)
Male Female
50
>50
Synchronous (1)
Metachronous
24 mo
Presentation
Disease-free
interval
>24 mo
Adrenocortical
Breast
Gastrointestinal
Reproductive tract
Melanoma
Renal
Other
Unknown
Primary minor
Primary tumor
Reproductive tract
Nonreproductive
tract
Yes
No
Yes
No
5 cm
>5 cm
I
>l
Unilobar
Bi lobar
RO
Rl
R2
Minor major*
Prior metastases*
Extrahepatic
disease
Size
Number
Distribution
Margin status
Resection type
Blood transfusion
Postoperative
complies (1)
Lions
Yes
No
Yes
No
Multivariate
Median CSS
Hazard Ratio
No.
(mo)
p-Value
48 93
55 86
52 40
42
41
37 48
NS
NS
34
0.04
39
102
71
70
15
29
12
52
40
48
21
39
17
II
13
5
39
102
115
17
48
32
11
115 36
24
117
41 100
48
40
42
46
42
37
49
34
46
40
49
17
10
40
52
52
37
40
49
88
53
88
53
100
41
116
19
6
65
76
79
62
46
95
170
Univariate
(95% CI)
p-Value
1.4(1.01.8)
0.03
NS
0.0!
Reference
0.7(0.41.3)
1.0(0.61.7)
0.8 (0.31.5)
0.02
0.4 (0.20.7)
1.5(0.72.7)
0.7 (0.31.3)
1.7(0.31.3)
Reference
0.02
NS
NS
NS
NS
NS
<0.0I
NS
NS
NS
Reference
2.1 (1.14.1)
2.7 (0.87.9)
<0.01
summary
Resection of noncolorectal, nonneuroendocrine liver metastases is associated with an improved progression-free and
overall survival in a selected subgroup of patients. However,
until now, these data have been mainly obtained by retrospective studies and probably are affected by selection bias, as
patients with lower performance status and poorer prognosis
are less likely to have undergone surgery. Due to these limitations, a conclusion regarding a direct comparison to nonsurgical approaches cannot be drawn. Each individual case
needs to be carefully assessed prior to a decision regarding a
surgical approach. Furthermore, to reduce the risks of postoperative morbidity and mortality, it is recommendable to
perform the surgical intervention on the liver at high-volume
centers (64).
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18
Chemotherapy-associated hepatotoxicity
Martin Palavecino, Daria Zorzi, and Jean-Nicolas Vauthey
introduction
Hepatic resection is the only therapy that offers a chance for
cure in patients with colorectal liver metastases, but only 20%
of the patients are candidates for resection at the time of diagnosis (13). For those patients who are resected, the 5-year
survival has been reported up to 58% (48). After hepatic
resection, the majority of patients will develop recurrence
within the liver with or without extrahepatic metastases. Systemic chemotherapy has been used preoperatively (9) or as an
adjuvant therapy after surgery to decrease the risk of disease
recurrence (10). During the last decade, an increasing number
of new therapeutic agents has been developed to improve the
response rates of the existing drugs (Fig. 18.1). Initially,
5-fluorouracil (5-FU)-based chemotherapy had a 20% response
rate with a modest improvement in survival (11). Capecitabine
was introduced as an oral alternative to intravenous 5-FU.
The addition of oxaliplatin and irinotecan in combination with
5-FU increased the response rate to 50% and the conversion of
unresectable metastases to resectable was subsequently reported in up to 38% of patients (12,13). Most recently, bevacizumab and cetuximab, antibodies vascular endothelial growth
factor and an antiepidermal growth factor receptor, respectively, have been associated with response rates of up to 70%,
when combined with standard chemotherapy (14).
The rationale for preoperative chemotherapy includes
(i) the downsizing of metastases, thus decreasing the amount
of resected parenchyma and increasing the rate of curative
resection; (ii) the identification of patients who will not benefit from surgical resection due to disease progression during
chemotherapy; (iii) the early treatment of micrometastases
(810). Nordlinger et al. (15) reported the results of a multicentric randomized controlled trial (EORTC Intergroup trial
40983), evaluating the outcome of patients with resectable
colorectal liver metastases (no more than four metastases, no
extrahepatic disease) with two arms: surgery alone versus six
cycles of FOLFOX4 before and after surgery. The trial showed
an increased progression-free survival at 3 years of 8.1%
(from 28.1% to 36.2%, p = 0.041) in all eligible patients; and
9.2% (from 33.2% to 42.4%, p = 0.025) in all patients undergoing resection (15).
Clinical and pathological studies have established associations between specific chemotherapeutic agents and histologic
changes in the liver. Current evidence suggests there are two
broad categories of chemotherapy-induced liver injury: nonalcoholic fatty liver disease (NAFLD), including steatosis and
steatohepatitis, and sinusoidal obstruction syndrome (9)
(Figs. 18.2 and 18.3). The use of sequential or combined treatments may result in mixed patterns of injuries. The objective
of the present chapter is to summarize the changes induced in
the liver parenchyma by chemotherapy and its effects on
surgical outcomes.
chemotherapy-associated nonalcoholic
fatty liver disease
Nonalcoholic fatty liver disease (NAFLD) encompasses different types of pathological changes in the liver, ranging
from steatosis to steatohepatitis. NAFLD affects up to 24% of
the general population and increases to 75% in patients with
a body mass index equal or greater to 30 kg/m2 (16). Usually,
NAFLD is asymptomatic, but it may progress to cirrhosis
and develop hepatocellular carcinoma in later stages of
disease (17,18).
The diagnosis of NAFLD can be suspected by laboratory
routine tests and imaging findings. However, the gold standard diagnostic method is the histological assessment of the
liver. Steatosis is defined as the fat accumulation in the hepatocytes. It can be graded according to the percentage of
affected cells (mild when less than 30% of the hepatocytes are
involved, moderate with involvement of 30% to 60% of the
hepatocytes, and severe with >60% hepatocytes involved).
Steatohepatitis is defined as steatosis associated with inflammation (neutrophilic portal and lobular infiltration, perisinusoidal fibrosis, hepatocellular ballooning, glycogenated nuclei)
(8). Kleiner et al. proposed a score based on three features (steatosis, lobular inflammation, and ballooning) evaluated semiquantitatively. A Kleiner score of 5 or greater correlates with a
diagnosis of steatohepatitis, while a score of 3 or 4 is considered borderline (19).
Steatosis
Different chemotherapeutic regimens, such as intraarterial
floxuridine (20), 5-FU and folinic acid (21), interferon and
5-FU (22), 5-FU, and levamisole (23) were reported to induce
steatosis. However, none of these early studies reported the
effects of steatosis on surgical outcomes (8). In 1998, Behrns
et al. (24) evaluated outcomes after major hepatectomy in
patients with steatosis. The authors found that patients with
moderate to severe steatosis (>30%) had a higher BMI, longer
operative times, and higher rates of postoperative morbidity,
mortality, and intraoperative blood transfusion. Similarly,
Kooby et al. (25) analyzed a cohort of patients with steatosis
who underwent liver resection. Steatosis was associated with
infectious complications but not with major complications or
postoperative mortality.
Two studies were carried out at The University of Texas M.D.
Anderson Cancer Center. The first showed an increased rate of
steatosis in patients treated with irinotecan, but Parikh et al.
found no increased mortality in patient with steatosis, even
when severe (26). In the second study, Vauthey et al. (9) studied
406 resected patients using the Kleiners score (19), and no
agent was found to be associated with steatosis and there
was no increased postoperative morbidity or mortality rate
(Table 18.1). However, many patients with steatosis have other
173
1980
1985
1990
1995
2000
2005
5-FU
RR% Median
survival
(months)
Capecitabine
2025
13
Irinotecan
Oxaliplatin
~55
2022
~70
>24?
Cetuximab
Bevacizumab
Figure 18.1 During the last 10 years, several new drugs were incorporated to
the armamentarium for the treatment of colorectal liver metastases. 5-FU,
5-fluorouracil; RR, response rate. Source: Modified from Ref. (33).
(A)
(B)
(C)
(D)
Figure 18.2 Nonalcoholic fatty liver disease (NAFLD). (A) Macroscopic view of a fatty liver (yellow liver). (B) Pathology specimen showing the aspect of a fatty
liver. (C) Microscopic view of a simple steatosis: accumulation of large globules of fat in the cells. (D) Microscopic view of steatohepatitis: different degrees of
inflammation in the field (ballooned and apoptotic cells). Source: Modified from Ref. (8).
174
CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY
(A)
(B)
(C)
Figure 18.3 Sinusoidal obstruction syndrome. (A) Macroscopic view of a liver with oxaliplatin-related sinusoidal injury (blue liver). (B) Pathology specimen
showing the aspect of a liver with sinusoidal injury. (C) Microscopic view of sinusoidal injury: centrilobular sinusoidal dilatation with scattered macrovesicular
steatosis. Source: Modified from Ref. (8).
Table 18.1 Published Data on Chemotherapy-Associated Hepatotoxicity and Its Effect on Postoperative Outcomes
Author, year
Behrns, 1998 (24)
Kooby, 2003 (25)
Parikh, 2003 (26)
Fernandez, 2005(28)
Karoui, 2006(39)
Vauthey, 2006 (9)
Nordlinger, 2008(15)
Nakano, 2008(40)
Reddy, 2008 (44)
Number of
patients
135
325 chemo, 160
controls
61 chemo, 47
controls
37
45 chemo, 22
controls
248 chemo, 158
controls
151 chemo, 152
controls
36 chemo
39 chemo, 57
controls
Major
hepatectomy
100%
69% chemo,
63% controls
100%
49%
100%
68%
N/A
100%
69%
Drugs
Morbidity
Mortality
5-FU irinotecan
Steatosis
Steatosis
NS
Higher
NS
NS
5-FU irinotecan
Steatosis
NS
NS
5-FU irinotecan/
oxaliplatin
5-FU irinotecan/
oxaliplatin
5-FU irinotecan
5-FU oxaliplatin
5-FU oxaliplatin
Steatohepatitis
N/A
N/A
Sinusoidal injury
Higher
NS
Steatohepatitis
Sinusoidal injury
N/A
NS
NS
Higher
NS+
NS
NS
Sinusoidal injury
N/A
Higher
NS
N/A
NS
5-FU oxaliplatin
Bevacizumab +
oxaliplatin
175
176
Resectable
Preoperative
therapy
23 months
Unresectable
Resectable
First-line
chemotherapy
re-evaluate 23 months
Hepatectomy
(one-stage or
two-stage)
PVE*
Second-line
chemotherapy
Postoperative
therapy
34 months
Third-line
chemotherapy
diagnosis
Liver function tests cannot be used to assess chemotherapyassociated liver injury, since many patients have normal laboratory values despite significant hepatic injury. A heightened
index of suspicion for chemotherapy-associated hepatic injury
is necessary in patients at risk for NAFLD due to obesity, diabetes, or hyperlipidemia, as well as patients who have received
prolonged courses of chemotherapy. Computed tomography
can identify patients with fatty infiltration by determining
the density of the liver compared to the spleen (at least 10
Hounsfield units lower than the spleen). Magnetic resonance
CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY
imaging (MRI) accurately predicts steatosis on the basis of
signal differences between fat and water. However, modern
imaging methods cannot differentiate between steatosis and
steatohepatitis. For these reasons, liver biopsy is the gold standard diagnostic procedure to confirm liver injury. Percutaneous liver biopsy may be associated with false-negative results,
due to the patchy distribution of the injuries. To overcome this
issue, laparoscopy with direct inspection and core biopsy may
be an alternative to image-guided percutaneous biopsy in
patients suspected of chemotherapy-associated liver injury,
especially in those patients who are candidates for major
hepatic resection. Grossly, sinusoidal injury results in the
so-called blue liver syndrome, characterized by a bluish, edematous, spongiform appearance and consistency (Fig. 18.3),
while steatosis results in a yellow liver (Fig. 18.2).
prevention
Several issues should be taken into account to prevent
chemotherapy-associated liver injuries. First of all, prolonged
unnecessary courses of preoperative chemotherapy should be
avoided. Different studies demonstrated that hepatotoxicity is
strongly related to chemotherapy duration. Karoui et al. (39)
analyzed two groups of patients who underwent liver resection
with or without chemotherapy (5-FU irinotecan/oxaliplatin).
In the chemotherapy group, five patients developed liver insufficiency versus none in the control group. Morbidity was
higher in patients who received at least six cycles of chemotherapy compared to those who received five cycles or less
(54% vs. 19%, p = 0.047). In another study, Aloia et al. (30)
concluded that patients who received more than 12 cycles of
oxaliplatin-based chemotherapy had a higher rate of reoperations and a longer length of stay compared to patients who
received 12 or fewer cycles. The optimal duration of preoperative chemotherapy to maximize therapeutic benefit, while avoiding hepatotoxicity, is likely up to 4 months (i.e., 8 cycles). In the
study from MDACC, patients received relatively short-course
oxaliplatin for 3 to 4 months, which was not associated with
increased morbidity or mortality after hepatic resection (9).
Another issue to be considered is the duration of the interval
between chemotherapy and liver resection. Several studies show
that a longer interval between chemotherapy and hepatic resection for CLM reduces hepatotoxicity and surgical complications.
However, this interval should be balanced with the risk of tumor
progression during the treatment-free interval. In the European
trial, Nordlinger et al. (15) reported an interval between the last
dose of chemotherapy and liver resection (in the chemotherapy
arm) of 2 to 5 weeks. Nakano et al. (40) observed a mean interval
between the last chemotherapy and surgery of 6.5 months in
patients without sinusoidal injury compared to 3.6 months in
patients with sinusoidal injury. Welsh et al. (41) observed a morbidity rate of 2.6%, 5.5%, and 11% when the intervals between
the last chemotherapy and surgery was 9 to 12 weeks, 5 to 8 weeks,
and 5 weeks, respectively (p = 0.009).
In patients with suspected chemotherapy-associated
liver injury, the functional future liver remnant should be
assessed prior to major liver resection to minimize postoperative complications. The future liver remnant (FLR) can be
assessed using three-dimensional contrast-enhanced computed
summary
During the last decade, several new chemotherapeutics agents
were introduced in the armamentarium for the treatment of
colorectal liver metastases. These new drugs were used as adjuvant treatment as well as preoperative treatment before liver
resection. The rationale for preoperative chemotherapy is as
follows:
177
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179
19
introduction
Colorectal cancer is a common malignancy and as many as
25% of patients will have liver metastasis (CRLM) at presentation and a further 20% to 30% will develop metachronous
disease following colorectal surgery (1). The vast majority of
disease-related deaths are due to metastatic disease. In metastatic disease the median length of survival without treatment
is approximately between 5 and 12 months (2).
Currently hepatic resection is established as the treatment
modality of choice for colorectal liver metastases (CRLM)
with 5-year survival rates of up to 60% being reported by some
groups (36). Unfortunately at the time of presentation only
20% to 30% are deemed suitable to resection because of tumor
location, number of metastases, other comorbidities, and lack
of hepatic reserve (7). Consequently, in recent times there has
been considerable interest in the use of oxaliplatin-based neoadjuvant therapy to reduce tumor burden, so increasing the
probability of achieving a curative resection and hence
improve overall disease-free survival. Even patients who initially had unresectable hepatic disease may respond to chemotherapy and become resectable (8). However, despite a more
aggressive approach to surgical resection and the use of combination regimens of highly active chemotherapy drugs, a
significant proportion of patients are still not eligible for resection. Additionally, the high rate of recurrence seen in the liver,
affecting 53% to 68% of patients requiring repeat resections
can only be tolerated by a subset of patients (9).
Hence, recently there has been considerable interest in
thermoablative techniques and their potential role in the management of CRLM. Ablative technologies involve the delivery
of localized treatment via open, laparoscopic, or percutaneous
route. Theoretical advantages include less physiological stress,
making treatments suitable for patients who may not otherwise be appropriate for formal resection. The potential for
either percutaneous or laparoscopic approach offers an alternative for patients unfit or unwilling to undergo major
abdominal surgery and general anaesthesia (913). Formal
resection is guided by vasculobiliary anatomy, with significant
amounts of healthy parenchyma being removed along with
disease. Targeted ablations minimize the removal of healthy
parenchyma, making it useful in patients with borderline
parenchymal volume and function. Anatomically difficult
lesions may not be amenable to formal resection, but accessible by probe ablation. Ablation can also be performed as an
adjunct to surgical resection in patients with bilobar disease,
where patients have the majority of their tumor burden formally resected with remnant disease burden being ablated.
However, there remains a need for more long-term survival
data regarding ablative therapies. There have been no randomized control trials comparing any ablative therapy to resections
in patients who would be candidates for either therapy or
180
cryotherapy
Cryoablation of hepatic metastases using insulated probes containing liquid nitrogen/argon have been used for the destruction
of CLRM (15). They are placed into each metastasis, whereupon
edge cryotherapy
Edge cryotherapy employs the application of cryotherapy to
the resection margins posthepatectomy in order to extend the
margins of resectability.
Several studies describe the use of cryotherapy when a histopathologically positive margin is expected. During this procedure, flat cryoprobes are placed against the resection edge of the
remnant liver, whereupon remnant liver tissue is frozen to a
depth of at least 1 cm (34). Reported 3- and 5-year survival for
these patients was 43% to 60% and 26% to 44%, respectively,
radiofrequency ablation
Radiofrequency ablation (RFA) uses radiofrequency radiation
to produce heat locally within the hepatic parenchyma. The
radiofrequency current generates ionic agitation, which in
turn is translated into heat, resulting in the subsequent breakdown of proteins and cell membranes (43). The main advantage when compared to cryotherapy is that the probes can be
placed percutaneously. However, as with all locally ablative
techniques, the efficacy of the treatment diminishes with
increasing size of the lesion. Hence, manufacturers have
designed a variety of electrodes that can be deployed in situ to
produce a number of tips.
RFA refers to coagulation from all electromagnetic resources
with a frequency less than 900 kHz, with the majority functioning within the parameters of 300 to 500 kHz. Initially, problems
existed with early radiofrequency designs due to the effects of
high temperatures in the tissue surrounding the probe. This is
due to tissue impedance secondary to tissue charring. Subsequently, this impedance results in reduced dissipation of current (44,45). This problem has been the major drawback of
RFA, though it has been countered somewhat by the use of
cooled electrode tips. However, the principle limiting factor of
RF ablation remains the size of the achievable ablated tissue.
This is because only the tissue immediately adjacent to the tip is
heated by ionic agitation. The remainder of the tissue is ablated
via heat produced via thermal conduction. This effect is magnified in the presence of large blood vessels, which further reduce
heat via a phenomenon known as the heat sink effect (19).
Both normal liver parenchyma and metastatic liver are
water-rich and also have an extensive blood supply (via angiogenesis in the case of metastases). Hence, thermal conduction
is facilitated, but as mentioned previously, this is a less efficient
means of ablation than ionic agitation. Therefore, current
opinion suggests that RFA is more susceptible to the heat sink
effect than microwave ablation. Various measures have been
used previously to reduce the heat sink effect, such as occlusion of the portal vein and hepatic artery at the time of ablation. Although the ablative area is increased, the risk of bile
duct damage and portal vein thrombosis is increased.
Because of the relative simplicity of the technique, the fact
that it can be performed percutaneously and the comparatively cheap devices employed, RFA is a technique that remains
widely practised (32).
181
182
N
44
116
55
172
56
86
30
61
20
49
15
1
3.9
4.2
4
3
3.38
1.7
5.1
1.4
5
4.4
3.6
2
4
2
Size (cm)
9.5
18
16
0
16
0
0
EHD
82
89
85
76
87
1 year
Year
1997
1998
1998
2000
2001
2002
2005
2006
Author
Korpan (35)
Dwerryhouse (37)
Seifert (38)
Finlay (39)
Gruenberger (40)
Rivoire (36)
Seifert (41)
Niu (42)
63
26
44
75
86
24
55
124
1
1
2
2
2.9
2.4
4.1
Metastases
(n)
3.1
5
5
5
4.5
3.5
5
Size (cm)
0
0
0
18
15
Extrahepatic
disease %
92
84
1 year
survival
%
Table 19.2 Summary of Studies Looking at Edge Cryotherapy (Survival and Complications)
Year
1998
1998
2003
2003
2004
2005
2005
2006
2007
2007
2007
Author
Seifert (20)
Seifert (21)
Seifert (22)
Yan (23)
Kerkar (24)
Brooks (25)
Joosten (26)
Chen (27)
Kornprat (28)
Paganini (open) (29)
Paganini (29) (lap)
Metastases
(n)
50.5
61
2 years
survival
%
56
65
67
61
54
2 years
60
54.7
58
43
3 years
survival
%
32.3
44
41
43
43
36
30.9
3 years
4 years
37
28
4 years
survival
%
24
44
26
24
5 years
survival
%
13
26
19
22
19
5 years
29
33
33
39
29
29
Median
survival
(months)
33
26
29
28
30
33
26
22.9
94.2
Median
survival
(months)
25
0.27
0.22
0.34
21
Major
22%
31%
28%
30%
30%
26%
70%
Major
34%
Minor
20%
55%
53%
Minor
microwave ablation
Microwave coagulation (MCT) was initially developed in the
early 1980s by Tabuse et al. in order to optimize haemostasis along
the plane of dissection during hepatic resection. The microwave
183
Ultrasound
probe
Ultrasound
beam
Iceball
surrounding
and encompassing
tumor
Probe
within
liver
Ultrasound
Cryoprobe
(A)
(B)
184
20
10
Chemo
(years)
0
0
O
53
N
59
Treatment
CT
44
60
34
RF+\-resection+CT
20
13
Figure 19.3 Three year PFS in the CLOCC study comparing RFA + chemotherapy (27.6%) to chemotherapy alone (10.7%) (p = 0.025).
Overall survival
100
90
80
70
60
50
40
RF + Chemo
30
20
Overall logrank test: p = 0.218
10
Chemo
(years)
0
0
O
39
N
59
31
60
15
Treatment
CT
53
19
RF+\-resection+CT
44
27
Figure 19.4 Thirty month OS comparing RFA+chemotherapy (63.8%) to chemotherapy alone (58.6%) (p = 0.218).
185
186
Year
2000
2000
2008
2009
2007
2008
2009
2006
2008
2006
2003
2007
2009
2006
2008
2007
2005
2005
2002
2001
2007
2007
2002
Author
De Baere (56)
Elias (57)
Park (58)
Knudsen (59)
Sorensen (60)
Lee (61)
Hur (62)
Lermite (51)
Veltri (63)
Aloia (64)
Oshowo (65)
Suppiah (66)
Reuter (67)
Hildebrand (68)
Berber (69)
Siperstein (70)
Gilliams (53)
Berber (71)
Iannitti (72)
Solbiati (73)
Terraz (74)
Abitabile (52)
Stippel (75)
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
Ablative
type
54
14
30
36
102
37
25
14
122
30
25
30
66
56
68
235
73
135
52
109
16
47
23
Number
1.8
6.2
1.2
3.25
2
1.63
1.9
2.8
3.5
1
2.8
4.1
3.2
2.7
1.6
1.75
3.12
5.57
Metastases
(n)
1.3
1.4
2
2.1
2.2
2.25
2.5
2.7
2.9
3
3
3.1
3.2
3.5
3.7
3.9
3.9
4.1
5.2
Size (cm)
No
No
No
No
20.5
28
15
38
23
No
30
8.7
EHD
81
87
90
79
75
92
91
87
84
88
1 year
95
62
54
45
67
77
67
68
80
2 years
26
46
60
54
38
57
52.6
7
42
20.6
20.2
28
50
33
57
3 years
26
4 years
34
46.5
25.5
22
27
21
30
18.4
25
5 years
36
39
32
40
31.5
37
23.2
27
28
20.5
24 overall
38
28.9
30
39
18
Median
survival
(months)
33.3
11
6.9
0
11.5
1.1
10
3.4
7.1
0.9
2.9
13
7
Major
5
49.1
2.9
6.4
2.9
Minor
2003
2003
2004
2005
2005
2006
2007
2008
2009
Pawlik (76)
Scaife (77)
Abdalla (3)
Elias (78)
Joosten (26)
Amersi (49)
Kornprat (28)
Gleisner (79)
Nikfarjam (80)
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
Ablative type
124
50
158
63
28
74
19
66
23
Number
3
2
2.4
3
3.3
5
2
1.8
2
15
2
3.56
2
2.5
size (cm)
Author
Seki (85)
Shibata (86)
Liang (11)
Yokoyama (87)
Tanaka (88)
Iannitti (89)
Kuang (90)
Ogata (91)
Zhang (92)
Bhardwaj (93)
Year
1999
2000
2003
2003
2005
2007
2007
2008
2008
2009
Ablative
type
MCT
MCT
MCT
MCT/RFA
MCT
MCT
MCT
MCT/RFA
MCT
MCT
N
15
14
28
12
16
33
11
32
34
24
Metastases
(n)
1
4.1
2
2.8
2.2
2.57
1.47
4
2.87
Size (cm)
2.1
2.7
3.12
2.4
4.8
3.6
2.75
2.8
No
No
No
No
No
EHD
EHD (%)
0
0
5
0
22
Year
Author
Metastases
(n)
92
93
92
1 year
1 year
71
91.4
80
82.1
40
Table 19.4 Summary of Studies looking at RFA Resection (Survival and Complications)
2 years
59.5
66
67
75
2 years
3 years
57
46.4
51
43/37
47
51.2
3 years
4 years
29
36/22
4 years
5 years
14
17
32
28
68
5 years
Median
survival
(months)
24.2
27
20.5
28
43
29
37.3
36
29.7
38.1
Median
survival
(months)
Major
(%)
14.0
0.0
19.0
16.1
4.0
3.4
0.0
2.6
20
22
27
11
13
11
Major
7.8
76.3
0
80.1
Minor
(%)
6.7
Minor
187
Year
Number
Metastases (n)
Size (cm)
EHD
Kessler (95)
2002
13 (inc HCC)
Unknown
Unknown
Unknown
Giorgio (96)
2003
47
Unknown
Unknown
Unknown
Recurrence
rates
Median
survival
Major
50% (inc
HCC)
Unknown
Unknown
8%
25%
Unknown
3%
17.7%
Minor
Recurrence (Range %)
Local
Overall
1 year
2 years
3 years
4 years
5 years
Major
complication
rates (%)
Cryotherapy
Ethanol
MCT
RFA
1239
513
1031
7888
5078
4786
84
73
85
59
60
67
37
30
36
21
29
30
17
16
24
29
5
7
6
Median
RFA + resection
Edge cryotherapy
5 Year
4 Year
3 Year
2 Year
1 Year
0
10
20
30
40
50
60
70
80
90
100
Figure 19.5 Survival figures for studies reviewed (ablation as adjunct to surgery).
conclusions
The ideal ablative therapy should cause complete tumor ablation, yet be parenchyma sparing, reproducible, safe, and be
minimally invasive. Current advancements, particularly in
RFA and MCT, are promising but the perfect ablative model is
still elusive.
The literature cannot support the use of percutaneous ethanol injection for the treatment of colorectal metastases, though
we accept that it has a role in the management of hepatocellular carcinoma. Similarly, the literature demonstrates that
although cryoablation has acceptable survival figures, its
ongoing use cannot be advocated given the high rate of local
complications (Table 19.7).
Ablative therapies offer great potential for lesions that cannot be formally resected. The increasing burden of metastatic
colorectal disease means that a growing number of patients
will have unresectable metastases and hence will be candidates
for ablation.
It is important that the ablation causes complete tumor
destruction within the treatment zone. Heat sink effect may
188
Median
Microwave ablation
Cryotherapy
5 Year
4 Year
3 Year
2 Year
1 Year
0
10
20
30
40
50
60
70
80
90
Survival (%)
Figure 19.6 Survival figures for ablative studies reviewed.
Ethanol ablation
Radiofrequency ablation
Microwave ablation
Cryotherapy
RFA+resection
Edge cryotherapy
10
15
20
25
Complication rates(%)
30
35
40
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3. Abdalla EK, Vauthey JN, et al. Recurrence and outcomes following hepatic
resection, radiofrequency ablation, and combined resection/ablation for
colorectal liver metastases. Ann Surg. 2004; 239(6): 81825; discussion 257.
4. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after
resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose
(FDG-PET). Ann Surg 2004; 240(3): 43847; discussion 4750.
5. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival
following liver resection for hepatic colorectal metastases. Ann Surg 2002;
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6. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on
survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005; 241(5): 71522, discussion 224.
7. Adam R, Huguet E, Azoulay D, et al. Hepatic resection after down-staging
of unresectable hepatic colorectal metastases. Surg Oncol Clin N Am
2003; 12(1): 21120, xii.
8. Nordlinger B, Van Cutsem E, Rougier P, et al. Does chemotherapy prior to
liver resection increase the potential for cure in patients with metastatic
colorectal cancer? A report from the European Colorectal Metastases
Treatment Group. Eur J Cancer 2007; 43(14): 203745.
9. Goldberg SN, Solbiati L, Hahn PF, et al. Large-volume tissue ablation with
radio frequency by using a clustered, internally cooled electrode technique: laboratory and clinical experience in liver metastases. Radiology
1998; 209(2): 3719.
10. Jiao LR, Habib NA. Experimental study of large-volume microwave ablation in the liver (Br J Surg 2002; 89: 10037). Br J Surg 2003; 90(1): 122.
189
190
38. Seifert JK, Morris DL. Cryotherapy of the resection edge after liver resection for colorectal cancer metastases. Aust N Z J Surg 1998; 68(10): 7258.
39. Finlay IG, Seifert JK, Stewart GJ, Morris DL. Resection with cryotherapy
of colorectal hepatic metastases has the same survival as hepatic resection
alone. Eur J Surg Oncol 2000; 26(3): 199202.
40. Gruenberger T, Jourdan JL, Zhao J, King J, Morris DL. Reduction in recurrence risk for involved or inadequate margins with edge cryotherapy after
liver resection for colorectal metastases. Arch Surg. 2001; 136(10): 11547.
41. Seifert JK, Junginger T. Prognostic factors for cryotherapy of colorectal
liver metastases. Eur J Surg Oncol 2004; 30(1): 3440.
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outcomes after hepatic resection with or without cryotherapy for liver metastases from colorectal carcinoma. Ann Surg Oncol 2007; 14(7): 207887.
43. Ruers T, Bleichrodt RP. Treatment of liver metastases, an update on the
possibilities and results. Eur J Cancer 2002; 38(7): 102333.
44. Livraghi T, Goldberg SN, Monti F, et al. Saline-enhanced radio-frequency
tissue ablation in the treatment of liver metastases. Radiology 1997;
202(1): 20510.
45. Wright AS, Sampson LA, Warner TF, Mahvi DM, Lee FT, Jr. Radiofrequency versus microwave ablation in a hepatic porcine model. Radiology
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46. Wong SL, Mangu PB, Choti MA, et al. American Society of Clinical Oncology 2009 clinical evidence review on radiofrequency ablation of hepatic
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47. Pawlik TM, Choti MA. Surgical therapy for colorectal metastases to the
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48. Berber E, Siperstein A. Local recurrence after laparoscopic radiofrequency
ablation of liver tumors: an analysis of 1032 tumors. Ann Surg Oncol
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49. Amersi FF, McElrath-Garza A, Ahmad A, et al. Long-term survival after
radiofrequency ablation of complex unresectable liver tumors. Arch Surg
2006; 141(6): 5817; discussion 78.
50. Jiang HC, Liu LX, Piao DX, et al. Clinical short-term results of radiofrequency ablation in liver cancers. World J Gastroenterol 2002; 8(4): 62430.
51. Lermite E, Lebigot J, Oberti F, et al. Radiofrequency thermal ablation of
liver carcinoma. Prospective study of 82 lesions. Gastroenterol Clin Biol
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Oncol 2007; 33(1): 6771.
53. Gillams AR, Lees WR. Radio-frequency ablation of colorectal liver metastases in 167 patients. Eur Radiol 2004; 14(12): 22617.
54. Kim SK, Lim HK, Ryu JA, et al. Radiofrequency ablation of rabbit liver
in vivo: effect of the pringle maneuver on pathologic changes in liver surrounding the ablation zone. Korean J Radiol 2004; 5(4): 2409.
55. Lu DS, Raman SS, Limanond P, et al. Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors. J Vasc Interv
Radiol 2003; 14(10): 126774.
56. de Baere T, Elias D, Dromain C, et al. Radiofrequency ablation of
100 hepatic metastases with a mean follow-up of more than 1 year. AJR
Am J Roentgenol 2000; 175(6): 161925.
57. Elias D, Goharin A, El Otmany A, et al. Usefulness of intraoperative radiofrequency thermoablation of liver tumours associated or not with hepatectomy. Eur J Surg Oncol 2000 Dec; 26(8): 7639.
58. Park IJ, Kim HC, Yu CS, et al. Radiofrequency ablation for metachronous
liver metastasis from colorectal cancer after curative surgery. Ann Surg
Oncol 2008; 15(1): 22732.
59. Knudsen AR, Kannerup AS, Mortensen FV, Nielsen DT. Radiofrequency
ablation of colorectal liver metastases downstaged by chemotherapy. Acta
Radiol 2009; 50(7): 71621.
60. Sorensen SM, Mortensen FV, Nielsen DT. Radiofrequency ablation of
colorectal liver metastases: long-term survival. Acta Radiol 2007; 48(3):
2538.
61. Lee WS, Yun SH, Chun HK, et al. Clinical outcomes of hepatic resection
and radiofrequency ablation in patients with solitary colorectal liver
metastasis. J Clin Gastroenterol 2008; 42(8): 9459.
62. Hur H, Ko YT, Min BS, et al. Comparative study of resection and radiofrequency ablation in the treatment of solitary colorectal liver metastases.
Am J Surg 2009; 197(6): 72836.
191
introduction
staging systems
diagnosis
Asymptomatic HCC is diagnosed either as an incidental
finding or on routine surveillance of at-risk population.
Ultrasound scan (with or without contrast enhancement)
with measurement of serum alfa-feto protein (AFP) is routinely used for screening (5,6). Once a suspicion of a focal
lesion is raised, further assessment with contrast-enhanced
computerized tomography (CECT) and/or magnetic resonance imaging (MRI) with contrast enhancement is needed
to confirm the diagnosis of HCC. Tumor biopsy is rarely
needed and in fact should be avoided in potentially resectable lesion due to the risk of tumor seeding along the needle
track and intra-celomic spread. Furthermore, CECT is a
good modality to look for the presence of cirrhosis, ascites,
and metastases. A typical HCC shows hyper vascular
enhancement with characteristic feature of early uptake of
contrast and portal venous washout, an enhanced pseudocapsule, vascular invasion on CECT which gives more than
80% accuracy in diagnosing these lesions (7). MRI is more
sensitive in detecting lesions 1 to 2 cm in size. A quarter of
intra-hepatic lesions smaller than 10 mm is miss-diagnosed
on pre-operative investigations. Diagnosing any lesion 2 cm
with characteristics CECT/MRI findings is possible with a
high degree of accuracy. In lesions 1 to 2 cm without concordance with two radiological investigations, a raised AFP of
400 /L and one radiological modality with positive features, diagnosis is possible (8). In lesions <10 mm, expectant
follow-up with repeat imaging at 3 to 6 months is an appropriate management algorithm (Fig. 20.1).
192
treatment
A number of treatment options are available for patients with
HCC. These include
1. Liver resection (LR)
2. Orthotopic liver transplant (OLT) including deceased/
cadaveric donor liver transplant (DDLT/CLT) and living donor liver transplant (LDLT)
3. Treatment prior to OLT: bridging the gap
4. Less invasive procedure involving chemical or
thermal destruction of liver parenchyma
5. Regional or systemic chemotherapy
6. Radiotherapy including external beam irradiation
or embolization with radioactive particles
Before selecting a treatment option, careful consideration
should be given to preoperative staging, underlying condition
of the liver and the general fitness of the patient. Staging laparoscopy is a mandatory prior to LR or OLT to rule out extrahepatic disease. Assessing the residual liver function in chronic
liver disease is very important before LR, as any major resection in a cirrhotic patient may result in fatal liver failure in the
immediate post-operative period. Traditionally, the Child
A/B/C scoring system has been used to assess the residual liver
function. However, the Model for End-stage Liver Disease
(MELD) scoring is used as an alternative in United States.
Ascites on CECT, bilirubin of >2 mg/dL, and iodocyanine
green retention test (used extensively in the East) (8) at
15 minutes of <30% bodes ill for residual liver function. Clinically relevant portal hypertension with hepatic vein gradient
of >10 mm of mercury, esophageal varices, splenomegaly, and
a platelet count of <100 109/L are accurate predictors of
post-operative liver decompensation (12). Patients with Child
Child-Pugh A
Solitary < 3 cm
Deep
location
Solitary 35 cm
Peripheral
location
Child-Pugh BC
23 nodules
< 3 cm
Solitary < 5 cm
23 nodules < 3 cm
Deep
location
Portal hypertension
Varices, platelets < 100,000/mm3
Yes
No
RF
ablation
Laparoscopic
resection
Open
resection
Transplantable
Transplantation
Recurrence
Not transplantable
Figure 20.1 Algorithm for management of transplantable hepatocellular carcinoma used at Henri-Mondor Hospital. Source: From Ref. (29).
Liver Resection
Liver resection in early HCC can be used in three different
settings: (a) primary therapy, (b) to obtain material for
morphological assessment of the tumor and to select patients
who would benefit OLT, and (c) as a bridge therapy for those
who are enlisted for OLT.
193
HCC
Stage 0
Stage AC
Stage D
Okuda 3, PST > 2, Child-Pugh C
Terminal
stage (D)
3 nodules 3 cm
Single
Portal pressure/bilirubin
Associated diseases
Increased
Normal
Resection
No
Liver transplantation
(CLT/LDLT)
Yes
PEI/RF
Curative treatments
No
Chemoembolization
Yes
New
agents
Symptomatic
treatment
Figure 20.2 Barcelona Clinic Liver Cancer staging classification and treatment schedule. Stage 0: Patients who have very early HCC are optimal candidates for
resection. Stage A: Patients who have early HCC are candidates for radical therapies (resection and ablation, liver transplantation, or percutaneous treatments).
Stage B: Patients who have intermediate HCC may benefit from chemoembolization. Stage C: Patients who have advanced HCC may receive new agents in the
setting of a randomized, controlled trial. Stage D: Patients who have end stage disease receive symptomatic treatment. Abbreviations: LDLT, living-related donor
liver transplantation; PEI, percutaneous ethanol injection; RF, radiofrequency. Source: From Ref. (30).
194
Salvage OLT
In patients who have had LR, PEI, or RFA as the primary treatment survival figures at the end of 5 years is 70% (11,14), 53%
(23), and 60% (24), respectively. In those with recurrence, salvage surgery in the form of OLT can be offered. In the Far East,
with perpetual shortage of donor liver, LDLT is being used more
frequently for salvage OLT. The selection criteria for LDLT are
far more liberal than the stringent CMC used for DDLT.
Chemical or Thermal Ablation
In patients with small tumor located deeply within the liver
parenchyma, tumor ablation performed percutaneously or
trans-arterially is possible. RFA (24,25) is used routinely not
only as a primary therapy but also as a pre-transplant therapy
to reduce the dropout rate. The limiting factor is the tumor
size and presence of larger vessel close to the tumor with complications occurring in 8% to 23% including abscess formation, biliary injury, and a potential for tumor seeding along the
track. PEI (26) is a cheaper alternative with fewer side effects,
but the use is limited by tumor size given the fact that best
results are seen for tumors <2 cm. Both provide a good cumulative survival benefits.
references
1. Okuda K, Fujimoto I, Hanai A, et al. Changing incidence of hepatocellular
carcinoma in Japan. Cancer Res 1987; 47: 496772.
2. Ross, RK, Yuan JM, Yu MC, et al. Urinary aflatoxin biomarkers and risk of
hepatocellular carcinoma. Lancet 1992; 339: 9436
195
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Okuda K. Clinical presentation and natural history of hepatocellular carcinoma and other liver cancers. In: Okuda K, Tabor E, eds. Liver Cancer.
New York: Churchill Livingstone, 1997: 112.
Forner A, Hessheimer AJ, Real MI, et al. Treatment of hepatocellular carcinoma. Crit Rev Oncol Hematol 2006; 60(2): 8998.
Makuuchi M, Sano K. The surgical approach to HCC: our progress and
results in Japan. Liver Transpl 2004; 10(2 Suppl 1): S4652.
Spangenberg HC, Thimme R, Blum HE. Serum markers of hepatocellular
carcinoma. Semin Liver Dis 2006; 26(4): 38590.
Jacobs JE, Birnbaum BA. Computed tomography imaging for focal
hepatic lesions. Semin Roentgenol 1995; 30: 308323.
Cormier JN, Thomas KT, Chari RS, et al. Management of hepatocellular
carcinoma. J Gastrointest Surg 2006; 10(5): 76180.
Vauthey J, Lauwers G, Esnaola N, et al. Simplified staging for hepatocellular carcinoma. J Clin Oncol 2002; 20: 152736.
Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepato cellular
carcinoma and prognosis in relation to treatment: a study of 850 patients.
Cancer 1985; 56: 91828.
Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the
BCLC staging classification. Semin Liver Dis 1999; 19: 32938.
Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular
carcinoma in cirrhotic patients: prognostic value of preoperative portal
pressure. Gastroenterology 1996; 111(4): 101822.
Ringe B, Pichlmayr R, Wittekind C, Tusch G. Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation
in 198 patients. World J Surg 1991; 2: 27085.
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N
Engl J Med 1996; 334: 693699.
Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular
carcinoma: Expansion of the tumor size limits does not adversely impact
survival. Hepatology 2001; 33: 13941403.
Lopez PM, Villanueva A, Llovet JM. Systematic review: evidence-based management of hepatocellular carcinomaan updated analysis of randomized
controlled trials [review]. Aliment Pharmacol Ther 2006; 23(11): 153547.
Cherqui D, Laurent A, Tayar C, et al. Laparoscopic liver resection for
peripheral hepatocellular carcinoma in patients with chronic liver disease:
mid-term results and perspectives. Ann Surg 2006; 243(4): 499506.
196
21
introduction
Traditionally a great deal of pessimism has been associated
with the treatment of gallbladder cancer (1). There are many
reasons for the skepticism associated with this disease entity
since its first description in 1778 (2). Foremost is the aggressive nature of this cancer for dissemination. Gallbladder cancer spreads early by direct invasion into the liver, as well as
through lymphatics to regional nodes, by peritoneal dissemination to produce carcinomatosis, and by hematogenous
means to produce synchronous liver and other distant metastases. As a result, gallbladder cancer often presents at a time
when surgical excision is either no longer possible or is technically difficult while alternative therapies including chemotherapy and radiation are generally ineffective. Therefore, it is not
surprising that in 1924 Blalock recommended that surgery be
avoided for gallbladder cancer if the diagnosis could be made
preoperatively (3). In fact, until recently, the 5-year survival in
most large series was less than 5%, and the median survival
was less than 6 months (4,5). In the modern era, liver resection
has become increasingly safe. More recent experience has
demonstrated that radical surgery may be a sensible and
potentially curative option in the treatment of this disease (6,7).
The data have demonstrated that surgical excision is the treatment option of choice for those patients whose gallbladder
cancers are confined to the local region of the liver and porta
hepatis (810).
Beginning in late 1980s, when the techniques for laparoscopic cholecystectomy were introduced, a new presentation
for gallbladder cancer was conceived. With the advent and
popularization of laparoscopic cholecystectomy, increasing
number of cases of gallbladder cancer were being discovered
laparoscopically. Currently, approximately 750,000 cholecystectomies are performed in the United States annually for presumed calculous biliary disease (11). Since gallbladder cancer
is encountered in 1% of cholecystectomies for cholelithiasis (7), a significant number of patients will present with
this clinical scenario. Therefore, meticulous inspection of the
gallbladder should be mandatory (12). The current chapter
will review data addressing the utility of subsequent radical
resection for laparoscopically discovered gallbladder cancer.
We will begin with a brief general review of gallbladder cancer,
which focuses on the natural history and results of surgical
treatment. Summarized data on presentation and results of
treatment for laparoscopically discovered disease will be discussed, including the differences of discovery by an open
rather than laparoscopic operation.
epidemiology
Gallbladder cancer is the most common biliary tract malignancy and the fifth most common gastrointestinal malignancy
in the United States. In fact, there are approximately 5,000 new
197
pathology
At early stages, gallbladder carcinomas are difficult to grossly
differentiate from chronic cholecystitis. As a result, they are
often found incidentally upon pathologic section. Even at late
stages, when the tumor can obstruct the common bile duct
and produce jaundice, gallbladder cancer is often mistaken for
benign disease since associated gallstones and Mirizzis syndrome are common (23). Therefore, a long-term obstruction
of the mid-common bile duct should be considered a gallbladder cancer until proven otherwise. Tumors that arise in the
neck and within Hartmanns pouch may also infiltrate the
common hepatic duct, making them clinically and radiographically indistinguishable from hilar cholangiocarcinomas.
Approximately 60% of tumors originate in the fundus of the
gallbladder, 30% in the body, and 10% in the neck (24). These
tumors grow most commonly in a diffusely infiltrative
form (25), with a tendency to involve the entire gallbladder,
and spread in a subserosal plane, which is the same as the surgical plane used for routine cholecystectomy. If such a tumor
is unrecognized at the time of surgery, a simple cholecystectomy will not completely excise the disease and may lead to
dissemination of tumor. Although the nodular type of tumor
may show early invasion through the gallbladder wall into the
liver or adjacent structures, it may be easier to control surgically than the infiltrative type because the margins are better
defined. The papillary growth pattern has the best prognosis
because even large tumors have only minimal invasion of the
gallbladder wall (14).
The most common histologic cell type of gallbladder cancers is adenocarcinoma (26). Other rare subtypes of gallbladder cancer include papillary carcinoma, mucinous carcinoma,
clear cell carcinoma, signet ring carcinoma, squamous cell carcinoma, small cell (oat cell) carcinomas (27), adenosquamous
tumors (28), sarcomas, carcinosarcoma, carcinoid, lymphoma,
melanoma, and gastrointestinal stroma tumors (GIST) (29,30).
patterns of spread
Gallbladder carcinoma commonly disseminates by four modes:
1. Direct extension and invasion of the liver and adjacent organs
2. Lymphatic spread
3. Shedding and peritoneal dissemination, and
4. Hematogenous spread to distant sites.
The gallbladder lies on segments IVb and V of the liver and
these segments are involved early in tumors of the fundus and
body. Direct extension into the portal structures (i.e., portal
vein, hepatic artery, and bile duct) commonly occurs and is a
major cause of symptoms. Lymphatic spread is also common
and most often involves cystic and pericholedochal nodes.
198
Tumor may then pass to lymph nodes posterior to the pancreas, portal vein, and common hepatic artery. Advanced disease may ultimately reach the interaortocaval, celiac axis, and
superior mesenteric artery lymph nodes. Gallbladder cancer
also has a remarkable propensity to seed and grow within the
peritoneal cavity, which may account for its ability to grow
along the tracts of needle biopsy sites and laparoscopic port
sites. Growth in those sites may be further exacerbated by bile
spillage during laparoscopic cholecystectomy (31,32). In fact,
another group demonstrated that the incidence of port site/
peritoneal recurrence was higher in patients with gallbladder
perforation (3/7, 43%) than in those without (0/21, 0%;
p = 0.011) (33). The long-term survival was worse in the seven
patients with gallbladder perforation (cumulative 5-year survival of 43%) as opposed to those without perforation (cumulative 5-year survival of 100%; p < 0.001). Hematogenous
spread is less common but will present most often as noncontiguous liver metastases, and more rarely as lung or brain
metastases. At postmortem examination, Perpetuo et al. (4)
reported that 91% of patients had liver metastasis and 82%
had intra-abdominal lymph node involvement, 60% had peritoneal spread, 32% had lung metastases, and 5% had
brain metastases.
staging
The multitude of staging systems (Table 21.1) used for this
disease has made it difficult to compare treatment results.
Nevin et al. (34) originally classified patients into five stages
based primarily on the thickness of invasion, and combined
patients with direct liver extension or distant metastases into
stage V. Donahue et al. (35) modified the Nevin system to
include tumors with contiguous liver invasion as stage III and
noncontiguous liver involvement as stage V. Stage IV continued to include lymph node metastases. The Japanese Biliary
Surgical Society staging system separated tumors into four
stages according to the degree of lymph node metastasis, serosal invasion, peritoneal dissemination, hepatic invasion, and
bile duct infiltration. The main weakness of this staging system
is that lymph node metastases are considered in the same stage
as microinvasion of the liver.
Despite these various systems, the most common system for
evaluating gallbladder cancer worldwide has been the American Joint Committee on Cancer (AJCC) TNM staging system
for gallbladder cancer (26). Unfortunately, the 6th edition of
the AJCC staging system underwent radical changes due to a
desire to match the staging of other biliary cancers. The staging
system was therefore not consistent with data. A recent paper
documented the deficiencies of the 6th edition staging system
using 10,705 cases of this disease from the National Cancer
Database (36). Thus, the new 7th edition staging will revert to a
system much more in line with past staging (Table 21.1).
According to this system, tumors without perimuscular invasion are considered stage I. Tumors with invasion into the perimuscular connective tissue but without extension beyond the
serosa or into the liver are considered stage II. Tumors that perforate the serosa and/or directly invade the liver and/or adjacent structures, such as the stomach, duodenum, colon,
pancreas, omentum, or extrahepatic biliary tree are stage IIIA if
Mucosal (T1N0M0)
II
III
IV
Modified Nevin
Japanese
Proposed 7th
edition AJCC
In situ carcinoma
Confined to
gallbladder
capsule
Mucosal
(T1N0M0)
Mucosal or
muscular
invasion
N1 lymph nodes;
minimal liver
orbile duct
invasion
Muscular invasion
(T2N0M0)
Transmural direct
liver invasion
N2 lymph nodes;
marked liver or
bile duct invasion
Lymph node
metastasis
Distant metastases
Transmural
(T3N0M0), or
T-3 with nodal
involvement
Metastatic disease,
or vascular
involvement with
nodal metastases
(T4N1M0)
[]
Distant metastases
[]
clinical presentation
The clinical presentation of gallbladder cancer is often identical
to biliary colic and/or chronic cholecystitis, making it difficult to
diagnose preoperatively. It is also difficult to easily distinguish
gallbladder cancer from benign gallstone disease from blood
tests. Elevated alkaline phosphatase and/or bilirubin levels are
found in cases of advanced tumors, but may also be found for
patients with gallstones. A CEA greater than 4 ng/ml is 93% specific for the diagnosis of gallbladder cancer, but is only 50% sensitive (37). A serum Ca 199 level (38) greater than 20 units/ml
has 79.4% sensitivity and 79.2% specificity, but neither test is
routine in patients suspected of having benign disease. Vigilance
for cancer in examination of preoperative sonograms or CT
scans is essential. Any mass or polyp associated with the gallbladder (Fig. 21.1) or the presence of a porcelain gallbladder
should raise concerns of a gallbladder cancer.Figure 21.1
It is often difficult to make the diagnosis of gallbladder cancer based upon clinical history as it often presents similarly to
benign calculous disease. In a report of 42 laparoscopically discovered gallbladder cancers, in only two of the cases did the
laparoscopic surgeon suspect a cancer prior to the surgical
procedure (39). The laparoscopic procedure consisted of 19
199
surgical management
radiologic workup
200
Total
metastases (%)
Peritoneal
metastases (%)
Nodal
metastases (%)
9
16
16
12
43
68
50
50
66
Table 21.3 Actuarial Survival Results Reported In Retrospective Reviews after Resection of Stage I Gallbladder Cancers
Author
Year
1987
1988
1990
1991
1991
1992
1992
1992
1992
1993
1992
14
11
6
7
366
39
6
56
38
4
6
32
Procedure
Not specified
Not specified
Simple cholecystectomy: 83%
Simple cholecystectomy
Not specified
Simple cholecystectomy
Simple cholecystectomy
Simple cholecystectomy
Extended cholecystectomy
Extended cholecystectomy
Simple cholecystectomy
Simple cholecystectomy: 69%
78
100
100
86
87
100
100
100
100
100
100
94
71.4
Not reported
100
86
78
100
100
100
100
100
100
94
201
Table 21.4 Actuarial Survival Results Reported in Retrospective Reviews after Resection of Stage II Gallbladder Cancers
Author
Year
1988
1990
1991
1991
1992
1992
1992
1993
1994
1996
1998
2007
2007
Jensen (65)
2008
DAngelica (66)
2008
73
12
499
7
35
10
25
9
17
52
8
5
34
9
25
769
196
41
Multi-institutional survey.
Chole, cholecystectomy.
202
Procedure
Not specified
67% Extended chole
Not specified
86% Simple chole
Simple chole
Extended chole
Simple chole
Extended chole
Simple chole
88% Simple chole
Extended chole
Extended chole
Extended chole
Simple chole Extended chole
Simple chole Extended chole
Extended chole
Table 21.5 Actuarial Survival Results reported in Retrospective Reviews after Resection of Stage III and IV Gallbladder Cancers
3-Year
survival (%)
5-Year
survival (%)
III
38
12
12
8
12
13
III
III
III
III/IV
III/IV
80
44
63
17
16
44
63
16
1990
1991
17
8
III/IV
III/IV
50
50
29
1992
1991
20
453
III/IV
IV
18
45
8
1991
1991
1992
27
14
27
IV
IV
IV
7
10
25
1994
1995
1996
11
14
7
IV
IV
IV
11
8
25
8
25
Kai (64)
DAngelica (66)
Jensen (65)
2007
2008
2008
16
63
119
III/IV
III/IV
III
40
45
18
36
28
9
Author
Year
1992
1994
1995
1996
1987
1989
Stage
Comments
Majority with common bile duct
resection
Extended resections only
Extended resections only
Extended resections only
Extended resections only
Includes 5 HPD, 10 extended
hepatectomy
Extended resections only
Includes only curative resection at initial
surgery
All patients have lymph node metastases
Multi-institutional series with 25%
simple cholecystectomy
All patients had IORT
All patients underwent HPD
Includes 3 HPD, 6 extended
hepatectomy, 11 CBD resection
Extended resections only
Japanese staging
Long-term survivors with no lymph
node metastases
CBD, common bile duct; HPD, hepatopancreatoduodenectomy; IORT, intraoperative radiation therapy.
203
204
Port
1
1
1
1
2
1
1
1
Umbilical
Umbilical
Umbilical
Umbilical
Umbilical
Epigastric
Umbilical
Umbilical
0
Not specified
Not specified
Various
3
4
174
adjuvant therapy
Because of the rarity of gallbladder cancer in general, as well as
the rarity of completely resected disease, there is only one prospective, randomized trial examining the utility of adjuvant
therapy for gallbladder cancer. This trial assessed 5-year overall survival in patients following noncurative resection who
received postoperative adjuvant chemotheraoy using mitomycin C and 5-FU. Survival was improved with adjuvant therapy
(26% vs. 1%, P = 0.03). (87) However, most data available is
derived from retrospective series. Conclusive data do not support the routine use of chemotherapy (8890).
palliative management
Palliative therapy should be considered in the context that the
median survival for patients presenting with unresectable
gallbladder cancer is 2 to 4 months (60,97). The goal of palliation should be relief of pain, jaundice, and bowel obstruction,
as well as prolongation of life. These should be done as simply
as possible given the aggressive nature of this disease. Biliary
bypass for obstruction can be difficult because of advanced
disease in the porta hepatis. A segment III bypass is usually
necessary if surgical bypass is chosen to relieve jaundice (98,99). However, such bypasses have a 12% 30-day mortality rate (99) In the event of a preoperative diagnosis of
advanced, unresectable gallbladder cancer in the jaundiced
patient, therefore, a noninvasive radiologic approach to biliary drainage is justified.
Systemic chemotherapy (100) and radiation therapy (101)
have little effect on these tumors. Patients with unresectable
disease and good functional status who desire therapy should
be directed to investigational studies to determine whether any
novel therapies may be of benefit.
summary
Gallbladder cancer is an aggressive disease with a dismal prognosis. It should not, however, be approached with a fatalistic
attitude. Appropriate workup and extended resection can
result in a cure. Gallbladder cancer will be encountered
approximately once every 100 times that a gallbladder is
removed for presumed benign gallstone disease. For those
patients discovered to have a T1 cancer during pathologic
analysis, no further therapy is indicated as long as all the margins, including the cystic duct margin, are negative (56,58).
However, T2, T3, or T4 tumors deserve consideration for reexploration (54,61,102106). Selection for re-resection relies
key points
Gallbladder cancer will be found in 1 per 100 cholecystectomy specimens (incidence 1.2 cases per 100,000 population
per year).
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3. Blalock AA. A statistical study of 888 cases of biliary tract disease. Johns
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4. Perpetuo MD, Valdivieso M, Heilbrun LK, et al. Natural history study of
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5. Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg
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6. Matsumoto Y, Fujii H, Aoyama H, et al. Surgical treatment of primary
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86. Fong Y, Blumgart LH, Fortner JG, Brennan MF. Pancreatic or liver resection for malignancy is safe and effective for the elderly. Ann Surg
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88. Chao TC, Jan YY, Chen MF. Primary carcinoma of the gallbladder associated with anomalous pancreaticobiliary ductal junction. J Clin Gastroenterol 1995;21(4):3068.
89. Oswalt CE, Cruz AB, Jr. Effectiveness of chemotherapy in addition to surgery in treating carcinoma of the gallbladder. Rev Surg 1977;34(6):4368.
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92. Todoroki T, Iwasaki Y, Orii K, et al. Resection combined with intraoperative radiation therapy (IORT) for stage IV (TNM) gallbladder carcinoma. World J Surg 1991;15(3):35766.
93. Bosset JF, Mantion G, Gillet M, et al. Primary carcinoma of the gallbladder.
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94. Hanna SS, Rider WD. Carcinoma of the gallbladder or extrahepatic bile
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96. Kresl JJ, Schild SE, Henning GT, et al. Adjuvant external beam radiation
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97. Wanebo HJ, Castle WN, Fechner RE. Is carcinoma of the gallbladder a
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207
22
introduction
Hepatocellular carcinoma (HCC) is the fifth most common
and the third most deadly cancer worldwide (1). HCC is
closely associated with chronic liver disease and more than
80% of cases occur in cirrhotic livers (2). Since functional
reserve of the liver is often significantly impaired, application
of treatment modalities such as liver resection, transarterial
chemoembolization, or local ablation therapy is limited. Not
only HCC recurrence, but also progressive deterioration of
liver function decrease patient survival.
Liver transplantation (LT) is the only treatment that offers a
chance of cure for the tumor and the underlying liver cirrhosis
at the same time, although there is an additional risk of accelerated tumor recurrence from immunosuppression. The outcome of LT for HCC in Western countries is encouraging, but
availability of liver grafts still remains the main limitation for
LT. Since the incidence of HCC combined with chronic liver
diseases is much higher, and organ donation from deceased
donors is much fewer in Asian countries compared to Western
countries, it is difficult to use Deceased Donor LT (DDLT) as
one of the main treatment modalities for HCC in Asia. In fact,
organ donation from deceased donors remains below five per
million per year in most Asian countries because of various
social and cultural reasons (Fig. 22.1) (3).
Because of these constraints, Living Donor LT (LDLT) is
now the main method of LT in a number of Asian countries,
and is an alternative to DDLT in every indication for LT.
Numerous technical innovations have been achieved to secure
donor safety as well as ensure patient survival. The outcomes
of LT for HCC in major Asian LT centers are acceptably favorable and also comparable to those seen in Western countries (3).
Patient selection criteria for HCC have also been proposed by
several major Asian LT centers based on their own data (47).
208
history of lt in asia
LT in Asia started early and yet progressed slowly when compared with Western countries (3). The first liver transplant in
Asia was performed in 1964 by Nakayama with a graft from a
non-heart beating donor in Chiba, Japan (18). This was only 1
year after Starzls first attempt in the world for human LT in
Denver, USA (19). It was a highly controversial exploit because
organ donation from a deceased person was not accepted in
Japanese culture at that time. The second transplant in Asia
was performed in 1978 in Shanghai, P.R. China (3,20). In 1984,
Chen, in Taiwan, performed the first liver transplant with
long-term survival in Asia at a time when there was still no
brain death law in that country (21). Legislation regarding
brain death was passed in Singapore (22) and Taiwan in 1987,
and subsequently in Japan and Korea (23).
In Asia, the serious scarcity of deceased donor organ donation and strong demand for LT provided a powerful driving
force for the development of LDLT as a practical alternative in
replacing DDLT. The first LDLT in Asia was performed by
Nagasue of Shimane University, Japan, in 1989 (24), only 1
year after the first attempt of LDLT by Raia in Brazil in
1988 (25). Subsequently Hong Kong, Korea, and Taiwan rapidly initiated pediatric LDLT programs transplanting a left lateral section or a left lobe graft from a parent donor to a child.
However, the ultimate need for LDLT was in adult patients.
Transplant centers in Asia have repeatedly advanced the frontier of adult-to-adult LDLT. In 1993, Makuuchi in Japan performed the first successful adult LDLT using a left lobe
10
10.7
12.8
14.4
19
20.9
22.2
22.8
24.6
25.2
35.1
10
15
20
25
30
Number of deceased donors per million of population
35
40
Figure 22.1 Comparison of organ donation rates from deceased donors in different countries in the East and West in 2005 (3).
graft (26). The left lobe graft, which usually comprises less
than 40% of the whole liver volume, is often too small for an
adult recipient. For successful LDLT for adult patients, graft
size is the most important factor in determining the outcome
of LDLT and is still a controversial concern for selection of the
ideal donor. The Kyoto group first reported the use of a right
lobe graft for a pediatric recipient as a result of a variance in
the donors arterial anatomy in 1994 (27). The first case
report (28), and subsequently the first series (29) of successful
adult LDLT, using a right lobe graft was reported from Hong
Kong in 1997.
Further technical advances in adult LDLT, including the
addition of the caudate lobe to a left lobe graft (30) and the use
of right lateral section grafts (31), were reported from Japan.
In 1999, authors proposed conservation of the middle hepatic
vein trunk to the donor, and the reconstruction of hepatic
venous drainage of the right anterior section of the liver graft
to avoid congestion injury of both the right lobe liver graft and
the donors remnant left lobe (32). Middle hepatic vein reconstruction has apparently increased the success rate of the right
lobe LDLT in adult patients and widened the safety margin
and the pool of living donors. As an attempt to provide adequate graft volume for an adult recipient and minimize the
risk of an individual donor, authors also performed implantation of dual grafts from two donors for one recipient in
2000 (33,34).
In Asia, where the supply of deceased donor organs remains
seriously limited and the demand for LT is persistently increasing, the applicability of LDLT will continue. For successful
LDLT, the risk to the donor should be balanced by the greater
benefit to the recipient. Every effort must be taken to minimize
donor morbidities, making this procedure beneficial to the
donor and the recipient (3538).
209
Center
Asan, Korea (4)
Tumor criteria
Diameter 5 cm; Number
of lesions 6; No gross
vascular invasion
Diameter 5 cm; Number
of lesions 10; PIVKA-II
400 mAU/mL
Diameter 5 cm; Number
of lesion 5
Total diameter 8 cm; or
total diameter >8 cm
and histopathologic
grades I and II, and AFP
400 ng/mL
Diameter 5 cm if single
lesion; or Diameter
3 cm if multiple lesions
and number of
lesions 3
Diameter 6.5 cm if single
lesion; or Diameter
4.5 cm if 2 lesions with
total diameter 8 cm
Type of
donor
Viral hepatitis
Number
of
patients
Patient survival
rate within
criteria
Patient survival
rate exceeding
criteria
1-year: 94.3%,
3-years: 87.5%,
5-years: 81.6%
5-years: 86.7%
1-year: 71.9%,
3-years: 37.2%,
5-years: 20.7%
5-years: 34.4%
Recurrence-free
3-years: 94%
1-year: 92.8%,
3-years: 70.7%,
5-years: 70.7%
Recurrence-free
3-years: 50%
1-years: 49.9%,
3-years: 27.0%,
5-years: 18.9%
4-years: 85%
4-years: 50%
Recurrence-free
1-year: 98.6%,
Recurrence-free
5-years: 96.7%
Recurrence-free
1-year: 80.4%,
Recurrence-free
5-years: 59.5%
LDLT: 100%
HBV: 93%,
HCV: 7%
221
LDLT: 100%
HBV: 34%,
HCV: 53%
125
LDLT: 100%
HCV: 62%
78
Not defined
HBV: 100%
195
DDLT: 100%
HBV: 23%,
HCV: 67%
48
DDLT: 93%,
LDLT: 7%
HBV: 23%,
HCV: 65%
168
Abbreviations: AFP, alpha-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; LDLT, living donor liver transplantation; PIVKA-II, prothrombin induced
by vitamin K absence II; UCSF, University of California at San Francisco.
210
1.0
0.8
0.8
Proportion of recurrence
Proportion of recurrence
Beyond Asan
Beyond UCSF
0.6
0.4
Beyond Milan,
within UCSF
0.2
0.6
Beyond Milan,
within Asan
0.4
Within Milan
0.2
Within Milan
0.0
12
24
36
48
Posttransplant months
0.0
60
(A)
12
24
36
48
Posttransplant months
60
(B)
Figure 22.2 Comparison of the hepatocellular carcinoma recurrence curves between the Milan and UCSF criteria (A) and between the Milan and Asan criteria (B) (4).
1.0
1.0
LT
0.9
0.9
0.8
Proportion of survival
Proportion of survival
0.8
0.7
0.6
0.5
Hepatectomy
0.4
0.3
0.6
0.5
Hepatectomy
0.4
0.3
0.2
0.2
P = 0.27
0.1
0.1
P = 0.047
0
0
(A)
LT
0.7
20
40
60
80
100
120
140
Postoperative months
0
(B)
20
40
60
80
100
120
140
Postoperative months
Figure 22.3 Comparison of the overall patient survival (A) and recurrence-free survival (B) between the patients who undergone hepatic resection and liver transplantation for hepatocellular carcinoma (HCC) <3 cm-sized, single nodule with ChildTurcottePugh class A cirrhosis (60).
response to neoadjuvant therapy may be potentially influenced by the selection effect for tumors with better biological
behavior. Such a selection bias also influences post-transplant
outcome (6870).
Salvage LT has been performed for recurrent HCC or deterioration of liver function after primary liver resection. From
the viewpoint of pre-transplant treatment, prior liver resection has two roles: primary treatment and bridging to LT. Considering the incidence of deceased donors and high proportion
of LDLT, many of prior liver resection may be intended for
primary curative treatment rather than bridge treatment.
There are two important points to be taken into account
before performing salvage LT (71). The first is the technical
feasibility of LT, especially for LDLT. The surgical condition of
patients with recurrent HCC after prior liver resection is not
very different to that of patients who underwent non-surgical
treatment, except that adhesion and anatomical distortion
exist within the abdomen, which could be overcome by technical skill (71). Some authors claim that every combination of
prior hepatectomy and living donor graft is feasible for patients
211
Number of operations
1,000
HCC
Non-HCC
800
600
400
200
0
1994
1995
1996
1997
1998
1999 2000
Year
2001
2002
2003
2004
2005
Figure 22.4 Annual proportions of liver transplants for hepatocellular carcinoma (HCC) in Asia (excluding mainland China) (3).
212
Proportion of survival
1.0
0.8
0.6
DDLT
0.4
0.2
LDLT
0.0
12
24
36
Months
Figure 22.5 Cumulative survival curves after the first detection of hepatocellular carcinoma recurrence in DDLT and LDLT groups. There is no statistically significant difference between these two groups (41).
conclusion
The high prevalence of HCC and subsequent high incidence of
HCC in the situation of very low organ donation rate in Asia
lead to making a unique pattern of indication and strategy in
the application of LT. HCC has begun to be a main indication
of LT, especially in the form of LDLT. Effective promotion of
deceased organ donation is essential in every Asian country.
Although LDLT has become the main form of LT in Asia,
donor safety should always be emphasized. The selection indication of LT for HCC is likely to be expanded further, but it
should be prudently adopted after qualified riskbenefit analyses. Application for small HCC in patients with preserved
liver function has also been an expanded indication after gradual improvements in peri-operative mortality. As before, new
innovative surgical techniques will emerge to solve currently
intractable technical problems. Emergence of new effective
treatment modalities for HCC recurrence will expand the
selection criteria further without compromising disease recurrence rate. The practice of LT in Asia will continue to evolve
further, giving more benefits to patients with HCC.
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75. Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis. Ann Surg 2003;
238: 50819.
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215
23
introduction
Hepatocellular carcinoma (HCC) is the fifth most common
cancer worldwide (1). Added to its worldwide prevalence,
there is a continued rising incidence of HCC in the western
hemisphere (2). More than 80% of patients present with
advanced or unresectable disease, and the recurrence rates
after surgical resection is as high as 50% (3).
Effective therapies for advanced HCC remain an immediate
need. In the field of local therapies for locally advanced disease, extensive work has been done in regard to the feasibility
and effectiveness of different ablative modalities, with several
issues still in debate.
In the more advanced and metastatic disease settings, recent
data showed an improvement in survival in advanced HCC
with sorafenib. This landmark study not only helped in defining a standard of care for advanced HCC, but also generated
several clinical questions among whom to treat, and how to
account for the cirrhosis and underlying liver dysfunction.
Second line therapies and future clinical trials are prime time
discussions.
216
(A)
(B)
(C)
Figure 23.1 (A) Pre-treatment CT (arterial phase) in patient with multi-focal HCC. (B) Non-treatment CT performed 12 hours after left hepatic and phrenic
artery particle (bland) embolization. Note retained contrast material and small gas bubbles in treated tumor. (C) Post-treatment CT (arterial phase) demonstrating imaging findings consistent with necrosis of treated tumor corresponding to treated tumor that had retained contrast and gas bubbles on immediate postembolization CT scan.
(A)
(B)
Figure 23.2 (A) Pre-treatment CT in patient with large HCC in right liver with tumor thrombus extending into portal vein (B) post-treatment CT 6 weeks after
bland embolization demonstrating imaging findings of necrosis of tumor within liver and portal vein.
217
218
systemic therapies
Historical Background
Chemotherapy has been studied extensively in HCC. Despite
reported responses ranging between 10% and 20%, no study
has shown an impact on survival. Doxorubicin has been studied extensively and there is still no agreement about its use in
advanced HCC, with response rates ranging between 0% (39)
and 79% (40). Despite the poor or debatable outcome of most
of these trials, doxorubicin became the default standard for
treatment, and a control arm for several comparative trials testing either other single agents or combination regimens (41).
PIAF (cisPlatin, Interferon, Adriamycin,
and 5-Fluorouracil)
Given the disappointing results of single agent doxorubicin
and other single agent therapies, combination regimens have
also been investigated. A combination of cisplatin, interferon,
doxorubicin, and 5-fluorouracil (PIAF) has demonstrated
promising activity in a phase II study. This regimen yielded a
response rate of 26% and a median survival of 9 months (42).
Of note, 13 patients (26%) who had a partial response, 9
underwent surgery, and 4 (9%) were found to have had a complete pathologic response to chemotherapy. These data were
encouraging enough to consider evaluating PIAF versus doxorubicin as part of a large randomized phase III study that failed
to show any survival advantage for PIAF (43). More importantly, the data of the phase II study of PIAF raised the possibility of using the combination in the neoadjuvant setting.
This approach would be recommended in that specific setting
of medically fit patients with good liver function in whom
tumor cytoreduction is necessary to permit respectability
(Level of evidence IIa, category C).
Anti-angiogenic Therapies
HCC is a highly vascular solid tumor, and a vascular endothelial growth factor (VEGF) has been shown to promote HCC
development and metastasis in preclinical models (44).
Sorafenib is a novel molecular targeted agents that inhibits
both pro-angiogenic (VEGFR-1, -2, -3; PDGFR-) and tumorigenic (RET, Flt-3, c-Kit) receptor tyrosine kinases (RTKs).
Sorafenib also inhibits the serine or threonine kinase
Raf-1 in vitro (45). A phase II trial of sorafenib evaluating
response in patients with advanced HCC showed 33.6% of
patients to have stable disease (16 weeks) commensurate
with a median time-to-progression (TTP) of 4.2 months and
the median overall survival of all patients was 9.2 months (46).
The reported stable disease was commensurate with an interesting observation of central tumor necrosis was found in
many patients in the study (Fig. 23.3). A sub-analysis evaluating the correlation between tumor necrosis and response was
performed (47). The ratio of tumor necrosis and volume
(N/T) was significantly associated with response, with
responders having greater increase in the ratio between necrosis and tumor volume relative to baseline, as compared to nonresponders (p = 0.02), This data stresses the need for radiologic
techniques other than RECIST to evaluate HCC response such
as dynamic imaging. For practical reasons, it is recommended
that patients on soarfenib be followed with triphasic CT scans
or MRI and any decision to continue or stop therapy should be
based on a multiple factors including patient clinical evaluation, imaging studies, and serum markers (where applicable).
(Level of evidence III, category C).
This phase II study led to the development of a large doubleblinded, randomized phase III trial evaluating single agent
sorafenib versus placebo in patients with advanced HCC and
no more than ChildPugh A cirrhosis (48). The trial demonstrated an improvement in survival of 10.7 months in the
219
Figure 23.3 Baseline and serial follow-up scans demonstrate tumor necrosis in a hepatocellular carcinoma patient.
220
conclusion
HCC remains prevalent worldwide and is showing a steady
rise in incidence in the western hemisphere. A high number of
patients are in need for either local or systemic therapies.
When disease is limited to the liver, a local-regional method of
treatment such as embolization or ablation should be the initial treatment. In some cases, combining these methods of
treatment or using them sequentially is appropriate. Sorafenib
is the first systemic treatment to demonstrate a survival advantage in a large, randomized, controlled phase III study and is
now approved by the FDA for patients with unresectable HCC.
Future studies are to look into improving the outcome with
sorafenib further by combining with other systemic therapies
or local therapies. Other uses of systemic therapies, that is,
adjuvant therapy, are also under investigation.
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a better prognosis than the other types (1520). The reason for
the better prognosis of the latter type of ICC is that this type
can be detected in the early stages based on positive radiologic
signs or by the detection of liver dysfunction because of biliary
obstruction. IG-ICC is often diagnosed before tumor extension beyond the bile ducts and patients with this type of ICC
present with smaller tumor sizes than patients with the other
types of ICC (20).
pre-operative diagnosis
Because previous surveys of ICC have failed to define highrisk groups (37), unlike the case for hepatocellular carcinoma,
early detection of ICC patients remains difficult. Moreover,
absence of early symptoms in most patients with ICC leads to
delays in diagnosis. Some of the possible symptoms associated
with ICC include abdominal pain, anemia, and weight
loss (38). In contrast to patients with extrahepatic bile duct
carcinoma, only 0% to 28% of patients with ICC present with
obstructive jaundice (5,6,38).
There are no definite tumor markers for ICC, although
carcinoembryonic antigen (CEA) and carbohydrate antigen
223
(A)
(B)
(C)
Figure 24.1 Morphologic classification of intrahepatic cholangiocarcinoma according to Liver Cancer Study Group of Japan. (A) Mass-forming type. (B) Periductalinfiltrating type. (C) Intraductal-growth type. Source : From Ref. 11.
surgical strategy
As with hepatocellular carcinoma, the counterpart of ICC as a
primary liver cancer, the only treatment that may offer a
224
80
70
60
50
40
N0 1,028
30
20
N1 495
10
0
12
24
36
48
60
72
84
Survival period (month)
96
108
120
132
144
Figure 24.2 Impact of lymph node metastasis on the overall survival rate of patients with ICC who underwent tumor resection. N0 indicates patients without
lymph node metastasis and N1 indicates those with lymph node metastasis. Source : From Ref. 11.
Table 24.1 Outcome After Liver Resection for Intrahepatic Cholangiocarcinoma in Literature
First author
Year
Country
Kawarada (68)
Cherqui (47)
Schlinkert (66)
Yamamoto (31)
Pichlmayr (63)
Nakeeb (9)
Jan (67)
Casavilla (54)
Madariaga (55)
Chen (38)
Valverde (65)
Inoue (3)
Okabayashi (4)
Weber (56)
DeOliveira (5)
Shimada (59)
Paik (6)
1990
1995
1992
1992
1995
1996
1996
1997
1998
1999
1999
2000
2001
2001
2001
2007
2008
Japan
France
USA
Japan
Germany
USA
China
USA
USA
Taiwan
France
Japan
Japan
USA
USA
Japan
Korea
11
14
6
10
32
9
41
34
34
138
30
52
60
33
44
47
97
1-year
survival, %
59.3
53.7
64
67
33
86
63
68
74.9
3-year
survival, %
5-year
survival, %
34
44.4
36.6
34
40
17
22
36
35
45
51.8
34
33
44.4
44
26.8
26
35
14
36
29
40
40
31.1
Median
survival, mo
14
12.8
22
12
19
28
37.4
23
225
80
70
60
50
40
30
3,499
20
10
0
12
24
36
48
60
72
84
Survival period (month)
96
108
120
132
144
Figure 24.3 Overall survival rates of all patients with ICC who underwent tumor resection. Source : From Ref. 11.
Year
Lymph
node
Vascular
invasion
Positive
margin
Tumor
size
Multiple
tumors
Bilobar
disease
Nakeeb (9)
Jan (67)
Chou (69)
Casavilla (54)
Madariaga (55)
Valverde (65)
Inoue (3)
Weber (56)
DeOliveira (5)
Paik (6)
1996
1996
1997
1997
1998
1999
2000
2001
2001
2008
9
41
27
54
34
30
52
33
44
97
U
U, M
U, M
U
U, M
U
U
U
U
U, M
U, M
U
U, M
U, M
U, M
U
U, M
U, M
U, M
U, M
U
U, M
U
U
Others
Lymphatic invasion
TNM stage
Left lobe
Morphologic type
U, significant by univariate analysis for overall survival; M, significant by multivariate analysis for overall survival.
226
adjuvant therapy
Because the prognosis after tumor resection alone is far from
satisfaction, adjuvant therapy may be considered in some
patients. There have been only a few reports of long-term survival with such therapy among patients with ICC (70,71).
Moreover, there have been no reported randomized prospective trials of adjuvant therapy in these patients, although the
CRUK BILCAP study of surgery versus surgery plus adjuvant
gemcitabine continues to recruit in the United Kingdom.
There have also been only a few anecdotal reports of chemotherapy for patients with recurrent or unresectable ICC, using
5-FU, cisplatin, epirubicin, gemcitabine, capecitabine, and
cetuximab (7276). Further therapeutic trials are therefore
warranted using recently developed treatment modalities or
those that are developed in the future, including radiotherapy,
immunotherapy, and chemotherapy with or without molecule-targeted drugs.
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25
background
Cholangiocarcinoma (CCA) is a malignancy arising from the
bile duct epithelium which has a very poor prognosis. The
incidence in the United States is approximately 1.2 in 100,000,
though it is far higher in Eastern Europe and Asia, and it
appears to be increasing worldwide (13). Although CCA can
occur anywhere along the intra- or extra-hepatic bile ducts,
the most common location is at the hilar region, involving the
confluence of the right and left ducts (60%) (4,5). While most
patients develop CCA de novo, risk factors for the development of CCA relate to chronic inflammation of the biliary
tree. In Western countries CCA is most often associated with
Primary Sclerosing Cholangitis (PSC), though other risk factors
include choledochal cysts, hepaticolithiasis, and parasitic infections including Clonorchis sinensis and Opisthorchis viverrini.
The prevalence of CCA in patients with PSC is 5% to 15% (6).
Establishing a timely diagnosis of hilar CCA is challenging.
The tumor is a desmoplastic lesion which typically grows
along the bile duct rather than in a radial diameter which limits early detection by cross-sectional imaging. Endoscopic
brushing and biopsy are often negative even in of the presence
well-established disease, and the tropism for bile producing
growth in a longitudinal fashion often leads to the lack of a
mass lesion, even in the face of biliary obstruction (7). Eventually, tumor growth becomes independent of bile and mass
lesions develop, which are demonstrable by cross sectional
imaging. Direct cholangiography (endoscopic retrograde
cholangiography and percutaneous transhepatic cholangiogram) best characterizes the site, extent, and configuration of
ductal CCA. However, the use of imaging modalities, including high-resolution CT and MRI, are also important for the
diagnosis of CCA by providing additional information regarding adjacent structures which differentiate CCA from benign
counterparts. While contrast-enhanced MRI and magnetic
resonance cholangio-pancreatography have improved the
diagnostic sensitivity and specificity of imaging, due to the
biologic principles of the tumor, early diagnosis remains a significant problem (810). A promising technique in obtaining a
tissue diagnosis may be the use of Spyglass cholangioscopy,
which allows biopsy if bile duct lesions under direct endoscopic visualization. Although this technique may prove to be
useful for diagnostic purposes, it will not enhance accuracy of
pre-operative tumor staging (11).
Thus far, no molecular markers in bile have proven reliable in
establishing a more timely diagnosis. The serum marker CA
199 has not been shown to be accurate enough for screening.
However, for patients with PSC and a malignant appearing stricture, serum CA 199 >130 U/mL has a sensitivity of 79% and a
specificity of 98% (12). Conventional cytology has a sensitivity of
only 20% to 40%, though the specificity is 100% (13). The limitation of conventional cytology is the paucicellular nature of a
229
while awaiting transplantation. Prior to undergoing transplantation, which is performed either with a deceased donor
or living donor allograft, patients undergo formal operative
staging (either open or more recently, using hand-assisted laparoscopy) with routine sampling of common hepatic artery
and peri-choledochal lymph nodes in addition to biopsy of
any other suspicious nodules.
Our initial experience with neoadjuvant chemoradiotherapy followed by transplantation was encouraging (36,37) and
was followed by a comparison of all 38 patients undergoing
OLT for unresectable hilar CCA from 1993 to 2002 versus all
patients who underwent resection of hilar CCA at the same
institution during the same time period (14). A comparison
between liver transplantation with neoadjuvant therapy and
resection is imperfect because the OLT protocol was restricted
to patients with unresectable disease. Nevertheless, transplantation provided superior outcomes, with 82% 5-year survival
versus 21% 5-year survival after resection. In this study, a survival benefit for transplantation versus resection was seen both
in patients with PSC and in those with de novo CCA. Our
most recent published survival data from December of
2006 includes 65 patients with a mean follow-up of 32 months.
Patient survival was 91% at 1 year and 76% at 5 years (38). To
date, 167 patients have enrolled in this protocol. There have
been 111 patients who have undergone OLT with 1- and 5-year
survival of 96% and 72%, respectively (see Figs. 25.2 and 25.3).
Though patient survival following the combined protocol
for treatment of hilar CCA is similar to other indications for
liver transplantation, the toxicity of the neoadjuvant therapy is
significant. Common complications include cholangitis, liver
abscess, duodenal ulceration, malnutrition, liver decompensation, and disease progression (14,3638). Approximately 20%
of patients have evidence of metastatic disease at operative
staging and are therefore not eligible for OLT (see Fig. 25.2).
Additionally, despite the aggressive pre-treatment protocol, 11
of 65 (17%) in the most recent published analysis still developed disease recurrence following liver transplantation (38). A
retrospective analysis of these 11 patients who developed disease recurrence determined that older patients, those with
Hilar cholangiocarcinoma
Mayo clinic protocol
Selected patients with unresectable hilar
cholangiocarcinoma (began in 1993)
Neoadjuvant radiation and chemotherapy
External beam radiotherapy with bolus 5-FU
Brachytherapy with protracted capcitabine
230
167 patients
Irradiation
+ 5-FU
12 deaths/disease progression
2 transplanted elsewhere
10 receiving neoadjuvant therapy
143 staging
operation
111 liver
transplantation
75 decease donor
35 living donor
1 domino donor
Figure 25.2 Results of a combined chemoradiotherapy followed by liver transplantation protocol for hilar CCA.
100
83 4%
90
72 6%
80
70
60
50
40
30
20
10
0
0
2
3
Years after transplantation
Figure 25.3 KaplanMeier analysis of survival for patients undergoing transplantation after completion of neoadjuvant therapy at Mayo Clinic.
organ allocation
The findings from the Mayo Clinic and Nebraska protocols as
well as the historical data for OLT without adjuvant therapy
were carefully considered by the Model for End Stage Liver Disease (MELD) Exception Study Group, which was assembled to
consider standardization of diagnoses which commonly led to
MELD exception scores (41). The conclusion of this group was
to recommend national standardization of MELD score exceptions for patients with early stage, unresectable hilar CCA provided they are enrolled in an approved protocol which includes
neoadjuvant therapy, and standard inclusion (i.e., diagnostic),
and exclusion criteria. The group proposed an allocation policy
applied nationally similar to that currently granted for HCC,
which is based on a 10% risk of mortality subject to readjustment every three months. Currently, organ allocation in the
United States for hilar CCA, as well as other diagnoses which
require MELD exception, varies considerably by each region. It
is possible that a national policy for MELD exceptions for common diagnoses may be considered in the future.
conclusions
Excellent outcomes can be achieved with neoadjuvant chemoradiotherapy followed by OLT for selected patients with early
stage hilar CCA. Obtaining a timely diagnosis remains a key
challenge regardless of whether resection or transplantation is
being considered. As with hepatocellular carcinoma, it is necessary to determine the risk for disease progression following
neoadjuvant therapy for patients awaiting transplantation.
Given the severe donor organ shortage, continued analysis of
outcomes in order to identify patients not likely to gain benefit
from this aggressive protocol is necessary. In light of the results
achievable with the combined neoadjuvant chemoradiotherapy protocol, however, a standardized approach to organ allocation which is applied nationally, as for HCC, is necessary
and will hopefully be forthcoming. Finally, with application of
the protocol across multiple centers, the key principles, such as
multi-disciplinary approach, pre-transplant staging to ensure
inclusion of only those without metastasis, replacement of
irradiated vessels when possible as well as monitoring for postoperative vascular complications, must be highlighted.
231
key points
1. The diagnosis of hilar CCA remains a challenge
(level II evidence).
2. Based on non-randomized analysis (level II evidence), neoadjuvant chemoradiotherapy followed
by liver transplantation for patients with early stage
unresectable hilar CCA offers excellent survival.
3. Percutaneous, open, or transgastric biopsy of the
primary tumor should not be performed due to
the risk of tumor seeding into the peritoneal cavity
(level II).
4. Radiation injury may lead to hepatic artery thrombosis and late vascular strictures. Native hepatic
arteries should be replaced by arterial conduits in
deceased donor transplantation to reduce early
thrombosis. Late strictures may be amenable to
endovascular treatment (level III).
5. Toxicity of the neoadjuvant therapy is significant, and a multi-disciplinary approach including
commitment from radiology, radiation oncology,
medical oncology, hepatology, and hepatobiliary/
transplantation surgery is necessary.
references
1. Shaib Y, el-Serag HB. The epidemiology of cholangiocarcinoma. Semin
Liver Dis 2004; 24: 11525.
2. Sripa B, Pairojkul C. Cholangiocarcinoma: lessons from Thailand. Curr
Opin Gastro 2008; 24: 34956.
3. Maggs JR, Chapman RW. An update on primary sclerosing cholangitis.
Curr Opin Gastro 2008, 24: 37783.
4. Bismuth H, Castaing D. Hepatobiliary malignancy. London: Edward
Arnold, 1994.
5. De Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J
Med 1999; 341: 136879.
6. Knan Sa, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and
treatment of cholangiocarcinoma: consensus document. Gut 2002; 51
(Suppl 6): VI 19.
7. Gores GJ, Nagorney DM, Rosen CB. Cholangiocarcinoma: is transplantation an option? For whom? J Hepatol 2007; 47: 45475.
8. Manfredi R, Barbaro B, Masselli G, et al. Magnetic resonance imaging of
cholangiocarcinoma. Semin Liv Dis 2004; 24(2): 15564.
9. Braga HJ, Imam K, Bluemke DA. MR imaging of intrahepatic cholangiocarcinoma: use of ferumoxides for lesion localization and extension. AJR
2001; 177: 11114.
10. Yeh TS, Jan YY, Tseng JH, et al. Malignant perihilar biliary obstruction:
magnetic resonance cholangiopancreaticographic findings. Am J Gastro
2000; 95: 43240.
11. Chen YK, Pleaskow DK. SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorder: a
clinical feasibility study. Gastrointest Endosc 2007; 65(6): 83241.
12. Levy C, Lymp J, Angulo P, et al. The value of serum Ca 19-9 in predicting
cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig
Dis Sci 2005; 50: 173440.
13. Moreno Luna LE, Kipp B, Halling et al. Advanced cytologic techniques for
the detection of malignant pancreatobiliary strictures. Gastroenterology
2006; 131: 106472.
14. Rea D, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005; 3: 45161.
15. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of
intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224: 46373;
discussion 4735.
232
introduction
Vascular hepatic tumors form a continuum going from the
completely benign hemangioma (HA) to the very aggressive
hemangiosarcoma (HAS). Sometimes due to their difficult
differential diagnosis and the rarity of the more malignant
varieties, and also to the limited worldwide experience with
liver resection and transplantation (LT) for these tumors, these
vascular lesions are often neglected or misdiagnosed and their
therapeutic management algorithm is unclear.
The rarity of malignant vascular liver lesions is well demonstrated by the data of the European Liver Transplant Registry
(ELTR). During the period January 1988 to June 2007, 12%
(8278) of all European LT were performed because of hepatobiliary tumors, but of these, only 125 (0.1%) were done
because of malignant vascular diseases.
In this chapter hepatic epithelioid hemangioendothelioma
(HEHE), infantile hemangioendothelioma (HIHE), and hemangiosarcoma (HAS) will be discussed, based on a recent literature review and of the experience gathered by the audited
ELITAELTR during the period 1988 to 2004 (1). The information obtained from both sources allows a more clear insight
into diagnosis and treatment of these rare liver diseases.
For the sake of completeness, benign Nodular Regenerative
Hyperplasia (NRH) is also included in this chapter because of
its vascular etiopathogenesis. Hemangioma and lymphangioma are discussed in a separate chapter dealing with benign
liver tumors.
hepatic epithelioid
hemangioendothelioma hehe
HEHE is a rare (<1 per million population), low-grade malignancy which has a malignant behavior potential between HA
and HAS (2). This vascular tumor was first recognized in 1982
by Weiss and Enzinger in soft tissues, later on in the head and
neck region, then in bones and finally in many other organs,
such as lungs and bronchi. Liver involvement occurs most
often as a primary tumor. HEHE is more frequent in young
adult women; with a peak incidence during the fourth decade.
This tumor has been rarely reported in children less than
15 years old. No definitive etiological factor has been clearly
identified (2).
Macroscopically, HEHE appears as multifocal fibrous masses
(Fig. 26.1A and B). Microscopically, HEHE is characterized by
pleiomorphic cells, both of medium and of large size, that are
epithelioid in appearance and that spread within sinusoids and
small veins at the periphery of the lesion, whereas the center is
fibrous and studded with elongated tumor cells, sometimes
The European Liver Transplant Registry is a service of the European Liver and Intestinal Transplant Association (ELITA); see www.eltr.org.
233
(A)
(B)
Figure 26.1 Intraoperative view of 7.6 kg heavy HEHE responsible for IVC syndrome and supine dyspnea (A). Characteristic gross appearance of a HEHE
hepatectomy specimen showing multiple fibrous masses with zoning phenomenon (B).
(A)
(B)
Figure 26.2 Histological features of HEHE at the periphery (A) and in the center (B) of the lesion. Source: C. Sempoux, Dept. of Pathology.
234
39 15 years
(range 0.465) 2 children
43 F and 16 M
59%
20%
19%
15%
14%
10%
49%
20%
10%
9%
9%
7%
2%
(A)
(B)
(C)
Figure 26.3 CT-scan of HEHE showing the initial peripheral nodular (A) and the later confluent patterns of the disease (B). Angiography confirming the avascular
nature and vascular displacement (C).
Extrahepatic localization
Lung
Mediastinum
Peritoneum
Spleen
Femoral vein
Brain and bone
Omentum
96%
86%
44.4%
9.4%
33% (18/54p) 4/18 pts (22%)
patients only positive on IHC
4/10 pts with extrahepatic EHE
localization were lymph node
positive
17% (10 pts)
4
1
1
1
1
1
bilobar disease in 96% of cases; 86% of the specimen contained more than 15 tumor nodules (Table 26.2). Moreover,
several reports documented disease recurrence, or LT because
of recurrent HEHE after partial resection; fortunately,
pre-transplant liver surgery doesnt seem to impair survival
after LT (6).
The assessment of non-surgical treatments, such as radiotherapy, local tumor destruction, hormonotherapy, systemic or
locoregional CHTH, trans-arterial embolization, and chemoembolization, is even more difficult because of the lack of uniform treatment modalities and of long-term follow-up (3).
The ELITAELTR study is the largest worldwide, detailed
long-term study in relation to HEHE (1). This study collected
59 European patients from 32 centers. The follow-up from
diagnosis is 104 72 months (median of 93 months) and from
LT 83 55 months (median of 79 months).
The study validated the place of LT in the treatment of this
disease and 5 and 10 years post-transplant survival rates are
83% and 74%, respectively, with 5 and 10 years recurrence-free
survival rates of 82% and 64%, respectively (Fig. 26.4A and B).
This study confirms that medical and/or surgical pre-LT treatment (present in 30% of pts), invasion of regional lymph node
(present in 33% of pts) and of (limited) extrahepatic disease
(present in 17% of pts) are not formal contraindications to LT.
Combined micro- and macrovascular invasion (present in
49% of pts) is the only parameter which significantly influences outcome after LT. Mitotic index and cellular pleiomorphism are other major histological prognostic criteria
reflecting more aggressive tumor behavior (10). Their influence on patient survival could not be analyzed in the ELITA
ELTR study due to the impossibility of obtaining central
pathology recording. The recently published UNOS data
reporting 128 patients with a median follow-up of 24 months
go in the same direction; 1- and 5-year patient survival rates
were 80% and 64%, respectively (11).
Recurrent disease after (partial and total) hepatectomy
should be treated aggressively as prolonged, sometimes even
disease-free, survival can be achieved (1,3). The role of re-LT
in the treatment of recurrent allograft disease is unclear as
only one single case has been reported (5).
It is conceivable that in view of the high incidences of extrahepatic disease localization, and of recurrence in- and outside the
allograft (22% in the ELITAELTR study) (Table 26.3), a more
radical approach combining total hepatectomy and antiangiogenic therapy, such as use of VEGF-antibodies, -interferon
and rapamycin could be of value in the treatment of
HEHE (1,12). Rapamycin is of particular interest in this context
as this drug is nowadays frequently used not only as a renal sparing but also as an anti-tumoral immunosuppressive drug in
liver transplant recipients. Such an approach, combined with a
better study of the molecular and genetic markers based on
tumor biology, will be of great assistance in further improving
outcome, monitoring efficacy of emerging neo- and adjuvant
treatments and in recognizing the aggressive subtypes of
HEHE (3,5,1315).
235
Survival %
2 yrs
1 yr
86%
93%
3 yrs
85%
4 yrs
83%
5 yrs
83%
6 yrs
80%
7 yrs
75%
8 yrs
72%
9 yrs
72%
10 yrs
72%
4 yrs
41
5 yrs
36
6 yrs
31
7 yrs
26
8 yrs
18
9 yrs
14
10
10 yrs
13
Disease free survival after liver transplantation for epithelioid hemangioendothelioma: 52 patients
100
90
80
70
60
50
40
30
20
10
0
0
Survival %
1 yr
2 yrs
90%
87%
3 yrs
85%
4 yrs
85%
5 yrs
82%
6 yrs
79%
7 yrs
76%
8 yrs
68%
9 yrs
64%
10 yrs
64%
4 yrs
36
5 yrs
31
6 yrs
27
7 yrs
23
8 yrs
16
9 yrs
11
10
10 yrs
11
Figure 26.4 Overall patient survival of HEHE after liver transplantation in the ELITA-ELTR study (A). Recurrent-free survival in the same patient cohort of
59 patients (B).
236
45 35 mo
5
Liver
1
1
2
49 mo (range 698)
AWD 59 (ChTh),
84 (Res) mo
DWD 23,41,73 mo
AWD 112 mo (Res, RF,
ChTh) 211 and 212 mo
DWD 15,73 (Res, ChTh),
79 mo (Burkitt)
DWD 9 mo
DWD 4 mo (ChTh)
DWD 19, 20 mo
(A)
(B)
(C)
(D)
Figure 26.5 Macro- and microscopic features of HIHE. The lesion can be either solitary (A) or multiple (B). Type 1 HIHE is made of multiple vascular channels
with a single layer of regular endothelial cells (C) whereas in type 2 HIHE more atypia are observed (D). Source: S. Gosseye, Dept. of Pathology.
237
Age
Gender
Invalidating tumor
(9 HEHE6 HAS)
Unclear diagnosis of liver
failure (22%)
Cryptogenic cirrhosis
Focal nodular hyperplasia
Hemochromatosis
Subacute failure
BuddChiari syndromea
Solitary hepatocellular cancer
BuddChiari syndrome,b
HEHE
HAS
HAS
a
15
5
1
1
1
1
1
1
3
2
1
1
Figure 26.6 CT-scan of HAS showing a diffuse nodular infiltration of the liver.
(A)
(B)
(C)
Figure 26.7 HAS. Macroscopy showing a diffuse spongy tumoral mass (A); microscopy showing the development of cavitary space (B) because of the sinusoidal
progressive growing of tumoral cells destroying the liver cell plates (C). Source: J. Rahier, Dept. of Pathology.
238
Survival function
1.0
Cum survival
0.8
0.6
conclusion
0.4
0.2
0.0
0
10
15
Postoperative months
20
25
Figure 26.8 Overall patient survival of HAS after liver transplantation in the
ELITAELTR study.
(A)
(B)
Figure 26.9 Microscopic features of NRH on a HE section (A) and reticulin stain (B). Source: C. Sempoux, Dept. of Pathology.
239
appendix
Recommended grading of categories of evidence
Ia:
Ib:
IIa:
IIb:
III:
IV:
240
references
1. Lerut JP, Orlando G, Adam R, et al. The place of liver transplantation in
the treatment of hepatic epitheloid hemangioendothelioma: report of the
European liver transplant registry. Ann Surg 2007; 246: 94957.
2. Ishak K, Goodman Z, Stocker J. Tumors of the liver and intrahepatic bile
ducts. Atlas of Tumor Pathology. Third series, fascicle 31 edn. Washington:
Armed Forces Institute of Pathology, 1999: 282307.
3. Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature
with emphasis on the surgical therapy. Cancer 2006; 107: 210821.
4. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma
of the liver: a clinicopathologic study of 137 cases. Cancer 1999; 85: 56282.
5. Demetris AJ, Minervini M, Raikow RB, et al. Hepatic epithelioid haemangioendothelioma biological questions based on pattern of recurrence in an
allograft and tumor immunophenotype. Am J Surg Pathol 1997; 21: 26370.
6. Lerut JP, Orlando G, Sempoux C, et al. Hepatic haemangioendothelioma
in adults: excellent outcome following liver transplantation. Transpl Int
2004; 17: 20207.
7. Nguyen BD. Epithelioid haemangioendothelioma of the liver with F-18
FDG PET imaging. Clin Nucl Med 2004; 29: 82830.
8. Lin E, Agoff N. Recurrent hepatic epithelioid hemangioendothelioma:
detection by FDG PET/CT. Clin Nucl Med. 2007; 32: 94951.
9. Madariaga JR, Marino IR, Karavia DD, et al. Long-term results after liver
transplantation for primary hepatic epithelioid haemangioendothelioma.
Ann Surg Oncol 1995; 2: 48387.
10. Kelleher MB, Iwatsuki S, Sheahan Dg. Epitheloid haemangioendothelioma of the liver. Clinicopathological correlation of 10 cases treated by
orthotopic liver transplantation. Am J Surg Pathol 1988; 89: 9991008.
11. Rodriguez JA, Becker NS, OMahony CA, Goss JA, Aloia TA. Long-term
outcomes following liver transplantation for hepatic hemangioendothelioma: the UNOS experience from 1987 to 2005. J Gastrointest Surg 2008;
12: 1106.
12. Kayler LK, Merion RM, Arenas JD, et al. Epithelioid hemangioendothelioma of the liver disseminated to the peritoneum treated with liver transplantation and interferon alpha-2B. Transplantation 2002; 74: 12830.
13. Theurillat JP, Vavricka SR, Went P, et al. Morphologic changes and altered
gene expression in an epithelioid hemangioendothelioma during a tenyear course of disease. Pathol Res Pract 2003; 199: 16570.
14. Calabr L, Di Giacomo AM, Altomonte M, et al. Primary hepatic epithelioid hemangioendothelioma progressively responsive to interferonalpha: is there room for novel anti-angiogenetic treatments? J Exp Clin
Cancer Res 2007; 26: 14550.
15. Miller MA, Sandler AD. Elevated plasma vascular endothelial growth factor levels in 2 patients with hemangioendothelioma. J Pediatr Surg 2005;
40: 179.
16. Lopez-Terrada DL, Finegold MJ. Liver tumors. In: Walker AW, Durie PR,
Hamilton JR, Walker-Smith JA, Watkins J, eds. Pediatric Gastrointestinal
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17. Selby DM, Stocker J Th, Waclawiw MA, et al. Infantile hemangioendothelioma of the liver. Hepatology 1994; 20: 3945.
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malformation with associated capillary proliferation. Hum Pathol 2004;
35: 2009.
20. Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg 2007; 42: 628.
21. Maluf D, Cotterell A, Clark B, et al. Hepatic angiosarcoma and liver transplantation: case report and literature review. Transplant Proc 2005; 37:
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22. Saleh HA, Tao LC. Hepatic angiosarcoma:aspiration biopsy cytology and
immunocytochemical contribution. Diagn Cytopathol 1998; 18: 20811.
23. Husted TL, Neff G, Thomas MJ, Gross TG, et al. Liver transplantation for
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24. Weitz J, Klimstra DS, Cymes K, et al. Management of primary liver sarcomas. Cancer 2007; 109: 13916.
241
27
introduction
While practicing in Hong Kong in 1930, Digby drew attention
to a condition which was subsequently known as recurrent
pyogenic cholangitis by reporting on eight cases of common
duct stones of liver origin (1). The term Recurrent Pyogenic
Cholangitis (RPC) was used by Cook et al. in 1954 when they
reported their experience with the condition in a series of
90 patients (2). The synonyms associated with this condition
include Asiatic cholangiohepatitis, oriental cholangiohepatitis,
Hong Kong Disease (3), Chinese biliary obstruction syndrome (4), and primary cholangitis (5). This condition is
commonly seen in Chinese living in Canton and Hong Kong
but is not restricted to the Chinese in the Orient since it also
occurs in Chinese immigrants in Malaysia, Singapore, North
America, and Australia (68). RPC is also common in Japanese
in Japan and Taiwanese in Taiwan. Although rare, RPC has also
been reported to afflict occidentals (9,10).
pathogenesis
In RPC the gallstones found within the biliary system are calcium bilirubinate stones or pigmented calcium stones. Calcium bilirubinate stones are prevalent in Asia and are very rare
in Europe and the United States. In addition to the presence of
these friable concretions of various shapes and sizes within the
biliary tree, the bile is often muddy in consistency and contains
numerous fine particles of calcium bilirubinate. Biochemical
analysis of these stones revealed a bilirubin content of 40.2%
to 57.1% and a cholesterol content of 2.9% to 25.6%. This differs greatly from cholesterol stones, which are common in
Europe and the United States, which contain >96% of
cholesterol in pure cholesterol stone, and >71.3% in mixed
cholesterol stone but the bilirubin content is only 0.02% to
5.0% (11). The peculiarity of the formation of calcium bilirubinate stones in RPC has been ascribed to the high incidence
of bile being infected with Escherichia coli (E. coli). In man, the
major portion of bilirubin is excreted in bile as bilirubin glucuronide. In the presence of -glucuronidase, bilirubin glucuronide is hydrolyzed into free bilirubin and glucuronic acid.
Normally, calcium is secreted into bile and when it combines
with the carboxyl radical of free bilirubin, insoluble calcium
bilirubinate is formed. Normal bile is free of -glucuronidase
activity, whereas bile infected with E. coli has intense
-glucuronidase activity. Bile calcium content increases in the
presence of biliary tract inflammation and this coupled with
the increased hydrolysis of bilirubin glucuronide by the
-glucuronidase from E. coli gives rise to the multiple stones
formation classically seen in RPC (11). There are two types of
pigmented stones, black, and brown. The infected type seen in
RPC is the brown pigment stone.
The postulated port of entry for the micro-organisms of
bowel origin is via the portal vein from an attack of enteric
242
(A)
(B)
Figure 27.1 (A) Magnified view of Clonorchis sinensis (12.5). (B) Numerous Clonorchis removed from the CBD of one patient.
pathology
Macroscopically, due to the repeated attacks of biliary sepsis, it
is common to find adhesions between the liver surface and the
surrounding parietal peritoneum, especially the diaphragmatic surface, at operation. The liver surface is scarred and
prominent dilated ducts may be obvious. The affected lobe of
the liver, usually the left, is normally atrophic with compensatory hypertrophy of the remaining lobe. On palpation, the
stones within the dilated biliary ducts are easily palpable.
Occasionally, the underlying lobe can be so destroyed by the
repeated attacks of cholangiohepatitis that what remains is a
cavernous biliary sac with minimal surrounding liver parenchyma (Fig. 27.2). Within the sac is a soup of biliary mud and
stones. The brown pigment stones are soft stones which crumble when squeezed between fingers or forceps. The size variation goes from fine grains to stones of 4 to 5cm in diameter.
The stones are irregular, can take up the shape of the biliary
duct or become faceted when the stones are packed (Fig. 27.3).
Apart from the stones, the bile duct is filled with biliary mud.
This is a broth of mucus, altered bile products, microcalculi,
desquamated epithelium, parasites, and pus.
The pathological hallmark of RPC is the steadily progressive,
recurrent cholangiohepatitis with periportal fibrosis. Histologically, in the early acute stage of an attack of cholangiohepatitis, it is similar to that of bacterial cholangitis associated
with cholecystitis and calculus obstruction seen in the Western
world (16), while the histological picture of the acute, chronic,
and advanced stage of the disease is not dissimilar to that seen
in sclerosing cholangitis (17). In the early lesions the lumen of
the small biliary ducts is filled with pus, with rapid extension
into the surrounding tissue. There is marked dissociation of
the liver cells by polymorphonuclear infiltration of the sinusoids together with Kupffer cell hyperplasia. In the lobules
around the affected duct there is a varying degree of cellular
necrosis. Resolution of the underlying inflammation leads to
dense round-cell infiltration, which is then replaced by fibrous
tissue. In the larger intrahepatic ducts, the duct wall becomes
inflamed, ulcerated, and destroyed together with the formation of cholangitic abscesses. Resolution results in intense
fibrosis which accounts for the undue prominence of the duct
wall seen on sectioning a liver affected by RPC. During the
acute episode, these larger ducts can become irregular in caliber and short segments of relative stricture can occur at intervals along the duct. The duct proximal to the stenosis dilates.
243
Figure 27.2 A totally destroyed left liver lobe consisting of a cavernous biliary
sac with negligible liver parenchymal tissue (f = falciform ligament).
Recurrent attacks of infection and resolution lead to permanent damage of the duct wall and the ducts remain dilated. The
relative stricture then becomes a true localized stricture. These
strictures are most frequently encountered at the site of ductal
confluence. One of the main concerns of these inflammatory
strictures is malignant transformation into cholangiocarcinoma. Ohta et al., from their autopsy studies, suggested that
repeated inflammatory damage to the ductal epithelium from
the attacks of cholangitis can lead to atypical epithelial hyperplasia, dysplasia, and eventually cholangiocarcinoma (18).
The left lobe of the liver is preferentially affected. The exact
reason for this is unknown. One possible explanation may be
the selective distribution of portal blood within the liver. Two
studies suggested that the left lobe of the liver receives blood
from the colon and the left lobe will be the first port of call for
enteric organisms such as E. coli which have entered the portal
venous system (19,20). Colonization of the bile with E. coli will
lead to the production of -glucuronidase in the biliary system. Another explanation is that the more oblique course of
the left hepatic duct results in poorer drainage of the left ductal
system as compared to the right hepatic duct, thus leading to
increased incidence of stone formation. If stones are found
in the right hepatic duct, almost invariably stones are found in
the left duct. In one study of 115 patients with hepatolithiasis,
the ratio of stones found in the left and right hepatic ducts was
6:1 (5). The stones form in the dilated ducts proximal to the
stricture site. These strictures can be multiple and bilobar in
distribution and commonly occur at the origin of the right
and left hepatic ducts. Stones within the common bile duct are
usually lodged at the supraduodenal portion of the duct or at
the ampulla. At ERCP, a patulous ampulla of Vater (probably a
result of repeated passage of stones) is not an uncommon
finding in patients with RPC.
The bile in patients with hepatolithiasis is usually infected
with enteric organisms. The two most common organisms isolated are E. coli and Klebsiella species. The overall positive bile
culture rate has been reported to be as high as 87% and the
incidence of positive culture in patients requiring surgical
244
Figure 27.3 Large number of pigment stones removed from one patient
with RPC.
clinical presentation
Patients with RPC tend to be younger (third and fourth
decade) than those affected by cholesterol stone disease, which
is much more prevalent in older women, in the Western world.
Although the condition does not have particular sex prevalence, those afflicted are almost invariably from the lower
socio-economic classes. The usual presentation consists of the
classical Charcots triad of abdominal pain, fever (with or
without chills and rigors), and jaundice which signifies an
attack of cholangitis. The patient may not notice the jaundice
but a history of tea-colored urine is usual. The jaundice is usually not severe since cholangitis secondary to a completely
obstructed biliary system will rapidly progress to acute suppurative obstructive cholangitis with septicemia. In addition
to the triad of symptoms, these patients also develop mental
confusion and shock, which is referred to as Reynauds pentad.
The epigastric or right upper quadrant pain is usually described
as a constant and gnawing or cutting (12) pain, which may
radiate to the back. Vomiting is not a constant feature. Patients
have spiking fever, not unlike that seen with an underlying
abscess or collection, which normally resolves rapidly when
the conservative treatment has been effective.
On examination, the patient looks unwell and restless with
a tinge of jaundice. The associated jaundice is typically mild
and clinically can be just discernible. Abdominal examination
may reveal the telltale signs of surgical scars from previous
investigations
Both the hematological and biochemical tests do not differentiate patients with RPC from those with other causes of biliary
obstruction and infection. Full blood count will reveal an
underlying leucocytosis with neutrophilia and mild thrombocytopenia in some patients. A number of patients will also
have a concomitant mild derangement of the clotting profile
with a prolonged prothrombin time. The deranged liver function test is compatible with an obstructive picture with a moderately raised level of bilirubin and a high serum alkaline
phosphatase level. The level of -glutamyltranspeptidase is
elevated. The slightly elevated alanine transaminase level in
some patients is a reflection of the parenchymal damage secondary to the underlying infection within the biliary system.
Other than showing the presence of pneumobilia, in some
cases a plain abdominal radiograph is not helpful. The calcium
bilirubinate stones are radiolucent because of the low calcium
and high bilirubin content. The least expensive and most helpful investigation is ultrasonography (USG). It can demonstrate
the presence of stones within the dilated intrahepatic and
common bile ducts, the presence or absence of an underlying
liver abscess and occasionally the presence of a solid liver mass
secondary to malignancy complicating a benign stricture. Also
it can reveal the presence or absence of gallstone(s) within the
gallbladder. Intra- and extrahepatic ductal stones are present
in the majority of patients, but cholelithiasis is much less common and is seen in the minority cases. Although intrahepatic
stones normally cast sonic shadows on USG, the presence of
air within the bile ducts (either spontaneously or secondary to
previous biliary drainage procedures) can give rise to highly
reflective echoes with posterior shadows, thus confusing and
misleading the radiologist in diagnosing the presence of stones
within the bile ducts. In about 3% of RPC, pneumobilia is
present (22). In some cases the amorphous and small stones
can form a cast of the biliary tree and, under such circumstances, highly reflective echoes and posterior acoustic shadowing on USG may be absent. It may then be difficult to
identify dilated bile ducts and the ducts can appear as soft tissue masses on USG (7).
USG images and its interpretations are operator dependent.
Computed tomography (CT) removes this bias and can provide images of the dilated intra- and extrahepatic ducts, even
if they are filled with sludge or pus. On CT scanning these
245
acute management
Figure 27.4 Typical truncated biliary tree appearance together with the arrow
or spear head sign (arrow) on ERCP. A large stone(s) in the left duct.
Figure 27.5 MR Cholangiogram demonstrating a stricture (arrow) at the confluence of the right and left hepatic ducts.
246
definitive management
The definitive management of RPC is to use a multidisciplinary approach (31), aiming to remove all biliary stones, to
247
(A)
(B)
(C)
Figure 27.6 (A) ERCP demonstrating the presence of stones proximal to a relative stricture (arrow) in the left hepatic duct, (B) the stricture is dilated with a balloon prior to stone retrieval, and (C) the dilated left duct is cleared of stones.
definitive surgery
Since RPC can and does affect the biliary tract at different sites
with varying degrees of severity, the aim of the surgery is to
provide adequate biliary drainage for bile and debris. This
encompasses stone extraction, stricturoplasty or excision of
248
stricture, resecting non-functioning liver segments and creating a bilioenteric bypass with a permanent percutaneous
access loop to the biliary tract to allow subsequent access to the
biliary system for stone extraction and dilatation of stricture(s).
Before embarking on definitive surgery, it is mandatory to
have a complete knowledge of the location of calculi and
stricture(s), and the uni- or bilobar extent of disease with or
without concomitant liver atrophy.
In the presence of predominantly extrahepatic disease, simple exploration of the common bile duct with intraoperative
choledochoscopy will suffice. In the absence of extrahepatic
ductal stricture, the incisions used for the exploration of the
CBD and hepatic ducts will depend on the location of the
stones (Fig. 27.7AD). We routinely remove the gallbladder in
these patients since, histologically, it shows underlying evidence of low grade inflammation. Furthermore, if the sphincter of Oddi has been previously destroyed, the gallbladder will
permanently be in a collapsed state. The placement of a large
T-tube following the exploration will allow post-operative
imaging of the biliary tracts and any residual stones found can
(A)
(B)
(C)
(D)
Figure 27.7 (A) Longitudinal incision for the exploration of CBD only,
(B) separate incisions for exploration of the CBD and the hepatic ducts, (C)
incision for the combined exploration of the CBD and one of the hepatic
ducts (left side is shown), (D) horizontal incision over the hepaticojejunostomy (---- = incision).
stones from the intrahepatic ducts. Once the effluent is relatively clear, a repeat choledochoscopy is performed. Any residual stones can be retrieved with a dormia basket. Segmental
ductal stricture is dilated prior to stone retrieval. Any impacted
or large stones can be shattered with the electrohydraulic lithotripter introduced through the working channel of the flexible choledochoscope. It is not always possible to clear the
intrahepatic ducts of stones completely. Once the large stones
and strictures are dealt with, small stones or fragments can be
left to fall out, provided an adequate biliary drainage procedure has been performed.
The thick, dilated CBD/CHD with an inelastic wall behaves
more like a cavernous sac which does not drain adequately,
even in the presence of a sphinteroplasty. Although it is reasonable to perform a supraduodenal choledochoduodenostomy as a biliary drainage procedure, this has the disadvantage
that patients may develop sump syndrome, developing
symptoms of pain and fever, which is thought to be a result of
debris being lodged in the diseased distal CBD. While the
sump syndrome can be treated by performing an endoscopic
sphincterotomy, supraduodenal choledochoduodenostomy is
contra-indicated in the presence of a proximal biliary tract
stricture or when the CBD is not wide enough. Under such
circumstances, we routinely perform an end-to-side hepaticojejunostomy with a retrocolic Roux-en-Y loop. This provides a
widely patent anastomosis for biliary drainage and for small
stones to fall freely into the loop of bowel. Furthermore, the
closed end of the Roux loop can provide a permanent access
route to the biliary tract.
With the hepaticojejunostomy it is crucial that the access
loop is short and has a straight course from the anterolateral
abdominal wall to the anastomosis. A poorly constructed jejunal loop with redundant length makes subsequent choledochoscopy and access to the intrahepatic ducts difficult. The
access loop can either be placed intraperitoneally, to be
accessed percutaneously under ultrasound guidance, or it can
be placed under the skin as a hepaticocutaneous jejunostomy.
We prefer to leave the loop intraperitoneally. In those cases
where immediate access to the biliary tract is not necessary,
the end of the loop is tacked to the peritoneal surface of the
anterolateral abdominal wall with catgut. The staples from the
GIA stapler used to transect the jejunum during Roux loop
formation or the ligaclips placed around the blind end of the
loop at the end of the operation allow the interventional radiologist subsequently to identify and access the loop percutaneously. Once the loop is punctured, the tract can be gradually
dilated to admit a twin channel choledochoscope for endoscopic manipulation (15). For those cases where access to the
biliary tract is required soon after the operation, a 24 Fr catheter is introduced through the anterolateral abdominal wall
into the access loop at the end of the operation. The tract is
allowed to mature for 4 to 6 weeks before instrumentation.
Hepaticocutaneous jejunostomy has been used by others (36).
Although the biliary tract can be accessed sooner through the
cutaneous stoma compared to our technique, the cutaneous
stoma is not without its complication. Fifteen percent of
patients with hepaticocutaneous jejunostomy, performed
either with the cutaneous stoma formed at the initial operation
249
250
complications
In RPC the biliary mud and stones within the common bile
duct can lead to acute pancreatitis. In 1971, Ong et al. reported
that approximately half of all patients with acute pancreatitis,
in Hong Kong, were associated with RPC (41). Another report
claims that about 20% of RPC patients had high serum amylase levels but were clinically asymptomatic (42). In some
patients, the big common bile duct stones can lead to the formation of a choledochoduodenal fistula.
Liver abscesses complicating RPC can present with rupture
into the peritoneal cavity or adjacent viscera. A left lobe liver
abscess can rupture into the pericardial cavity and cause cardiac tamponade (43), while a right lobe abscess can lead to the
formation of a pleurobiliary or bronchobiliary fistula (44). A
chronic abscess can, on clinical and radiological grounds, be
indistinguishable from an underlying cholangiocarcinoma.
The final diagnosis can only be certain after histological examination of the resected specimen.
Cholangiocarcinoma complicating RPC has been reported.
The higher incidence of cholangiocarcinoma in areas where
RPC is also prevalent has been attributed to the presence of
Clonorchis sinensis infestation (45). In a necropsy study of 50
cases of cholangiocarcinoma, 92% of the cases were associated
with clonorchiasis and intrahepatic stones were found in 20%
of the cases (45). In a huge series of 1105 cases of hepatolithiasis studied over the period 1978 to 1990, Chen et al. (46)
reported that the incidence of cholangiocarcinoma in these
patients increased from 2.4% (between 1978 and 1987) to
13.7% (between 1988 and 1990), despite a decreasing incidence of clonorchiasis in the population.
Thrombophlebitis of the branches of the portal vein due to
the underlying periductal inflammation can lead to portal
venous thrombosis with an enlarged spleen (6). Occasionally,
septic emboli to the pulmonary tree can lead to the development of lung abscesses and significant pulmonary hypertension (6,47).
Despite multiple operations, RPC patients with long-standing severe disease can develop secondary biliary cirrhosis and
liver failure (48). When cirrhosis sets in, portal hypertension
and bleeding esophageal varices ensue, thus making further
corrective surgery for the underlying stricture(s) more hazardous. In these patients the only available option is liver
transplantation.
conclusions
As the name implies, RPC runs a recurrent and unrelenting
course with variable frequencies of attacks of cholangitis.
Medical therapy is ineffective and surgical treatment is not
entirely satisfactory. Despite surgery, stones and strictures can
return. In Hong Kong and Taiwan, the peak age incidence of
RPC has changed over the years from the third to the fifth
decade in the 1950s and 1970s to the seventh decade in the
early 1990s (49). This is due to an increasing proportion of
patients who have survived previous surgery, only to have RPC
recur again in later life. In Hong Kong, young patients in their
third and fourth decade of life who present to us with RPC are
invariably immigrants from mainland China. RPC is a dying
disease in Hong Kong, but is still common in China. Although
there are various theories on the pathogenesis of RPC, we
believe the condition is closely linked to the level of social and
economic conditions of a community. Surgery merely deals
with the consequences of the condition, but does not address
its roots. With better living conditions and public hygiene,
perhaps RPC can be eradicated in this millennium. Until then,
a judicious choice of a mixture of treatment, both medical and
surgical, is necessary to achieve a satisfactory and long-lasting
solution to a recurrent inflammatory condition.
key points
references
1. Digby KH. Common-duct stones of liver origin. Br J Surg 1930; 17: 57891.
2. Cook J, Hou PC, Ho HC, et al. Recurrent pyogenic cholangitis. Br J Surg
1954; 42: 188203.
3. Mage S, Morel AS. Surgical experience with cholangiohepatitis (Hong
Kong Disease) in Canton Chinese. Ann Surg 1965; 162: 18790.
4. Harrison-Levy A. The biliary obstruction syndrome of the Chinese. Br J
Surg 1962; 49: 67485.
5. Choi TK, Wong J, Ong GB. The surgical management of primary intrahepatic stones. Br J Surg 1982; 69: 8690.
6. Chou ST, Chan CW. Recurrent pyogenic cholangitis: a necropsy study.
Pathology 1980; 12: 41528.
7. Federle MP, Cello JP, Laing FC, et al. Recurrent pyogenic cholangitis in
Asian immigrants. Use of ultrasonography, computed tomography, and
cholangiography. Radiology 1982; 143: 1516.
8. Lam SK. A study of endoscopic sphincterotomy in recurrent pyogenic
cholangitis. Br J Surg 1984; 71: 2626.
251
252
28
introduction
Hepatic abscess is an uncommon disorder that continues to be a
challenge to identify and treat. The three major types of hepatic
abscesses are (i) pyogenic, most often polymicrobial, due to
aerobic and anaerobic bacteria, (ii) amebic, due to Entamoeba
histolytica, and (iii) fungal, principally due to Candida species.
Pyogenic hepatic abscesses are seen most commonly in temperate climates, and in the United States they account for approximately 80% of the cases. Amebic abscesses account for about
10% of U.S. patients but are relatively more common in semitropical and tropical climates (1). Fungal abscesses are seen in
10% of U.S. cases and are increasing in frequency secondary to
more immunocompromised patients as well as those having
invasive hepatic procedures with prolonged antibiotic exposure (2,3). This chapter focuses on the pathogens, diagnosis, and
current management of liver abscesses.
amebic abscess
Amebic liver abscess was not recognized as a separate entity
until the nineteenth century. Several European investigators
had suggested a relationship between dysentery and liver
abscess; however, in 1875 Feder Losch discovered that
Entamoeba histolytica was the causal agent. In 1890, Sir William
Osler described the first North American case of amebic liver
abscess when he found amoeba in a patients liver and stool
sample (4). Open surgical drainage was the treatment of choice
of amebic abscess until the 1930s, when aspiration and emetine
became the standard of therapy. During this time, mortality
decreased remarkedly from 57% to 14% by using therapeutic
aspiration combined with amebicidal therapy (5). Further
advancement in management happened with the introduction
of serologic tests, improved radiologic imaging, and new
amebicidal agents.
Epidemiology
Amebiasis is a widespread parasitic disease that affects people
in developed and underdeveloped countries in tropical climates. Mexico, India, East and South Africa as well as Central
and South America have the highest epidemic activity of
E. histolytica (6). Worldwide, an estimated 500 million people
are carriers of E. histolytica, and 50 million people worldwide
develop amebic colitis or amebic liver abscesses resulting in
50,000 to 100,000 deaths each year (7). High-risk groups in the
United States include immigrants, tourists who travel to
endemic areas, institutionalized people, and the homosexual
population. Amebic liver abscess is much more common in
men, with a male to female ratio of 10:1. Low socio-economic
status and unsanitary conditions are significant risk factors.
Other associated risk factors include patients with heavy alcohol consumption, impaired immunity, malnutrition, and
chronic infections (8).
Pathogenesis
Infection occurs after fecaloral transmission of E. histolytica,
which exists in either an immobile cyst form or the invasive trophozoite form. The main sources of infection are from asymptomatic carriers who transmit the cysts from water to vegetables
contaminated with feces, food contaminated by fertilizers, or
the hands of infected food handlers (9). The cystic form is swallowed and passes unaffected through the stomach into the intestine where the outer cyst wall is then digested by pancreatic
enzymes. The trophozoite form is released into the intestine
where it lives and multiplies. In most patients, the trophozoite
asymptomatically colonizes the intestine, but some patients may
develop amebic dysentery. The trophozoite invades through the
intestinal mucosa, enters the mesenteric venules and lymphatics, travels to hepatic venules by the portal vein, and aggregates
in the liver parenchyma (7). Accumulation of enough trophozoites leads to thrombosis, and necrosis and formation of an
abscess. The outer rim of the abscess wall is infested by E. histolytica. The liquefied hepatic parenchyma has the appearance of
anchovy paste (10). More than 80% of patients with amebic
liver abscess have excess alcohol intake and thus a vulnerable
liver to Entamoeba (11). Higher rates of tissue invasion are
found in patients with Human Immunodeficiency Virus (HIV),
splenectomy, and corticosteroid administration.
Diagnosis
The clinical presentation of amebic liver abscess is significantly
different from pyogenic (Table 28.1). More than 90% of cases
occur in men who usually live in or have a travel history to an
endemic area in the last 2 to 5 months (5). Typical symptoms
include fever, chills, anorexia, right upper quadrant pain,
abdominal tenderness, and hepatomegaly with point tenderness over the liver or subcostal region. Diaphragmatic involvement causes right-sided pleural pain or pain referred to the
shoulder (12). Patients with amebic liver abscess rarely have
concurrent amebic dysentery, but 10% to 35% of patients have
gastrointestinal symptoms that include nausea, vomiting,
abdominal cramping, or distention (12). Jaundice, septic
shock or a palpable mass may rarely be seen.
Patients with an amebic liver abscess usually have a mild leukocytosis without eosinophilia (8). Mild anemia with moderate elevation of alkaline phosphatase and other liver function
tests also may be present. The most common abnormality is an
increased prothrombin time (12,13). Young males who are
alcoholics may have normal or increased hemoglobin. If concurrent colitis is present, the wet mount prep will contain trophozoites 70% of the time if three separate stool samples are
examined (11). If the patient has no colitis and a solitary liver
abscess, stool samples are positive in 40% to 50% of cases (6).
The definitive diagnosis of amebic liver abscess is by the
detection of E. histolytica trophozoites in the abscess and by
253
that is highly effective against both intestinal and extraintestinal infection. The standard dose is 500 mg IV q6 hr
with oral administration of 750 mg q8 hr for a total of 7 to
10 days (6). Most patients have rapid clinical improvement
in 72 hours, and 90% are cured with metronidazole.
Patients who have a persistent abscess and do not respond
to metronidazole within 5 days may require the addition of
chloroquine (17). Approximately 10% of patients have a
recurrence of their abscesses if the intestinal colonization is
not treated (18).
The majority of patients do not require percutaneous aspiration of the amebic abscess because they respond to amebicidal therapy. Blessmann and colleagues reported that
therapeutic aspiration had minor benefit and was insufficient
to justify routine needle aspirations (19). A 2009 Cochrane
Review also found that simple aspiration of uncomplicated
amebic liver abscesses did not help patients (20). However,
simple aspiration may be beneficial in patients with failure to
respond to drug therapy within 5 to 7 days. Aspiration should
also be considered in patients with abscesses greater than
5 cm in size because of the risk of rupture or in patients with
abscesses in the left hepatic lobe that have increased frequency
of peritoneal leak or rupture into the pericardium and a
higher mortality (Fig. 28.1) (21). Aspiration may be indicated
if a pyogenic cause needs to be ruled out or for treatment of
pulmonary, peritoneal, and pericardial complications. The
procedure can be performed safely with US- or CT-guided
aspiration. The fluid of an amebic abscess is odorless, and
Gram stain and cultures are negative. Amoeba are recovered
254
Amebic abscess
Pyogenic abscess
2040 years
>10:1
1 in 80%
Yes
>50 years
1:1
1 in 50%
No
Uncommon
Common
Uncommon
Uncommon
Common
Common
Uncommon
Common
Common
Common
Common
Common
Uncommon
Uncommon
Common
Common
Uncommon
Common
No
Yes
Yes
No
1
2
8
9
4
7
5
Figure 28.1 Paths of extension of amebic liver abscesses located within (A) the
right hepatic (labels 17) and (B) the left hepatic lobe (8,9).
Epidemiology
Pyogenic liver abscess is the most common form of liver
abscess accounting for approximately 80% of all liver abscesses
in the United States (1). The disease process has significantly
increased over the past 30 years, presenting in about 15 cases
per 100,000 admissions. Seeto and Rocky reported an incidence
nearly double that of earlier reports (22 per 100,000) due to a
more aggressive management approach to hepatobiliary and
pancreatic diseases (27). The predominant etiology of pyogenic liver abscess has changed from an intra-abdominal septic source to a biliary origin with more reports of cryptogenic
liver abscesses in recent years. Advanced imaging techniques,
improved antibiotics, and numerous treatment modalities
have decreased morbidity and mortality.
Pathogenesis
The liver is a sterile organ that has Kupffer cells that filter out
microorganisms. Abscesses form when the normal liver fails to
clear the organisms, and the infection causes parenchymal
necrosis. Potential sources of these microorganisms are (i)
biliary, secondary to ascending cholangitis or biliary malignancy, (ii) portal, pyemia secondary to appendicitis, diverticulitis, or other intra-abdominal source, (iii) arterial, from
generalized septicemia, (iv) direct extension, (v) trauma, and
(vi) cryptogenic (Table 28.2).
Ascending infection of the biliary tree causing obstruction
now accounts for 35% to 40% of all pyogenic liver abscesses (1).
The etiology of the biliary obstruction has some geographic
differences. In Western countries, 40% of pyogenic liver
abscesses have underlying malignant disease (28). In Asian
countries, hepatolithiasis and associated biliary strictures
predominate as the cause of pyogenic liver abscess (29).
Percutaneous or endoscopic manipulation or stenting can
introduce infection into the biliary tree causing cholangitis,
which has the propensity to cause pyogenic liver abscess. Other
causes include Carolis disease, invasion of the biliary tree by
parasites and/or a previous biliary-enteric anastomosis.
In the past, the most common source of pyogenic liver abscess
was appendicitis. In Ochsners study, appendicitis accounted for
43% of all abscesses seeded via the portal vein (23). Today, even
though intestinal pathology is responsible for 20% of all pyogenic liver abscesses, appendicitis accounts for only 2% of all
pyogenic liver abscesses. Diverticulitis and perforated colon
cancers remain more common causes of pyogenic liver abscesses.
Hematogenous spread of infection from sources like endocarditis, dental abscess, and intravenous drug abuse are examples of generalized septicemia that may lead to a pyogenic liver
abscess. Transarterial embolization or ablative therapies for
liver tumors are also associated with liver abscess formation
(30,31). Direct extension of empyema of the gallbladder, perforated gastric or duodenal ulcers, and subphrenic abscess also
may cause a pyogenic liver abscess.
Liver trauma from penetrating or blunt injury may cause
parenchymal necrosis, hemorrhage, or intrahepatic biloma that
may become infected and develop into pyogenic liver abscess
(32). Hepatic artery thrombosis after liver transplantation or
ligation after a pancreatobiliary operation may lead to a liver
abscess especially following obstructive jaundice. In some
255
256
Streptococci viridians. An abscess secondary to biliary tract disease or originating from a gastrointestinal source is more likely
to be polymicrobial with aerobic and anaerobic organisms.
Bacteroides is the most common isolated anaerobic organism,
followed by Fusobacterium (10). The increased use of indwelling biliary stents has resulted in an increased incidence of
Klebsiella, streptococcal, staphylococcal, and pseudomonal
species in liver abscesses (28). Fifteen percent of patients have
a negative culture that may be attributed to poor anaerobic
culture technique or the use of broad-spectrum antibiotics
prior to abscess drainage. This factor also is thought to be
responsible for the increased incidence of fungal abscesses (6).
In patients with Acquired Immune Deficiency Syndrome
(AIDS) the most common infecting organism for hepatic
abscesses is Mycobacterium tuberculosis (36).
Diagnosis
The clinical presentation of pyogenic liver abscess is nonspecific and includes malaise, nausea, anorexia, weight loss,
headaches, and myalgias. These symptoms may be present for
many weeks before the appearance of more specific symptoms
such as fever, chills and abdominal pain in the right upper
quadrant (RUQ) (Table 28.1). The classic triad of fever, jaundice, and RUQ tenderness is present in less than 10% patients.
Diarrhea also occurs in 10% of patients (37). On physical
examination, some patients may also have a tender and enlarged
abdomen. Abscesses adjacent to the diaphragm may cause
pleuritic chest pain, cough, and dyspnea. Septic shock may be
present in patients with cholangitis or peritonitis after rupture
into the peritoneal cavity. Laboratory investigations demonstrate leukocytosis (70% to 90%), hyperbilirubinemia (50% to
67%), and elevated alkaline phosphatase (80%) in a majority of
patients. Many patients may also have anemia, hypoalbuminemia, and prolonged prothrombin time (34,37,38). Patients
with pyogenic abscesses are also more likely than those with an
amebic abscess to have diabetes mellitus.
Table 28.3 Spectrum of Microorganisms That Cause
Pyogenic Liver Abscess
Gram-positive aerobes
Streptococcus milleri
Staphylococcus aureus
Enterococcus spp.
Others
Gram-Negative Aerobes
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Proteus spp.
Enterobacter cloacae
Citrobacter freundii
Others
Gram-positive anaerobes
Clostridium spp.
Peptostreptococcus spp.
Gram-negative anaerobes
Bacteroides spp.
Fusobacterium spp.
Treatment
The principles of treatment for liver pyogenic liver abscesses
are to start appropriate antibiotics, drain the pus, and treat the
underlying cause, if identified. Although antibiotics alone may
be curative, these patients have a higher risk of recurrence and
complications such as abscess rupture. Ultrasound and CT
scans have allowed for earlier diagnosis and facilitated treatment by percutaneous aspiration and drainage (Fig. 28.2). The
combination of antibiotic therapy and percutaneous drainage
has become the first line treatment for most pyogenic liver
abscesses (Table 28.4).
Initial antibiotic therapy should be started to cover gramnegative and gram-positive aerobes and anaerobes. Multiple
single antibiotics such as pipacillin/tazobactam, ticarcillin/clavulanate, imipenem/cilastin, or meropenem may be started
initially if a biliary source is suspected. Alternative therapies
including a third-generation cephalosporin or a fluroquinolone
(A)
(B)
(C)
(D)
Figure 28.2 (A) CT demonstrating pyogenic abscess with air/fluid level in segment VI of the liver. (B) CT scan showing residual abscess after initial percutaneous
drainage. (C) Further percutaneous drainage catheters. (D) CT demonstrating resolution of abscess.
257
Diagnosis
Treatment
Amebic
Clinical Suspicion
US or CT scan
Positive amebic serology
Pyogenic
Clinical Suspicion
US or CT scan
Aspiration
Immunocompromised
patient
US or CT scan
Aspiration
Amebicidal therapy
Lumenal agent
Drainage of
complicated
abscess
Systemic antibiotics
Drainage of abscess
Fungal
Systemic antifungal
Drainage of abscess
Systemic antibiotics
for polymicrobial
abscess
258
Ultrasonic
probe
Aerobic
culture
Site of unilocular
abscess
T-extension
Deep multiloculated
abscess
Gallbladder
Loculations
within
abscess
Liver
Anaerobic
culture
Liver
Abscess
(A)
(B)
Figure 28.3 (A) Intra-operative ultrasound, aspiration, and anaerobic culture of abscess, and liver incision for pyogenic abscess. (B) Aerobic culture, manual disruption of loculations, and irrigation of the pyogenic abscess. Source: Reproduced from Ref. (51).
Treatment
Fungal liver abscesses are treated with intravenous antifungal
therapy as well as drainage of the abscess by simple aspiration,
percutaneous drainage or open surgical drainage (Table 28.4).
Caspofungin is the agent of choice for these patients (49,50).
Patients with mixed bacterial and fungal abscesses should also
be treated with appropriate systemic antibiotics for the isolated
bacteria. An adequate course of caspofungin should be employed
as an earlier analysis suggested that inadequate treatment with
amphoteracin B was associated with a high mortality.
Outcomes
Very few patients develop pure fungal abscesses. Most patients
have polymicrobial fungal and bacterial abscesses. The overall
mortality rate is 50% because patients who do not receive antifungal therapy in early stage develop systemic fungemia (12).
In addition, the underlying disease in the majority of these
patients is associated with a high mortality. Moreover, the
majority of these abscesses are multiple. As a result, patient
survival is not influenced by different drainage procedures.
references
1. Pitt HA. Surgical management of hepatic abscess. World J Surg 1990;
14:498504.
2. Simpfendorfer CH, Henderson JM. Hepatic abscess. In: Cameron J, ed.
Current Surgical Therapy, 9th edn. Philadelphia, PA: Elsevier-Mosby,
2008: 31721.
3. Lipsett PA, Huang CJ, Lillemoe KD, et al. Fungal hepatic abscess: characterization and management. J Gastrointestinal Surg 1997; 1:7884.
4. Martinez BM. Historical introduction. In: Martinez-Palomo A, ed. Amebiasis.
Human Parasitic Diseases, Vol. 2. Amsterdam, Holland: Elsevier; 1986: 19.
5. Hughes MA, Petri WA Jr. Amebic liver abscess. Infect Dis Clin N Am 2000;
14: 56582.
6. Wells CD, Aruqedas M. Amebic liver abscess. S Med J 2004; 97: 67382.
7. Santi-Rocca J, Rigothier MC, Guillen N. Host-microbe interactions and
defense mechanisms in the development of amoebic liver abscesses. Clin
Microbiol Rev 2009; 22: 6575.
8. Tanyuksel M, Petri WA. Laboratory diagnosis of amebiasis. Clin Microbiol Rev 2003; 16:71329.
9. Salles JM, Moraes LM, Salles MC. Hepatic amebiasis. Braz J Infect Dis
2003; 7:96110.
10. Leslie DB, Dunn DL. Hepatic abscess. In: Cameron J, ed. Current Surgical
Therapy, 8th edn. Philadelphia, PA: Elsevier Mosby; 2004: 298303.
11. Petri WA Jr, Singh U. Diagnosis and management of amebiasis. Clin Infect
Dis 1999; 29: 111725.
12. Haque R, Huston CD, Hughes M, et al. Current concepts: amebiasis. N
Engl J Med. 2003; 48: 156573.
13. Barnes S, Lillemoe K. Liver abscess and hydatid cyst disease. In: Zinner M,
Schwartz S, Ellis H, Ashley S, McFadden D, ed. Maingots Abdominal
Operations, 10th edn. Stamford, CT: Appleton & Lange; 1997: 151345.
14. Haque R, Mollah NU, Ali IKM, et al. Diagnosis of amebic liver abscess and
intestinal infection with the techLab Entamoeba histolytica II antigen
detection and antibody tests. J Clin Microbiol 2000; 38: 32359.
15. Sepulveda B, Manzo NTG. Clinical manifestations and diagnosis of amebiasis. In: Martinez-Palomeo A, ed. Amebiasis: Human Parasitic Diseases,
No. 2 Amsterdam: Elsevier, 1986; 16987.
16. Stanley SL Jr. Amebiasis. Lancet 2003; 361: 102534.
17. Lodhi S, Sarwari AR, Muzammil M, et al. Features distinguishing amoebic
from pyogenic liver abscess: a review of 577 adult cases. Trop Med Int
Health 2004; 9: 71823.
18. Thomas PG, Ravindra KV. Amebiasis and biliary infection. In: Blumgart
LH, Fong Y, ed. Surgery of the Liver and Biliary Tract, 3rd edn. London:
WB Saunders; 2001: 114765.
19. Blessmann J, Binh HD, Hung DM, et al. Treatment of amebic liver abscess
with metronidazole alone or in combination with ultrasound-guided
needle aspiration: a comparative, prospective and randomized study. Trop
Med Int Health 2003; 8: 10304.
20. Chavez-Tapia NC, Hernandez-Calleros J, Tellez-Avia FI, et al. Imageguided percutaneous procedure plus metronidazole versus metronidazole
alone for uncomplicated amoebic liver abscess (Review). The Cochrane
Library 2009 Issue 2.
259
260
37. Branum GD, Tyson GS, Branum MA, et al. Hepatic abscess: changes in
etiology, diagnosis and management. Ann Surg 1990; 212: 65562.
38. Leslie DB, Dunn DL. Hepatic abscess. In: Cameron J, ed. Current
Surgical Therapy, 8th edn. Philadelphia, PA: Elsevier Mosby 2004;
298303.
39. Saini S. Imaging of the hepatobiliary tract. New Engl J Med 1997;
336:188994.
40. Ng FH, Wong WM, Wong BC, et al. Sequential intravenous/oral antibiotics vs. continuous intravenous antibiotics in the treatment of pyogenic
liver abscess. Aliment Pharmacol Ther 2002; 16: 108390.
41. Lederman ER, Crum NF. Pyogenic liver abscess with a focus in Klebsiella
pneumoniae as a primary pathogen: an emerging disease with unique
clinical characteristics. Am J Gastro 2005; 100: 32231.
42. Matoba M, Tonami H, Kuginuki M, et al. Intermittent hepatic artery
antibiotic infusion for pyogenic hepatic abscess. Acta Radiol 2004; 45:
1317.
43. Giorgio A, Tarantino L, Mariniello N, et al. Pyogenic liver abscess: 13 years
of experience in percutaneous needle aspiration with US guidance. Radiology 1995, 195: 1224.
44. Ch Yu S, Hg Lo R, Kan PS, et al. Single and multiple pyogenic liver abscess:
treatment with needle aspiration. Clin Radiol 1997; 52: 9126.
45. Rajak C, Gupta S, Jain S, et al. Percutaneous treatment of liver abscess:
needle aspiration vs. cathetar drainage. AJR 1998; 170: 10359.
46. Chou FF, Sheen-Chen SM, Chen YS, et al. Single and multiple pyogenic
liver abscesses: clinical course, etiology and results of treatment. World J
Surg 1997, 21: 3849.
47. Lublin M, Bartlett DL, Danforth DN, et al. Hepatic abscesses in patients
with chronic granulomatous disease. Ann Surg 2002; 235: 38391.
48. Christein JD, Kendrick ML, Que FG. What affects mortality after the
operative management of hepatic abscess? HPB 2006; 8:1758.
49. Lai CH, Chen HP, Chen TL. Candidal liver abscesses and cholecystitis in a
37-year-old patient without underlying malignancy. World J Gastro 2005;
11: 17257.
50. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004; 38: 16189.
51. Cameron JL, et al. Liver abscess. In: Atlas of Surgery. Philadelphia, PA: BC
Decker; 1990.
introduction
As diagnostic radiological imaging techniques have improved
and become more widely applied, benign solid lesions of the
liver have become an increasingly common incidental finding.
These lesions are often detected in asymptomatic patients
without significant liver disease and there may be an increasing trend to resect such lesions with the introduction of laparoscopic liver surgery, an issue that remains contentious (13).
Although the etiology of these lesions is not well understood,
benign liver lesions can be classified according to their cellular
origin (Table 29.1).
Benign solid liver lesions can arise from hepatocytes, biliary
epithelium, surrounding mesenchymal structures, or mixtures
thereof. Some of these lesions are sufficiently rare that they can
be regarded as medical curiosities, although they may present
genuine diagnostic and management challenges. A comprehensive understanding of the clinical and pathological features
of benign solid liver lesions will facilitate differential diagnosis
and allow rational management.
The principal issues to be resolved in the management of
this group of patients are
1. Confirmation that the lesion is benign.
2. Determining whether the lesion requires surgical
treatment.
Detailed history addressing relevant risk factors and relevant
clinical examination will guide further investigation. While
commonly asymptomatic, benign liver lesions may present as
surgical emergencies with acute local or systemic symptoms
and signs due to hemorrhage, rupture, vascular thrombosis, or
necrosis. Commonly, patients present with symptoms that are
unrelated to an incidentally detected liver lesion. These
patients frequently require further assessment to exclude an
alternative cause for their symptoms. Particular aspects of the
history may increase the pre-investigation probability of a particular diagnosis, for example, pain, weight lossmalignancy;
known gallstonesbiliary colic; previous cancermetastasis;
primary sclerosing cholangitis or ulcerative colitis
intrahepatic cholangiocarcinoma; oral contraceptive use: adenoma; cirrhosis, viral hepatitis, inborn errors of metabolism:
hepatocellular carcinoma.
While liver biochemistry is usually normal, this finding can
be helpful in supporting the diagnosis of a benign lesion.
Abnormal results may reflect a complication such as hemorrhage, infarction, or the presence of neoplasia. Systemic phenomena, more commonly associated with hepatic malignancies,
are exceptional with benign liver lesions.
Advances in imaging have meant an increasing majority of
benign liver lesions are diagnosed solely on radiological features, particularly in the case of hemangiomata, focal nodular
hyperplasia, and confounding focal fatty change. Percutaneous
biopsy or surgical resection may be helpful in cases of diagnostic uncertainty, symptomatic lesions, or potentially premalignant conditions. Our institutional practice is to reserve biopsy
for non-surgical candidates and only in cases where the biopsy
result will influence subsequent management (recommendation strength: D). The role of percutaneous needle biopsy
remains controversial, potential problems including bleeding
from vascular lesions and a risk of tumor seeding. Needle
biopsy and cytology are also subject to sampling errors which
can lead to misdiagnosis.
Current challenges for clinicians managing this group of
patients include
In a recent clinical database review, surgery for benign disease accounted for 5% of patients undergoing resectional liver
surgery (4). Advances in preoperative assessment, perioperative
care, anesthesia, and surgical technique, including the increasing application of minimally invasive laparoscopic approaches,
have the potential to decrease the morbidity and mortality rates
associated with resectional liver surgery (5,6). A recent European
study reported 87 patients treated laparoscopically with zero
mortality and a low-postoperative complication rate (5%) (7).
These improvements have altered the analysis of clinical risk
versus benefit required when managing a patient with a diagnosis of a solid benign liver lesion but should not increase the
prevalence of unnecessary liver resection.
imaging
Ultrasound (US) is often helpful in confirming an intrahepatic mass and will differentiate most cystic from solid parenchymal lesions. However, axial imaging in the form of
contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) is usually required for adequate lesion characterization. Recently developed MRI
contrast agents (superparamagnetic iron oxide, SPIO; gadobenate dimeglumine, Gd-BOPTA) have improved the ability
to differentiate between solid benign lesions on MRI.
Improvements in these modalities mean that angiography is
261
now less commonly a part of initial patient assessment. Positron emission tomography (PET) is undergoing further evaluation as a diagnostic adjunct and laparoscopy is used
increasingly to allow direct visualization of liver lesions and
can be enhanced by intraoperative US. Nuclear medicine
techniques such as single positron emission computerized
tomography (SPECT) and tagged RBC scans, although less
commonly applied, may facilitate differentiation of hemangioma from hepatocellular carcinoma. 99mTc-sulfur colloid
scanning may help differentiate focal nodular hyperplasia
from hepatocellular adenoma.
hemangioma adult
Hemangiomata are the most common benign solid tumor of
the liver. In terms of focal liver lesions they are second only to
simple cysts in frequency. Autopsy studies have shown a prevalence of up to 20% (8). Adult hemangioma differs in both
presentation and histology from infantile hemangioendothelioma, which is considered elsewhere. An extremely rare adult
262
capillary hemangioma
In comparison to the more common cavernous form, capillary
hemangiomata are generally smaller in size and are more frequently multiple. These smaller lesions are a common incidental finding in an asymptomatic patient. Once the diagnosis is
established, no further treatment is required (recommendation strength: D).
cavernous hemangioma
Pathology
Cavernous hemangiomata occur in up to 8% of autopsy studies. These lesions are the second most common solid hepatic
tumor (10). Cavernous hemangiomata occur principally in
women (F:M = 5:1) and are more common in the right liver.
Large peripheral lesions may become pedunculated. The
mean age at diagnosis is 50 years with most being detected
between the third and fifth decade. Their prevalence is greatest
in those with higher parity (11,12). Although there is no proven
association with oral contraceptive use, the relationship
remains controversial.
Hemangiomata are generally asymptomatic until they reach
diameters of over 10 cm. Symptoms include non-specific
abdominal pain, pressure symptoms, and fever. Pain may be
due to capsular stretching by larger lesions. Jaundice and rupture are rare. Cavernous hemangiomata may reach massive
proportions, with reported lesions reaching several kilograms
in weight. Giant hemangiomata are defined as those measuring
5 cm and above in diameter (13) and are multiple in 10% of
cases (10).
Hepatic cavernous hemangiomata may be associated with
similar lesions in other organs (14). Other associated conditions, for example, liver cysts, gallbladder disease, gastroduodenal ulcers, or hiatus hernia are reported in 42% (15). In the rare
KasabachMeritt syndrome intravascular coagulopathy may
progress to systemic fibrinolysis and thrombocytopenia. The
condition has a reported mortality rate of 20% to 30% (16).
Macroscopically, cavernous hemangiomata appear purplish
in color and may collapse on sectioning. A plane can generally
be identified between the hemangioma and surrounding liver
parenchyma. Thrombosis, fibrosis, and calcification are common features (Fig. 29.1). Cavernous hemangiomata may
undergo complete fibrous transformation. Hemorrhage is
remarkably rare and rupture exceptional. This lesion probably
represents a congenital hamartoma with endothelium-lined
spaces and fibrous septa being typical microscopic features.
Lesions enlarge through ectasia rather than hypertrophy or
hyperplasia.
Imaging Features
Hemangiomata are usually hyperechoic on US, although US is
often inadequate for differentiating between solid liver lesions.
Color-flow Doppler shows peripheral vessel filling. Axial
imaging with CT or MRI is usually sufficient to confirm the
diagnosis. The principle challenge in managing small (<3 cm)
hemangiomata is differentiating them from other lesions, particularly in cases with atypical enhancement and significant
arterio-venous shunting.
Lesions tend to be hypodense on non-contrast CT and show
peripheral followed by central enhancement. Isoenhancement
with the arteries is typical. Delayed scans show persisting contrast enhancement and features such as corkscrewing and cotton wool appearance reflect the abnormal vessels within the
lesion. Globular enhancement isodense with the aorta has
been shown to be 67% sensitive and 100% specific in differentiating hemangiomata from metastases (17).
Hemangiomata are hypointense on T1-weighted sequences.
They appear very bright on T2-weighted sequences (the light
bulb sign). Peripheral nodular enhancement on dynamic
gadolinium-enhanced images and a non-intact ring appearance immediately after contrast with centripetal enhancement
(maximal at 90s) are typical. Hemangiomata do not take up
SPIO or manganese dipyridoxyl ethylenediamine diacetate
(bis)phosphate (Mn-DPDP) as they do not contain Kupffer
cells or hepatocytes. 99mTc-SPECT is effective in assessing hemangiomata but appears inferior to MRI (18).
Management
Biopsy of hemangiomata is generally contraindicated given
the risk of hemorrhage and samples obtained from hemangiomata may resemble fibrosis. Resection may be justified rarely
for symptomatic lesions and in cases where the diagnosis cannot be established despite investigation. Surgical resection or
enucleation remains the principal effective therapies (19). Use
of liver transplantation has been reported for unresectable disease in association with KasabachMerritt (20). The use of
arterial ligation and embolization has not been widely
Pathology
FNH occurs in up to 3% of the population and is the second
most common solid benign liver lesion after hemangioma (21,22).
Ninety percent of patients are females in their second and
third decades, although cases have been reported in males.
Less than 10% of FNH is symptomatic and, in contrast to
hepatocellular adenomata, hemorrhage and rupture are
rare (23). Presence of hemorrhage raises the possibility that a
hepatocellular adenoma has been misdiagnosed as FNH. The
incidence of FNH is increasing, although this increase appears
unrelated to oral contraceptive introduction. The effects of
female sex hormones on the natural history of FNH remain
controversial. However, discontinuing oral contraceptive use
may be associated with a decrease in size of FNH (24,25).
There is insufficient evidence to recommend avoiding pregnancy in the presence of FNH.
FNH usually forms a firm lobulated lesion in otherwise normal liver (Fig. 29.2) and is more common in the right liver (26).
Lesions are typically well circumscribed but lack a definite
capsule. Differentiating FNH from other focal liver lesions,
particularly hepatocellular adenoma, remains a challenge. The
classical finding of a central scar (Fig. 29.3) may be absent in
approximately 40% of FNH cases (27).
Twenty percent of patients exhibit multifocal FNH and up
to 20% of FNH coexist with hemangiomata (28). FNH and
adenomata may also coexist. A histological diagnosis of FNH
does not mean coexisting lesions will also be FNH. Furthermore, co-existing malignancy is reported in 6% of patients
with an indeterminate presumed benign liver lesion (29).
NH has a microscopic appearance similar to that of cirrhosis, exhibiting regenerative nodules. Normal hepatocytes with
intervening connective tissue septa and bile ductules are typical. FNH is thought to be a hyperplastic response to abnormal
vascularization, rather than a neoplastic process and is not
regarded as having malignant potential (23). Moderate lymphocytic infiltration and mild cholestasis are common. It is
unusual for FNH to undergo rapid changes in size and this
should call the diagnosis into question. Calcification is a less
common finding, occurring in approximately 1.4% of
cases (30), and should alert the clinician to the possibility of
fibrolamellar hepatocellular carcinoma.
Telangiectatic FNH
Telangiectatic FNH (TFNH) accounts for 10% to 15% of FNH
cases and usually presents with multiple soft nodules without
a central scar (31). Intra-lesion bleeding is more common in
TFNH than in FNH. TFNH lesions commonly exhibit high
levels of angiopoietin 2 gene expression (32). Although the
origin of TFNH remains controversial, it is regarded by some
as a neoplastic lesion and may in fact represent a variant of HA
rather than a subtype of FNH.
263
FNH-Like lesions
FNH-like lesions have close histological similarity to FNH.
Although due to a variety of processes, the common etiological factor appears to be abnormal liver vascularity, specifically
increased arterial flow and decreased venous flow. Investigators have noted that FNH and hepatic adenomata occur more
often in patients who have coexisting vascular tumors, portal
venous thrombosis or occlusion, and those with significant
portohepatic venous shunts (33,34). Other conditions associated with FNH-like lesions include BuddChiari syndrome,
hereditary hemorrhagic telangectasia, and congenital hepatic
fibrosis. FNH-like lesions have a tendency to increase in number or size, unlike classical FNH.
Imaging Features
Radiological diagnosis of FNH can be challenging and a multimodality approach is often required. CT has a reported 82%
sensitivity and 97% specificity (35). A well-defined hypervascular lesion with a single central artery and spoke wheel
centrifugal vessel filling is typical. FNH and FNH-like lesions
are hyperintense T1-weighted MRI and hypointense on
T2-weighted series. Strong arterial enhancement is often
observed. MRI has a reported sensitivity of 70% and a specificity of 98% (36). In a recent study, differentiation between HA
and FNH was not possible on the basis of precontrast or
dynamic phase images alone. However, images acquired 1 to
3 hours after gadobenate dimeglumine enhancement, allowed
differentiation between FNH and HA/adenomatosis with a
specificity, PPV, NPV, and overall accuracy of 96.9%, 100%,
100%, 96.4%, and 98.3%, respectively (37).
Management
Management of patients with FNH and FNH-like lesions
depends on the level of certainty of diagnosis. Once the diagnosis of FNH is established with confidence, no further intervention is required. In cases of diagnostic uncertainty,
laparoscopic or open biopsy may be helpful and may be preferable to percutaneous needle biopsy. Although observation
may be more appropriate for some patients, resection or
264
hepatocellular adenoma
Pathology
Hepatocellular adenoma is usually identified as a solitary lesion in
an otherwise normal liver. Adenomata are well defined but lack a
capsule. Approximately 90% occur in women, most being diagnosed in the third to fifth decade. The lesions occur more commonly in the right liver. Adenomata are significantly less common
than both hemangiomata and FNH. Ninety percent of patients
report oral contraceptive use. The incidence is 34/100,000/year if
oral contraceptive use has exceeded 2 years and their diagnosis has
increased following the introduction of the oral contraceptive (38).
Higher dose and longer duration of oral contraceptive use appear
to promote adenoma development. Anabolic steroid use is also a
risk factor for the development of a hepatocellular adenoma.
Patients may present with pain due to hemorrhage into or rupture of an adenoma. The risk of bleeding is increased in larger
and rapidly growing adenomata, and in patients using OCP,
particularly when use is prolonged (39).
Hepatocellular adenomata are associated with abnormalities
of carbohydrate metabolism. Adenomata are observed more
frequently in glycogen storage disease type 1 (glucose-6phosphatase deficiency), type 3 (glycogen debrancher deficiency), galactosemia, and iron overload. In these patients,
adenomata develop at an earlier age and tend to show a male
preponderance (2:1) (40,41).
Sectioning reveals a yellow or pale brown tumor with surrounding normal tissue and a variable degree of encapsulation
(Fig. 29.4). There may be evidence of hemorrhage (Fig. 29.5).
Adenomata are generally uniform masses consisting of benignappearing hepatocytes without ducts or portal triads. Hepatocytes are pale due to increased levels of glycogen or fat. Venous
lakes (peliosis hepatis, vide infra) may be present. Initially,
Kupffer cells were thought to be absent from adenomata but
molecular techniques have confirmed their presence in these
lesions. However, adenomata generally do not sequester
99m
Tc-sulfur colloid which is taken up preferentially by Kupffer
(A)
(B)
Figure 29.4 (A) Intraoperative image of pedunculated peripheral hepatocellular adenoma. (B) Section through resected hepatocellular adenoma.
PET appears to be useful in differentiating benign from malignant liver lesions (43) and 11C-acetate PET may have additional
benefit in detecting HCC. In a study by Ho et al., benign tumors,
such as adenomata and hemangiomata, were not 11C-acetate-avid.
FNH showed only mild 11C-acetate uptake (44).
cells. Adenomata fall into three molecular pathological subgroups: (1) those with inactivated hepatocyte nuclear factor
1-alpha (HNF-1alpha, chromosome 12q)-, (2) those with betacatenin activation, and (3) those with inflammatory changes.
These subtypes reportedly display differing characteristics
on MRI (42).
Imaging Features
Hepatocellular adenomata are usually heterogeneous in
appearance on US. CT appearances are iso/hypodense precontrast with variable enhancement. There may be evidence of
recent hemorrhage or infarction.
MRI demonstrates a well-defined fatty lesion which is iso/
hyperintense on T1 sequences and mildly hyperintense on T2
MRI. Gadolinium-enhanced studies show hypervascularity in
the arterial phase. Enhancement is often heterogeneous. Angiography demonstrates a peripherally supplied hypervascular
lesion with areas of hypovascularity due to hemorrhage or
infarction. Isotope scanning may help differentiate hepatocellular adenoma from FNH, an adenoma appearing as a filling
defect (black hole sign).
Management
In cases of acute hemorrhage, resuscitation may be combined
with hepatic arterial embolization or laparotomy and packing
to facilitate transfer to a specialist center. Formal hepatic resection represents optimal treatment for this group of acute
patients, although this may be deferred in a stable patient with
confined hemorrhage (recommendation strength: D).
Discontinuing oral contraceptive use is probably advisable
since there have been reports of lesion regression on their cessation, although there is little compelling evidence to support
this position for all patients (recommendation strength: D).
Although adenomata may regress following discontinuation
of the oral contraceptive (45,46), malignant transformation
has also been reported despite its discontinuation and in contraceptive-naive patients (47).
Adenomata are currently thought to be premalignant with
an approximate transformation rate of 10% (48). Transformation should be suspected in adenomata that increase in size,
particularly in conjunction with increasing alpha-fetoprotein
levels. The risk of malignant transformation is higher in males
and in patients with large lesions.
Difficulties in differentiating adenomata from FNH or HCC
are commonly encountered in young female patients. Because
of the abnormal vasculature typical of these lesions, biopsy is
associated with a significant risk of hemorrhage and is generally contraindicated. In summary, if a focal liver lesion is
suspected to be an adenoma, surgical resection should be
considered, especially for symptomatic or large (5 cm or more
in diameter) adenomata, provided resection can be accomplished safely (49) (recommendation strength: C).
hepatocellular adenomatosis
Pathology
Hepatocellular adenomatosis is a rare condition, first recognized by Flejou et al. in 1985 (40). The condition is defined
265
266
pseudolipoma
These unusual lesions consist of well-differentiated subcapsular adipose tissue and may occur if an adherent fatty structure
becomes detached and incorporated into the liver parenchyma. Pseudolipomata may require differentiation form
metastasis, although they require no specific treatment.
Peliosis Hepatis
Peliosis hepatis refers to the development of multiple abnormal vascular channels with secondary fibrosis. This condition
is associated with anabolic steroid use as well as with tuberculosis and, in some cases, other tumors.
267
key points
appendix
Recommended Grading of Categories of Evidence
Ia:
Ib:
IIa:
IIb:
III:
268
IV:
C:
D:
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17. Leslie DF, Johnson CD, Johnson CM, Ilstrup DM, Harmsen WS. Distinction between cavernous hemangiomas of the liver and hepatic metastases
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18. Krause T, Hauenstein K, Studier-Fischer B, Schuemichen C, Moser E.
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269
270
30 Liver trauma
introduction
The size and location of the liver account for its high susceptibility to both blunt and penetrating trauma. The type and
severity of liver injuries vary greatly and associated organ injuries are common. The leading cause of death is hemorrhage,
with road traffic accidents accounting for an ever increasing
proportion of blunt liver injuries. It also presents a large target
for penetrating injuries to the trunk and these, including gunshot wounds, can be difficult to manage. The intimate connections between the liver capsule, the major hepatic veins, and
the retrohepatic inferior vena cava anchor the liver within the
upper abdominal cavity and most of the venous return from
the lower body flows within these thin-walled veins. Injuries to
these vulnerable, high-volume-flow juxtahepatic vessels
pose a uniquely challenging aspect of severe liver trauma.
Dramatic advances in the management of liver trauma have
been reported in recent years and algorithms of management
continue to evolve. The last two decades have witnessed a
major paradigm shift in the management of liver trauma, with
Non-Operative Management of Liver Injury (NOMLI) now
firmly established as the standard of care for the majority of
patients. For those undergoing surgery, the philosophy of
damage control at abbreviated laparotomy prevails and the
technique of perihepatic packing has come to serve a dominant role. Multidisciplinary interventions are indispensible in
managing both the inevitable consequences of NOMLI and as
adjuncts to surgical intervention. Unsurprisingly, little or no
Grade III evidence exists from randomized or controlled
studies of liver trauma, and recommendations for management are based on large descriptive studies, including multiinstitutional prospective cohort studies, and the clinical
experience of respected authorities in the field.
271
IV.
V.
VI.
Gradea
Injury descriptionb
Hematoma
Laceration
Hematoma
Laceration
Hematoma
Laceration
Laceration
Laceration
Vascular
Vascular
hemoperitoneum (17) and demonstration of associated intraperitoneal and retroperitoneal injuries (Fig. 30.2). Technical
refinements such as the development of rapid spiral CT scanners, protocols optimizing vascular contrast enhancement,
and CT-scanning suites adjacent to the emergency department
and equipped for critical care monitoring have established the
central role of CT in the management of all but the most
unstable cases of liver trauma (16).
Despite concerns regarding the reliability of CT in the detection of hollow vicious injuries (18), the incidence of missed
injuries following non-operative management based on clinical and CT findings is reported to be as low as 0.2% (7).
Although reliable predictors of failure of non-operative management are lacking, contrast extravasations (pooling or a
blush) merits emphasis as a cardinal sign of active hemorrhage mandating prompt (angiographic and / or surgical)
intervention (7,15,16,19,20) (Fig. 30.3). Fang and colleagues
reported contrast pooling in eight out of 150 stable patients
treated non-operatively, six of whom (75%) developed hemodynamic instability requiring liver-related laparotomy (20).
Figure 30.1 Selective hepatic angiography (right hepatic artery arising from
superior mesenteric artery) demonstrates contrast extravasation (arrows).
Angioembolization was performed.
were successfully managed by hepatic embolization as definitive therapy. The alternative management of hemorrhage
from Grade V juxtahepatic venous lacerations by percutaneous hepatic venous stenting has also been reported (14).
Clearly much depends on the timing of such intervention and
the prompt availability of appropriate expertise (with an operating room on standby) (12,15).
Abdominal CT is established as the primary screening
modality for the hemodynamically stable patient with suspected blunt liver trauma (16). Detailed cross-sectional imaging of the abdominal organs permits precise delineation of the
type and extent of the liver injury, estimation of the volume of
272
LIVER TRAUMA
Figure 30.2 Grade V blunt liver trauma associated with right renal hematoma
in a hemodynamically unstable patient responding to fluid resuscitation and
angioembolization.
Figure 30.3 Abdominal CT performed after perihepatic packing for blunt liver
trauma showing intra-parenchymal contrast extravasation (arrow). The
patient was transferred from the referring hospital and underwent day 1 relaparotomy because of deteriorating LFTs and evidence of the abdominal
compartment syndrome.
systemic inflammatory response may be expected. The anticipation and management of specific complications is integral
to the successful non-operative management of severe liver
injuries. Typically these include arterio-venous fistulas, bile
leaks, intra- or peri-hepatic abscesses, and vascular-biliary
communications (bilhemia and hemobilia). Such complications should be regarded as virtually obligatory consequences
of non-operative management (36). This re-defines the philosophy of surgical abstention recognizing that delayed surgery and/or interventional procedures should be deemed an
inherent part of the overall management plan rather than
treatment failure.
Carillo and colleagues reported that 32 patients out of 135
(24%) with severe blunt liver trauma managed non-operatively
during 1995 to 1997 developed such complications (15).
Strategies employed in their treatment included angioembolization (37%), CT-guided drainage of collections (31%), ERCP
(25%), and laparoscopic drainage of collections (7%). A more
recent multicenter study of 453 patients with Grades 3 to 5
blunt liver trauma managed by NOMLI at seven urban level 1
American trauma centers between 2000 and 2003 revealed 87
complications in 61 patients (13%)(37). Similarly, these comprised bleeding, biliary complications, abdominal compartment syndrome, and infective complications, which required
86 multimodality interventions.
Hemorrhage
Ongoing or recurrent bleeding in the non-operatively managed patient is typically recognized by hemodynamic instability with a gradually declining hematocrit and the requirement
for repeated transfusions at an early stage. Angioembolization
is usually effective for the relatively small proportion of
patients who exhibit the signs of early ongoing hemorrhage or
late re-bleeding, though this is unusual beyond 3 days postinjury (37). Liver enzyme derangement is common in the
273
274
LIVER TRAUMA
Angioembolization plays an important role in this group of
patients for treatment of false aneurysms or active
bleeding (56,57). It remains to be seen whether diagnostic
laparoscopy will be increasingly adopted to identify the
isolated non-bleeding LGSW as suggested by some (6164).
Early Decision Making During Laparotomy
Arrest of hemorrhage is the priority at initial operation and
rapid decision making is required of the surgeon who encounters major liver injury at laparotomy. Most liver injuries are
relatively minor and can be dealt with by simple maneuvers
such as bimanual compression of the adjacent parenchyma,
diathermy or suture ligation of visible bleeding points. Ongoing bleeding which is not easily controlled in this way requires
temporary vascular inflow control by the Pringle maneuver,
which serves both therapeutic and diagnostic roles. Grade IVV
injuries with hepatic venous/caval lacerations may not respond
to inflow occlusion and any attempts to mobilize the liver or
inspect the retrohepatic space may be met with profuse venous
bleeding. Consideration of perihepatic packing as the mainstay of the Damage Control Laparotomy (DCL) should now
occur (6567).
Perihepatic Packing
Perihepatic packing is acknowledged as one of the most
important factors in reducing the mortality following liver
trauma in recent years (7). Temporary resuscitative packing
may be distinguished from definitive therapeutic packing. The
former aims to achieve hemodynamic stability, allows the surgeon to regain his composure, repair other priority vascular
injuries, await more experienced surgical assistance, and/or
facilitate transfer to a major trauma or hepatobiliary center
for definitive treatment (67,68). Pack tamponade is the key
maneuver underpinning the philosophy of surgical restraint
and damage control during abbreviated laparotomy (69).
Its judicious use may pre-empt the rapid cascade of events
leading to refractory hypotension, dilutional coagulopathy,
hypothermia, acidosis, and metabolic failure. A decision can
then be taken either to attempt definitive control of bleeding
or to proceed with therapeutic packing with abdominal closure and staged reoperation. The timing of the decision to
pack is critical and the avoidance of packing as a desperate last
resort when all other measures have failed should be emphasized (70). Indeed, a multicenter study identified failure to
recognize the value of timely packing as the most common
scenario in which patients died from fatal exsanguinations in
the operating room (10). Furthermore, initially effective
packing may engender a false sense of security when a pack
and peek sequence develops and it is important to avoid the
vicious cycle of repeated packing, resuscitation, unsuccessful
attempts at definitive hemostasis, and repeated re-bleeding
into shock (71).
Perihepatic packing requires careful insertion of large, folded,
dry gauze laparotomy packs around the diaphragmatic surfaces
of liver and aims to restore its external contours (66,67)
(Fig. 30.3). Sufficient packs must be inserted to provide adequate external counterpressure to achieve tamponade (without
causing abdominal compartment syndrome), most of this
external force being provided by the body wall and rib cage following wound closure. In this regard, Krige and colleagues
describe a six-pack technique(72). The patient is later
returned to the operating room for re-laparotomy and pack
removal according to the progress of metabolic recovery. The
Cape Town experience supports delay of liver pack removal
beyond 48 hours without increased risk of septic complications
or bile leaks, whereas early re-look laparotomy performed
within 24 hours was associated with re-bleeding (73).
A refinement in therapeutic perihepatic packing is the mesh
hepatorrhaphy technique which employs a synthetic (polyglycolic acid or polygalactin) absorbable mesh and obviates the
need for re-laparotomy (74). The technique seems logical for
extensive lobar stellate lacerations, but unsurprisingly is ineffective in instances of juxtahepatic or caval injury and does not
seem to have achieved widespread acceptance. Similarly, the
use of a non-permeable liver bag following failure of conventional packing has been described (75).
Refractory Bleeding Following Perihepatic Packing
Continued bleeding through the packs that ceases with the
Pringle manouevre and recurs with its release indicates hepatic
arterial bleeding. Selective hepatic artery ligation remains an
option although is regarded by some authorities as obsolete
(76,77) and of historical interest only (78). Rather, postoperative transfer to the angiography suite for selective angioembolization has been identified as a major advance in this
scenario (42,79). Asensio and colleagues reported early angioembolization as an adjunct to surgical intervention in 23 out
of 57 survivors (40%) with grades IVV liver trauma, and the
use of angiography in this way was identified as a significant
independent predictor of outcome associated with decreased
mortality (80).
Persistent bleeding despite inflow occlusion suggests retrohepatic caval or hepatic venous injury and critical decisions
must be made regarding the next level of intervention and
whether to attempt definitive control of parenchymal / vascular bleeding with or without debridement of devascularized
parenchyma (Fig. 30.4).
Definitive Surgical Procedures in Complex Liver Trauma
The latter option requires the use of one or more recognized
manouevres. Although these techniques all have their proponents and detractors, they are nevertheless not mutually exclusive. No controlled trials exist to provide an evidence base for the
superiority of one particular method over the other and much
depends on anecdote, local expertise, and individual experience.
Hepatotomy and Selective Vascular Ligation
Rapid exposure and selective vascular suture/ligation of deepseated, actively bleeding, intra-hepatic vessels under hepatic
inflow control have long been advocated as a mainstay in some
centers (7). In the series of 107 patients with Grade IIIIV liver
injuries reported from New York, finger-fracture hepatotomy
technique was successful in controlling hemorrhage in no less
than 100 cases (93.5%) for a cumulative mortality of 15% (81).
It should be noted, however, that 83% of these patients had
penetrating injuries. Similarly, Beal reported the use of
275
Figure 30.4 Laparotomy and perihepatic packing was performed for postangioembolization hemodynamic instability. The patient continued to bleed
and re-laparotomy with hepatic segmentectomy 7/8 and repair of a middle
hepatic vein laceration was performed.
276
always achieving complete hemostasis and hemodynamic stability, nevertheless permitted patient transfer and avoided early
death from exsanguinations (76).
Type B juxtahepatic injuries implicate extra-hepatic venous
avulsion with uncontained hemorrhage around the liver, and
are likely to require additional operative measures when the
severity of hemorrhage defies control by perihepatic
packing (86). Such injuries are more likely to require exposure
and direct vascular control. Total hepatic vascular isolation, with
cross-clamping of both suprahepatic and infrahepatic segments
of the IVC (87), may seem a daunting prospect to the uninitiated in the face of heavy bleeding, and the hypovolaemic patient
may not tolerate trial caval occlusion without circulatory collapse. Also, reperfusion with gut endotoxins may cause tachyarrhythmias following clamp removal. However, good results
have been reported for direct repair of penetrating juxtahepatic
IVC injuries when total vascular isolation techniques were
employed (88). Khaneja and co-workers reported operative survival in nine out of ten such patients presenting with Grade V
stab and gunshot wounds between 1988 and 1996 for an overall
survival of 70% (88). Others have reported more modest survival rates of 42% following direct venous repair (89).
The concept of atrio-caval shunting (84,85,90) seems logical
but in reality outcomes have been poor with >90% mortality
and the technique is generally regarded as obsolete (77).
Anatomical Hepatic Resection
The decision to embark upon an anatomical liver resection for
complex liver trauma must be regarded as one of the most difficult and controversial as most authorities emphasize a policy
of conservative surgery and damage limitation. Detractors of
formal resection cite prohibitive mortalities of 40% to 60%
(71,91), and observe its dwindling usage (2% to 4% incidence)
in the trauma centers of North America (7). Others recommend limiting hepatic resection to the management of the rare
instance of major burst injuries with extensive lobar devitalization (72).
The rationale for hepatic resection is nevertheless logical in
fulfilling the dual role of eradicating both the site of hemorrhage and source of necrosis (Figs. 30.530.7). Although there
is a paucity of evidence for anatomical resection in this
scenario, the principles of surgical restraint observed in most
North American trauma centers have also been challenged by
surgeons in Japan (92) and France (93).
Data supporting an enhanced role for anatomic resection in
severe liver trauma from Brisbane comprised 37 such patients
(76). Right hepatectomy was the most commonly performed
procedure (27 cases (73%)), and Grade V juxtahepatic venous
injuries were encountered in 11 patients (30%). There were no
on-table deaths, three post-operative deaths, the overall mortality was 8% and re-exploration was performed in seven
instances (three of which were for removal of post resection
packs) (76). This experience should be considered in the context of a specialist hepatobiliary team with experience in elective liver resection and transplant techniques. Initial
laparotomy had previously occurred at the referring hospital
in two thirds of cases, and in this regard the life-saving role of
perihepatic packing prior to transfer was emphasized.
LIVER TRAUMA
Figure 30.5 Hemodynamically unstable patient with severe blunt liver trauma
underwent laparotomy, common hepatic artery ligation, liver suture, perihepatic packing, and was transferred for definitive management. Re-laparotomy
and pack removal on day 1 revealed that active bleeding had stopped but the
gall bladder was necrotic and there was a major bile leak from the sutured
right liver laceration.
Figure 30.7 Abdominal CT performed 2 weeks later shows satisfactory hypertrophy of the remnant left hemiliver and no complications.
tion was still <1%, and the availability of experienced hepatobiliary and liver transplant surgeons at this institution was
again a significant factor (95). It remains to be seen whether
such results are reproducible widely, or whether the role of
major resections in this context will remain the preserve of the
surgical virtuoso.
For deep penetrating liver injuries, including central bilobar
LGSWs, balloon tamponade is an innovation which offers the
chance of salvage (9698).
Total hepatectomy is the ultimate strategy in desperate circumstances when hemorrhage from a shattered liver cannot be
controlled, or when a Grade VI avulsion injury renders the
liver remnant non-viable. However, the logistical and ethical
dilemmas presented by this scenario are daunting as the future
survival of the patient depends at the very least on the availability of a suitable donor organ. While an increasing number
of reports have testified to the feasibility of this approach
(99,100), the reality was illustrated by the Hannover experience in which six out of eight such patients died (101). The
authors emphasize the importance of the (early) timing of
hepatectomy, but stress that this approach can only be justified
in exceptional circumstances.
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Figure 30.6 Formal right hepatectomy was performed and the patient made
an uncomplicated post-operative recovery.
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279
31
Portal hypertension
Michael D. Johnson and J. Michael Henderson
introduction
Portal hypertension has undergone major changes in understanding its pathophysiology, investigation, and management
over the past 3 decades. It has moved from a dominantly surgical syndrome to a predominantly medical one, but in day-today practice includes a broad group of disorders that require a
multidisciplinary team for evaluation and management. Basic
science has defined the pathophysiology, allowing the introduction of pharmacologic therapies for treating many of the
complications of portal hypertension. Technology advances in
endoscopic therapies and endovascular stenting have changed
the treatment options for variceal bleeding. The coming of age
of liver transplantation has dramatically altered the management of patients with end stage liver disease and portal hypertension, and is now the dominant surgical option for suitable
patients. This chapter will address these changes and present
the evidence supporting management choices for the main
clinical presentations of portal hypertension.
etiology
Portal hypertension can be divided into prehepatic, intrahepatic, and posthepatic causes based on the location of obstruction to portal blood flowTable 31.1. Most of the prehepatic
causes have a normal liver which improves overall prognosis
for this group. Portal vein thrombosis should prompt a workup
for hypercoagulable states (1). Rarely, a procedural induced
arteriovenous fistula or functional fistulae associated with
Osler Weber Rendu disease (Hereditary hemorrhagic telangiectasia) (2,3), can cause portal hypertension.
Intrahepatic portal hypertension is usually secondary to cirrhosis with its multiple causes. The severity of the liver disease
is the most important factor in determining prognosis. Intrahepatic presinusoidal obstruction occurs in congenital hepatic
fibrosis and schistosomiasis, and liver function is well preserved. Schistosomiasis accounts for 200 million cases of portal hypertension worldwide (4,5).
Posthepatic portal hypertension is rare and includes Budd
Chiari Syndrome (BCS) and veno-occlusive disease. BCS
results from obstruction of either the hepatic veins or suprahepatic vena cava, and is often associated with a myeloproliferative or hypercoagulable disorder. Outcome is determined
by the extent of hepatic vein involvement, the rapidity of
development, and the underlying liver function (6,7).
pathophysiology
Portal hypertension occurs when portal venous pressure rises
above the normal pressure of 8 mmHg and becomes clinically
important above 10 to 12 mmHg. The cascade of events that
follow portal flow obstruction are illustrated in Figure 31.1. As
portal pressure rises, additional dynamic factors come into
play as a result of neurohormonal changes. Vasoconstriction
280
with endothelins (8), norepinephrine, angiotensin II, vasopressin whose levels are elevated in cirrhotic patients plays a
role (9). Insufficiency of local vasodilators, such as nitric oxide
and carbon monoxide has been implicated, and while levels of
Nitric Oxide Synthase (NOS) are normal, NOS activity is
depressed, partly due to increased expression of caveolin (10).
Splanchnic vasodilation and the development of portosystemic collateral are influenced by Vascular Endothelial Growth
Factor (VEGF) and Platelet Derived Growth Factor (PDGF).
VEGF receptor inhibition has been shown to prevent the formation of portosystemic collaterals in animal models (11,12)
and reverse the adverse hemodynamic consequences of established portal hypertension (13).
These neurohumoral changes lead to increased splanchnic
hyperemia and a hyperdynamic systemic circulation with a
low arterial blood pressure and increased cardiac output.
clinical manifestations
Variceal Bleeding
Variceal bleeding is one of the major complications of portal
hypertension requiring medical and surgical therapies (14).
Screening endoscopy in cirrhotics shows that patients with
more advanced liver disease and a lower platelet count are more
likely to have varices (15). Epidemiologic studies have shown
linear progression of varices over time (16). All patients with
cirrhosis should undergo an initial screening upper endoscopy
for varices: if none are present this should be repeated every
2 years. If present, intervention with prophylactic therapy to
prevent bleeding (primary prophylaxis) should be considered.
Ascites
Ascites is a marker of advanced liver disease that develops later
than varices. Refractory ascites which does not respond to salt
restriction and diuretics and has consistently been linked to
increased mortality (17). In addition, refractory ascites is
potentially complicated by fluid and electrolyte imbalances,
spontaneous bacterial peritonitis, and a higher incidence of
abdominal wall hernias (18).
Hypersplenism
Portal hypertension can lead to splenomegaly and hypersplenism, with anemia, leukopenia, and thrombocytopenia. Blood
is sequestered and destroyed in the spleen due to morphologic
changes (19). Hypersplenism improves with decompression of
the portal hypertension and rarely is splenectomy needed. Partial splenic embolization has been advocated by some (20), but
is less effective.
Pulmonary Syndromes
Hepatopulmonary syndrome (HPS) is characterized by hypoxemia with the development of right-to-left intrapulmonary
PORTAL HYPERTENSION
shunts and a widened alveolar-arterial oxygen gradient (21).
Treatment is with liver transplantation which usually reverses the
syndrome with survival rates similar to non-HPS cohorts (22).
Pulmonary hypertension is also seen in patients with portal
hypertension and carries a more sinister prognosis than HPS.
Unless pulmonary arterial pressure can be reduced to normal
ranges, liver transplant is contraindicated in these patients.
Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma is a common cause of death among
patients with cirrhosis and has increased in importance as
other causes of mortality have declined (23). The most common conditions leading to HCC are hepatitis B and C and
alcoholism. Screening is recommended for patients with cirrhosis using hepatic ultrasound. However effectiveness of this
approach has been questioned (24). Early detection of HCC in
patients with well-compensated cirrhosis who are eligible for
resection or can be prioritized for transplantation is the goal.
evaluation
The three essential components in evaluating patients with
portal hypertension are (i) assessment of liver function,
(ii) endoscopic study, and (iii) radiologic imaging.
Liver Function is assessed from clinical and laboratory
parameters. Ascites, jaundice, muscle wasting, and encephalopathy are markers for advanced liver disease. Biochemical
and hematologic lab profiles include a complete blood count,
prothrombin time, serum electrolytes, and liver chemistries.
Specific markers of liver disease include hepatitis panels,
antinuclear antibody, antimitochondrial antibody, iron and
copper levels, alpha 1 antitrypsin, and alpha fetoprotein for
HCC screening. The Child-Pugh and MELD scoring systems
combine clinical and laboratory variables to determine prognosis in chronic liver disease.
Endoscopy focuses on the presence, extent and size of esophageal and/or gastric varices and Portal Hypertensive Gastropathy (PHG). Grading of varices, using, for example, the North
Italian Endoscopic Club (NIEC) system, risk-stratify based on
variceal size, severity of red wale markings. When combined
with ChildPugh class, such grading can help to guide
therapy (25,26). Similar grading systems have been developed
and validated for PHG and gastric varices (27,28).
Intrahepatic
Post hepatic
Increased production
vasoconstrictors
Increased hepatic
vascular tone
Increased hepatic
vascular resistance
Increased production
vasodilators
Peripheral, BP
Splanchnic
hyperemia
Activate neurohumoral
Increased C.O.
Increased
collateral
flow
Portal hypertension
Copyright 2007 by Saunders, an imprint of Elsevier Inc.
Figure 31.1 Pathophysiology of portal hypertension demonstrating complex
vascular and neurohormonal responses. BP, blood pressure; CO, cardiac
output; PVT, portal vein thrombosis. Source: From Ref. (97).
281
Endoscopy
No varices: f/u
endoscopy 2 yrs
Varices
(moderate or large)
1. Somatostatin/octreotide
2. Conservative resuscitation
3. Antibiotics
Non-cardioselective -blocker
(Propanolol or Nadolol)
Endoscopy
-Diagnostic
-Therapeutic: sclerotherapy
or ligation
Intolerance to -blockers
or high-risk varices
Continued bleed
or rebleed
Band ligation
Figure 31.2 Primary prophylaxis to prevent an initial variceal bleed. Management algorithm based on variceal size. Source: From Ref. (97).
282
-Balloon tamponade
-TIPS
PORTAL HYPERTENSION
nitrates) and EVL (Grade 1b evidence). The latter should be
performed in 2 to 4 sessions, 7 to 10 days apart until variceal
obliteration is achieved. Combination therapy has succeeded in
lowering rebleeding rates to as low as 14% at 2 years (47). The
lowest rates of rebleeding are found in patients deemed
responders based on HVPG measurements as mentioned
earlier. Patients with a HVPG < 12 mmHg or a 20% decrease in
HVPG have a 10% rebleeding rate (4850). Some have argued
that pharmacologic therapy should be tried first, with EVL added
for non-responders. In a meta-analysis of 12 randomized controlled trials comparing TIPS to endoscopic therapy for preventing variceal rebleeding, TIPS performed better in the prevention
of rebleeding and deaths due to rebleeding, albeit with a higher
rate of encephalopathy (51) (Grade 1a evidence). However, half
of the studies used sclerotherapy alone for secondary prophylaxis. Subgroup analysis showed EVL was statistically equivalent
to TIPS in terms of rebleeding, mortality, and encephalopathy.
The data suggest TIPS should be used only once the combination
of pharmacologic and endoscopic therapies has failed.
Variceal Decompression
Variceal decompression, either with a radiologic shunt (TIPS)
or a surgical shunt, is indicated in patients that continue to
bleed despite adequate medical and endoscopic therapy. TIPS
has largely replaced surgical shunts both for patients with
good hepatic reserve, and as a bridge to transplantation.
Evaluation
Varices obliterated
-blocker
-Repeat banding
-or decompress
TIPS
DSRS
End-stage liver disease
Transplant
Copyright 2007 by Saunders, an imprint of Elsevier Inc.
Figure 31.4 Prevention of recurrent variceal bleeding with cascading therapy
options. TIPS, transjugular intrahepatic portosystemic shunt; DSRS, distal
splenorenal shunt. Source: From Ref. (97).
TIPS
Since its introduction in the 1990s TIPS has undergone a
number of modifications, allowing it to become the primary
means of portal decompression with a rebleeding rate at 1 year
of about 13% (52). It is functionally an intrahepatic side-toside portocaval shunt which lowers the portal venous pressure
and sinusoidal pressure. Initially, the main limitation of TIPS
was stenosis, with the need for frequent surveillance and reintervention in the first year (50 % to 80%). The use of polytetrafluoroethylene (PTFE)-covered stents has markedly reduced
the need for reintervention to <25%. Two randomized trials
demonstrated improved primary patency rates with no impact
on rate of encephalopathy or survival (53,54) (Grade 1b evidence). The other main side effect of TIPS is the development
or worsening of encephalopathy which occurs in approximately 30% of patients (52). This is often amenable to medical
management or modification of the TIPS itself.
TIPS Procedure
Venous access is usually obtained through the right internal
jugular vein into the right or middle hepatic veins. The main
right portal vein is identified by a retrograde hepatic venogram, and the portal venous system is entered above the bifurcation. After a contrast portal venogram confirms correct
positioning, the TIPS is placed with a gentle curve to the prosthesis to prevent kinking. It is also important to choose a stent
of the correct length, not extending too far into either the
hepatic vein or the portal vein. At the same time, the entire
hepatic vein segment should be covered to prevent the development of a stenosis at this end. Portal venous pressures are
measured before and after the TIPS is deployed, and a completion venogram is obtained. The goal is a portal vein to right
atrial gradient of <10 mmHg. Recurrence of variceal bleeding
often heralds TIPS dysfunction and warrants recatheterization
of the shunt to assess for patency and measure the gradient.
Surgical Shunts
Surgical shunts can be classified as total, partial, or selective.
Total shunts divert all portal venous blood flow either a direct
side-to-side portocaval shunt or an H-graft shunt using a
10-mm or greater PTFE graft. Portal decompression and resolution of variceal bleeding are excellent at greater than 90%;
however, encephalopathy develops in up to 45% (55). Partial
shunts use an 8 mm graft to partially decompress the portal
venous system while preserving some hepatopedal blood flow.
Prevention of variceal rebleeding remains greater than 90%
with lower rates of encephalopathy compared to total
shunts (56,57) (Grade 3 evidence). Selective shunts, such as
the Distal Splenorenal Shunt (DSRS), selectively decompress
gastroesophageal varices while maintaining portal hypertension (Fig. 31.5). These became the most widely used surgical
shunts from 1980s to 1990s. Most series demonstrated rebleeding rates from 5% to7% and encephalopathy in 5% to 19%
range. An NIH-funded prospective, randomized trial (1997 to
2003) compared DSRS to TIPS in patients with Childs class A
and B cirrhosis (58) (Grade 1b evidence). At the close of this
study (mean follow-up of 46 26 months with a range 24 to
96 months), the survival rates were not different at 2 and
283
Transplantation
Liver transplantation constitutes the ultimate shunt with
normalization of portal venous hemodynamics and restoration of liver synthetic function. Ongoing improvements in
operative techniques and immunosuppression are responsible
for a modern 5-year patient survival rates approaching 75% (62).
The major shortcoming of transplantation remains a shortage
of available donor organs. Strategies to deal with this have
included split liver and living-related transplantation.
Devascularization Procedures
These series of operations were devised to decrease variceal
inflow, while preserving portal hypertension and therefore
decreasing the rate of encephalopathy. These have been used
much more extensively in the Mid and Far East on patients
with non-alcoholic liver disease with good results. In their
original series of 276 patients, Sugiura and Futagawa reported
an operative mortality of 4.3% and 2.3% rate of variceal recurrence (59). Various modifications have been made to the procedure that generally consists of splenectomy, devascularization
of the upper two-thirds of the greater and lesser curvature of
the stomach and 7 cm of distal thoracic esophagus, esophageal
transection and reanastomosis, and pyloroplasty (60). Outside
Japan, experience with gastroesophageal devascularization has
not been quite as impressive. In the largest series in the Western hemisphere, Orozco et al. reported an operative mortality
of 22% and rebleeding rate of 10% but included patients with
Childs class C cirrhosis (61). Encephalopathy rates have generally been less than 10% in most series. Currently, devascularization procedures are most appropriate for patients with
extensive thrombosis of the portal venous system with recurrent variceal bleeding and preserved liver function who lack
shuntable veins (Grade 3 evidence).
ascites
This is the most common complication of cirrhosis and portal
hypertension and is an important source of morbidity and
mortality. Figure 31.6 presents a management algorithm.
Ascites develops as a result of sinusoidal portal hypertension
and the concomitant vasodilatation within the splanchnic
circulation with an imbalance between hepatic lymph
production and return to the systemic circulation. A relative
hypovolemia is sensed by the kidneys due to reflex systemic
vasoconstriction that, in turn, activates the reninangiotensin
system leading to sodium and water retention.
Paracentesis is used in the diagnosis and management of
ascites. For diagnosis, a Serum-Ascites Albumin Gradient
Treatment of ascites
Ascites
Mild/moderate
Refractory
Persistent ascites
Large volume
paracentesis
albumin infusion
Increased
frequency TIPS
? Transplant
Figure 31.5 Distal splenorenal shunt selectively decompresses gastroesophageal varices while maintaining portal perfusion through the superior mesenteric and portal veins. Source: From Ref. (97).
284
PORTAL HYPERTENSION
(SAAG) greater than 1.1 is highly suggestive of cirrhosis. Other
causes of ascites (malignancy, infection, pancreatic ascites)
usually have a SAAG less than 1.1. In the cirrhotic patient with
ascites, abdominal pain and signs of infection, paracentesis
should be performed to evaluate for possible spontaneous bacterial peritonitis, which carries a mortality of around 37% (63).
Diagnosis of SBP requires the presence of at least 250 polymorphonuclear cells per cubic millimeter of ascitic fluid (64). As
with gastroesophageal varices, a systematic approach should be
taken in the management of ascites.
The cornerstones of treatment of mild to moderate ascites
are sodium restriction, to less than 2 g/d and diuretics (65).
Spironolactone is the first-line diuretic acting as an aldosterone
antagonist. Therapy starts with 100 mg daily and can be titrated
up to a maximum dose of 400 mg daily. Furosemide can be
added to assist with natriuresis and reduction of peripheral
edema, but caution must be exercised to prevent overdiuresis.
Refractory ascites fails to respond to maximum medical
management and carries a poor prognosis. It interferes significantly with quality of life and requires a more aggressive
approach that may include Large Volume Paracentesis (LVP),
TIPS, or transplant. LVP removes 5 or more liters of ascites,
with or without concomitant albumin infusion. A metaanalysis of four randomized trials comparing LVP to TIPS,
showed that TIPS was superior to LVP in terms of control of
ascites and transplant-free survival but carried a higher risk of
hepatic encephalopathy (66) (Grade 1a evidence). Patients
with refractory ascites are best served with transplantation for
long-term survival.
portopulmonary syndromes
Lung dysfunction may develop for a variety of reasons in
patients with cirrhosis and portal hypertension, with the two
main clinical entities of hepatopulmonary syndrome (HPS)
and portopulmonary hypertension (PPH). (Figure 31.7 summarizes key features of these two syndromes.
HPS is characterized by a defect in arterial oxygenation in the
setting of liver disease due to arteriovenous shunting in the pulmonary vascular bed (21). HPS manifests most commonly
with dyspnea, digital clubbing, cyanosis, and hypoxemia. Diagnosis of this syndrome requires (1) advanced liver disease, (2)
arterial hypoxemia (PaO2 < 80 mmHg or alveolar-arterial oxygen gradient > or = 15 mmHg), and (3) pulmonary vascular
dilatation (67). The precise etiology for the pulmonary vascular
changes that take place are not entirely known, but are thought
related to elevated pulmonary nitric oxide levels. Diagnosis can
be made with the use of contrast-enhanced transthoracic echocardiography with agitated saline to produce microbubbles. In
the presence of the abnormally dilated pulmonary vascular bed
typical of HPS, microbubbles can be seen in the left atrium
within 3 to 6 cardiac cycles. Alternatively, a more sensitive
method involves the injection of technetium-99m-labeled
microaggregated albumin into a peripheral vein with quantitative uptake in the brain. Liver transplantation is the only known
definitive treatment for HPS with a 5-year survival of 76% in
one series compared to 23% for patients not undergoing transplant (22) (Grade 3 evidence). Given the progressive nature of
the disease and inferior outcome after transplant for those with
severe hypoxemia (PaO2 < 50 mmHg), patients diagnosed with
HPS should be prioritized for transplantation.
Portopulmonary hypertension is defined by the presence of
the following in the setting of portal hypertension: elevated
pulmonary artery pressures (>25 mmHg), elevated pulmonary vascular resistance (>240 dyne s1 cm5), and pulmonary
artery occlusion pressures <15 mmHg (68). As with HPS, the
presence or severity of PPH does not seem to correlate with
the degree of liver disease or portal hypertension. The hyperdynamic circulation that accompanies portal hypertension
leads to increased sheer stress and vascular remodeling in the
pulmonary vasculature which, in turn, leads to elevated resistance. The most common symptom is dyspnea on exertion but
fatigue, syncope, palpitations, and chest pain can also be seen.
Transthoracic echocardiography is a good initial screening test
to perform if PPH is suspected with right-heart catheterization used to confirm the diagnosis along with its severity.
Milder cases of PPH may be reversible with liver transplant,
but severe PPH is associated with high post-transplant mortality (69) (Grade 3 evidence). Aggressive medical therapy with
prostanoids and other pulmonary vasodilators is mandatory
prior to considering patients for transplantation.
Variables
Hepatopulmonary
Syndrome (pO2 < 70)
Portopulmonary
Hypertension (RVSP > 40)
Prevalence
820%
312%
Pulmonary
vascular changes
Vasodilatation
Vasoconstriction
Contributors
Liver dysfunction
portal hypertension
Portal hypertension
Transplant?
Curative
Contraindicated
Figure 31.7 Pulmonary syndromes in liver disease: characteristics and management. RVSP, right ventricular systolic pressure. Source: From Ref. (97).
285
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67. Krowka MJ. Hepatopulmonary syndrome versus portopulmonary hypertension: distinctions and dilemmas. Hepatology 1997; 25(5): 12824.
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69. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and
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70. Mansour A, Watson W, Shayani V, et al. Abdominal operations in patients
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72. Puggioni A, Wong L. A metaanalysis of laparoscopic cholecystectomy in
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74. Northrup PG, Wanamaker RC, Lee VD, et al. Model for end-stage liver
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75. Teh SH, Nagorney DM, Stevens SR, et al. Risk factors for mortality after
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287
32
introduction
Since the first successful liver transplant in 1963, liver transplantation (LT) has become an established form of therapy for
patients with acute and chronic liver failure. With reported 5and 10-year survival rates for patients with liver transplant of
70% and 60%, respectively (1), indications for LT have
expanded resulting in an increasing demand in this era of
donor shortage. To augment the donor pool, expanded donor
criteria and novel LT techniques are utilized increasingly. Artificial liver systems and hepatocyte cell transplantation, while
still much in development, are exciting potential therapies to
reduce the organ shortage burden. This chapter will look at the
latest development in LT for acute and chronic liver failure and
their indications.
288
1 point
2 points
3 points
units
<34 (<2)
>35
<1.7
None
None
3450 (23)
2835
1.712.20
Suppressed with medication
Grade III (or suppressed with medication)
>50 (>3)
<28
>2.20
Refractory
Grade IIIIV (or refractory)
mol/l (mg/dl)
g/l
No unit
No unit
No unit
Class
56
79
1015
A
B
C
100
81
45
85
57
35
selection of donor
The ideal deceased donor profile is as follows: age <40 years,
trauma as the cause of death, donation after brain death,
hemodynamic stability at the time of procurement, no steatosis or any other underlying chronic liver lesions, and no transmissible disease (33). This implies a very low risk of initial
poor graft function or primary graft failure resulting in death
or retransplantation. However, the profile of deceased donors
is changing and the past decade has seen an increasing proportion of donors >50 years of age with cerebrovascular disease as
cause of death (34,35).
Expanded Criteria Donor
The impact of changing deceased donor characteristics and
widening gap between the donor pool and the waiting list
means that deceased donors with features deviating from the
donor profile are increasingly utilized (36,37). The term
extended or expanded criteria donor (ECD) has been coined
for such donors (Table 32.3), which suggests a higher risk of
graft failure and decreased survival. Rather than a clear good or
bad liver graft, ECD represents a spectrum of cumulative donor
risks which should be taken into consideration (33,38,39).
Steatosis and Abnormal Liver Function
A recent international consensus meeting on ECD grafts (40)
recommended against using liver allografts with severe steatosis (>60%) and from elderly donors in HCV-infected recipients.
Abnormal liver function tests are not contraindications but
careful assessment of other donor factors is essential, especially
if there is a marked rise in gamma glutamyl transpeptidase level
(>200 UI/L).
Elderly Donors
Patients with liver transplant from elderly donors have shown
comparable survival, provided that there are no additional risk
factors (41,42). While there is no clear age limit in utilizing an
289
elderly donor liver, there are two caveats: (i) liver grafts of
advanced age have reduced regenerative capacity and synthetic
function, and are more susceptible to cold ischemic injury and
(ii) elderly liver grafts should not be used for HCV-positive
patients because of the high risk of severe HCV recurrence (43)
and reduced graft and patient survival (44).
Donors with Infection
The use of donors with bacteremia or bacterial meningitis
seems safe as the risk transmission is low (4%) (40,45), especially when appropriate prophylactic antibiotic therapy is
instituted (46). However, donors with systemic sepsis, multiorgan failure, tuberculosis, or infected with multi-resistant
organisms should be avoided (46,47).
Donors with Hepatitis B Core Antibody Positive
The use of hepatitis B core antibody (anti-HBc) positive donor
livers and post-operative management remain controversial.
Recipients who receive anti-HBc-positive livers are at a greater
risk of developing de novo HBV with reported incidences of
72% (48) to 78% (49), compared to candidates who had antiHBc-negative livers (0.5%) (49). This is due to detectable levels
of HBV DNA in serum and/or liver tissues of anti-HBc-positive
donors, despite no other serological markers of HBV being
present (50,51). Interestingly, studies have shown that recipients who are anti-HBc and/or anti-HBs-positive are protected
with a much lower risk of de novo HBV from an anti-HBcpositive liver (48,52).
Management strategies to prevent de novo HBV in recipients of anti-HBc-positive livers involve using lamivudine and/
or hepatitis B immunoglobulin (HBIG) depending on the
serological status of the donor and recipient. Recently, adefovir dipivoxil was proposed as an alternative to HBIG (23).
There is no consensus as yet on the prophylactic strategies
with some units preferring HBIG monotherapy (53) and others using lamivudine only (54). Our units protocol comprises
of long-term lamivudine for recipients of anti-HBc-positive
livers. For patients receiving hepatitis B surface antigen-positive
livers, long-term lamivudine and adefovir regimens are used.
290
Level of Risk
Recommendations
0
81
Low
Extreme
0
40
39
19
Low
High
High
Intermediate
Breast
29
Intermediate
61
Intermediate
Choriocarcinoma
93
Extreme
291
292
The senior author has used VVB only once in the last 100 liver
transplants and has only once used a portocaval shunt.
Operative Technique of Orthotopic Liver Transplantation
Hepatectomy of Recipients Native Liver
OLT can be performed using a variety of incisions, most commonly the Mercedes incision in the literature, but the senior
author prefers an inverted L, gentle rooftop or midline incision
in order to offer a better cosmetic result. A mechanical retraction
system is used to allow adequate exposure to the liver. The common bile duct (CBD) and hepatic artery are ligated and divided,
preserving length to increase implantation options. The portal
vein is then isolated. Hepatectomy begins with mobilization of
the liver from the abdominal wall and IVC with ligation of retrohepatic and caudate lobe veins. The portal vein is clamped and
divided and then the hepatic veins are stapled or suture-ligated
and divided, allowing completion of the hepatectomy.
Implantation of Deceased Donor Liver
In the authors center, IVC anastomosis is by triangular cavocavostomy or self-triangulating cavocavostomy in most cases
(90). Both surgical techniques have the advantage of having no
posterior suture line and by triangulating the cavocavostomy,
the outflow tract is widened, reducing the risk of venous outflow obstruction (90). The self-triangulating cavocavostomy is
worthy of description. A side-biting clamp is placed on the
IVC, below the level of the hepatic veins, to allow a 6 to 8 cm
cavotomy, without occluding the IVC. The donor IVC is
bisected from the top posteriorly for 4 to 6 cm, trimming the
excess IVC from the split to create a 5 mm cuff of IVC around
the caudate lobe. Two 3-0 polypropylene sutures are used for
caval anastomosis, one from the top end and the other from
the bottom end of the cavotomy of recipient IVC. The graft is
flushed through the portal vein with 500 ml of 4.5% albumin
(as UW is high in potassium and adenosine content), and the
lower end of the donor IVC closed using a vascular stapler.
End-to-end portal vein anastomosis is performed 5-0 polypropylene and the liver is reperfused. Removal of the IVC
clamp creates the triangulation as the cuff of donor IVC will
open the anastomosis transversely.
Hepatic artery reconstruction is performed onto the recipients hepatic artery using 7-0 or 8-0 polypropylene sutures.
CBD anastomosis is performed either end-to-end with recipients CBD or hepaticojejunostomy if there is a significant
donorrecipient CBD size discrepancy or if recipients liver
disease involves biliary strictures (e.g., primary sclerosing
cholangitisPSC). Once satisfactory hemostasis is achieved,
drains are placed in the subhepatic regions and abdominal closure is performed under minimal tension. Modern liver transplant surgery takes on average 3 to 4 hours, although complex
cases may take considerably longer.
Post-operative Management and Immunosuppression
Patients are normally nursed in the intensive care unit initially,
although most will be extubated and returned to the general
ward within 24 hours. Unit protocols vary but we use an intravenous infusions of heparin (40 units/kg/24 hours) and
N-acetylcysteine (10 g over 24 h) for the first 4 to 7 days.
Antifungal Therapy
5 days of 200 mg fluconazole per day (reduced dose in renal impaired
recipients, according to serum creatinine)
1428 days fluconazole (reduced dose in renal impaired recipients,
according to serum creatinine)
293
294
295
296
Varicella 1
Non-ABC 4
HAV 2
L Hep 5
L Trix 2
LLSx 17
L Hep 11
R Trix 2
R trix +
caudate 1
R Hep 4
L Hep 2
R Hep 4
LLSx 1
L Hep 4
R Hep 7
NR
Whole 5
Whole
Caudate 2
LL 20
LLS 8
R Tri 6
R Tri +
Caudate 1
RL 5
LL 2
LLS 2
Whole 2
LL 2
RL 4
LLS 1
LL 4
RL 7
Whole 5
R Tri 16
RL 7
LL 4
LLS 8
(only 40
recorded op)
LLS 2
LL 3
RL 1
LL 6
RL 9
NR
NR
Whole 13
Donor Liver
Transplant
R Trix 13
Native Liver
Operation
NR
11
APOLT 6
HALT 5
NR
Biliary
Complication
Vascular
Complication
6
APOLT 3
HALT 3
Primary
Nonfunction
Retransplant
18
APOLT 10
HALT 8
11
Mortality
57
62
APOLT 71
HALT 33
66
66
67
80
69
1-yr Survival
100
38
25
80
60
53
100
ALT Off
IS (%)
Contains both adult and children recipients; bLiving donors; Abbreviations: LLSx indicates left lateral sectionectomy; R Hep, Right hepatectomy; L Hep, Left hepatectomy; R Trix, Right trisectionectomy; L Trix, Left
trisectionectomy; LLS, Left lateral section; LL, Left lobe; RL, Right lobe; R Tri, Right Trisectional graft; AOD, Acetominophen overdose; AIH, Autoimmune hepatitis; HAV, Hepatitis A virus; HBV, Hepatitis B virus;
EBV, Epstein-Barr virus; HALT, Heterotropic auxiliary liver transplantation; APOLT, Auxiliary partial orthotopic liver transplantation; Whole, Auxiliary whole orthotopic liver graft transplantation; NR, Not recorded.
Source: From Ref. 157.
Omaha (156)a
1997
12
47 (includes
12 HALT)
HAV 1
HBV 2
Drug 1
Unknown 7
Other 1
Viral 18
Nonviral 29
(AOD 5)
Clichy (129)
2002
Villejuif (133)a
2001
EURALT (130)a
1999
HAV 3
HBV 3
Drugs 4
Others 5
HBV 6
15
Strasborg (120)a
2002
HBV 1
Unknown 5
Non-ABC 24
AOD 15
HBV 4
Drug 3
AIH 2
Mushroom 1
49
AOD 13
Indications
13
Patients
Kyoto (134)ab
2005
Leeds (124)
2008
London (122)a
2008
Studies
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33
introduction
Benign cystic lesions of the liver were historically an uncommon clinical entity, presenting only when symptoms or complications occurred. However, with the wider availability of
sophisticated radiological techniques, these lesions are being
recognized more commonly. In spite of this they sometimes
represent a diagnostic challenge. Common cystic lesions range
from the single, simple, small liver cyst to the florid appearance of polycystic liver disease. More uncommon lesions are
mesenchymal hamartomas (in pediatric patients), biliary
hamartomas, and ciliated foregut hepatic cysts. Once a firm
diagnosis is made, management is usually expectant unless
symptoms worsen.
simple cysts
Simple biliary hepatic cysts are congenital lesions which are
thought to result from progressive dilatation of biliary microhamartomas, otherwise known as von Meyenbergs complexes.
They are lined by flattened biliary epithelium which rests on a
thin underlying rim of fibrous stroma, without a distinct separation from adjacent hepatic parenchyma. They may be solitary or multiple, and do not normally communicate with the
biliary tree (1). The cysts contain serous fluid which is continuously excreted by the lining epithelial cells.
clinical presentation
Most simple hepatic cysts are asymptomatic and are detected
as an incidental finding during imaging of the abdomen for
other indications. Ultrasound scanning demonstrates a
rounded, anechoic intra-hepatic mass with good-through
transmission and an imperceptible wall (2). On unenhanced
computed tomography (CT) imaging a simple cyst appears as
a homogenous lesion of low attenuation, with no enhancement of the wall or content following the administration of
contrast (3) (Fig. 33.1). With magnetic resonance (MR) scanning, simple cysts show low attenuation on T1-weighted
images (Fig. 33.2A) and homogeneous, very high signal intensity on T2-weighted images (Fig. 33.2B).
The differential diagnosis includes multiple cysts arising as a
result of polycystic liver disease, juvenile hydatid cysts, parasitic liver cysts, and biliary cystadenomas or cystadenocarcinomas. The differentiation between these lesions can largely be
made on imaging characteristics. Hepatic metastases can occasionally appear cystic, particularly neuroendocrine tumors
and sarcomas.
natural history
An early series, based on findings at laparotomy, estimated a
low prevalence of simple hepatic cysts of 0.17%, although
many small cysts were probably missed (4). More recent data
based on imaging studies suggests the prevalence is between
1.6% and 18% (59). Females are affected more than males (6).
The frequency of diagnosis increases with age with the peak
incidence occurring between the ages of 50 and 60 years (10,11).
Typically, patients with simple hepatic cysts have no symptoms. However, larger cysts may exert a mass effect and cause
upper abdominal discomfort and early satiety. Symptoms are
more common with right sided cysts (10). Complications are
rare but include intra-cystic hemorrhage (12), biliary obstruction due to compression of the biliary tree (13,14), vascular
compression (15), cyst rupture (16), and cyst torsion. Bacterial
infection can occur within a cyst, particularly when there is
communication with the biliary tree (17).
treatment
The vast majority of simple hepatic cysts are incidental and,
once the diagnosis is established, require no treatment. Even
for those patients with abdominal symptoms the possibility of
another underlying cause must always be considered and
investigated.
aspiration
Ultrasound-guided percutaneous cyst aspiration has little role in
the treatment of symptomatic simple cysts as the recurrence rate
is high (78100%) (1820), sometimes as rapid as 2 weeks (18).
However, cyst aspiration can be used as a trial of therapy. If symptoms persist after needle aspiration then the cyst is unlikely to be
the cause, and other pathology must be sought. Conversely, if
symptoms abate after cyst aspiration, and return with recurrence
of the cyst, then a definitive treatment of the cyst is indicated.
aspiration sclerotherapy
Aspiration sclerotherapy is a well-tested therapeutic technique
for the treatment of simple hepatic cysts. The procedure
involves the aspiration of cyst fluid followed by the instillation
of a sclerosant. A number of sclerosing agents have been used
including tetracycline (21,22), minocycline (23,24), pantopaque (25), and alcohol (11,2629).
The procedure is performed under ultrasound or CT guidance. A pigtail catheter is inserted into the cyst, and the cyst
fluid aspirated. The fluid is usually clear and should be sent for
cytology to exclude malignancy, culture to exclude infection,
and microscopy to look for hydatid scolices. In addition the
fluid should be assessed for the tumor marker CA199 which,
if elevated, suggests an underlying diagnosis of cystadenoma
or cystadenocarcinoma (30). Any bile staining of the fluid
would suggest a communication with the biliary tree and
would mandate abandoning the procedure and further assessment with cholangiography. The consequence of inadvertent
injection of sclerosant into the biliary tree is devastating, and
following cyst drainage a contrast cystogram should always be
performed (28).
301
surgical treatment
Figure 33.1 Multidetector computed tomography (MDCT) image with iodinated intravenous contrast media. A large simple cyst is seen in segments 6 and
7. A small cyst is noted on the periphery of segment 2.
(A)
(B)
Figure 33.2 (A) T1-weighted MRI image through the upper abdomen showing multiple cysts throughout the liver. Fluid is dark on T1-weighting (B) T2-weighted
coronal view of the abdomen of the same patient as in Figure 33.2A. The cysts are clearly seen as bright throughout the liver. This section is taken through the
vascular pedicle of the liver.
302
laparoscopic surgery
In recent years, the technique of laparoscopic cyst fenestration
has developed and should now be the first-line surgical
approach for patients with symptomatic simple cysts. Laparoscopic cyst fenestration has all the advantages of minimally
invasive surgery including reduced postoperative pain, shorter
hospital stay, and quicker recovery. The laparoscopic procedure was initially recommended for cysts in segments II, III,
IVb, and V. However, with increasing experience, location
should not be considered a contraindication to laparoscopic
surgery (40). A standard 4 port laparoscopic technique is used
with the patient in a supine position, although for right-sided
posteriorly placed cysts a left lateral position can give superior
access. An angled laparoscope (30 or 45 degrees) gives superior
views of the cyst cavity. The cyst can be punctured by insertion
of a trocar through the exposed wall. The contents are sent for
analysis. A wide excision of the cyst wall is then made, taking
great care not to venture into the hepatic parenchyma. Various
techniques have been employed to achieve hemostasis of the
remnant cyst wall including diathermy, over sewing of the
remnant cyst wall edge and using a laparoscopic linear cutting
vascular stapler to excise the cyst wall. The authors preference
is to use harmonic shears.
The resected cyst wall is removed in an endoscopic retrieval
bag, and the remnant cyst wall is inspected. Although unusual,
if a bile leak is identified it must be controlled either with a
suture or with a laparoscopic clip. Some authors advocate
obliteration of the residual cyst wall with electrocautery. If this
is attempted it should be done without breaching the cyst wall
as major vascular structures, distorted by the cyst, can lie just
underneath. The argon beam coagulator is probably best
suited to the task (41) as the burn is very superficial. There is
the potential risk of gas embolus and careful control of intraperitoneal pressure must be maintained.
To prevent recurrence of the cyst, particularly when the
exposed cyst cavity will come to lie against the abdominal wall,
an omentoplasty should be performed. A pedicle of omentum
is mobilized from the transverse colon and advanced into the
cyst cavity. It can be secured either with sutures or with laparoscopic clips. A cholecystectomy is not routinely performed
unless there is evidence of cholecystolithiasis, or where the cyst
drainage leaves the gallbladder excessively mobile and at risk
of subsequent torsion.
open surgery
With the development of the laparoscopic technique, the procedure of open cyst fenestration for benign simple cysts should
be reserved for those patients with recurrent disease or with
extensive abdominal adhesions that preclude the laparoscopic
technique. More radical procedures, including cystectomy and
liver resection, carry a greater morbidity and mortality than
cyst fenestration (44). Cystectomy can be particularly dangerous as the adjacent parenchyma is compressed and major vascular structures are often within the walls of the cyst. The main
indication for resection is when there is suspicion that the cyst
may be neoplastic in nature.
clinical presentation
The majority of patients with PCLD are asymptomatic and, as
with simple cysts, the diagnosis is made during routine investigation (50). Laboratory tests of liver function including bilirubin, alkaline phosphatase, alanine aminotransferase, and
prothrombin time are usually normal. Symptoms tend to
occur in patients with longstanding disease and are related to
liver enlargement and compression of adjacent organs. Patients
may complain of an increase in abdominal girth, upper
abdominal pain, early satiety, nausea, respiratory compromise,
and limitation in physical ability.
More significant complications include hemorrhage into a
cyst, infection within a cyst and compression of vascular and
303
Type III
Figure 33.3 Portal venous phase MDCT image showing multiple large cysts
throughout the liver. Cysts are also noted within the kidneys.
Features
Limited number (<10) of large cysts with
large areas of non-cystic parenchyma.
Diffuse involvement of liver with multiple
medium sized cysts with remaining large
areas of non-cystic parenchyma.
Massive diffuse involvement of all areas of
liver by small and medium-sized cysts with
only a few areas of normal parenchyma
between cysts.
aspiration sclerotherapy
The techniques of serial cyst aspiration (55) and serial aspiration sclerotherapy (56) have been used with success in the
treatment of PCLD. However, there is a higher rate of recurrence in PCLD than seen in the treatment of simple hepatic
cysts, one explanation being that the more rigid hepatic parenchyma prevents complete collapse of the cysts (27). As a result,
this technique is probably best suited to patients with Gigot
type I disease in whom more aggressive surgical options would
be contraindicated. One exception would be in treating the
life-threatening complication of cyst infection where a combination of antibiotic therapy and cyst drainage is required to
reduce mortality (52).
surgical treatment
Figure 33.4 T2-weighted MRI image of the upper abdomen showing the
appearance of multiple fluid filled simple cysts both in the liver and in the left
kidney of a patient with PCLD. Fluid is bright on T2-weighting.
treatment
Therapeutic intervention should only be considered for
those patients with significant symptoms or complications
304
Surgical options for the treatment of PCLD include cyst fenestration, liver resection, a combination of cyst fenestration and
liver resection, and liver transplantation.
The procedure of cyst fenestration, either by an open or by
a laparoscopic approach, involves the progressive deroofing
of liver cysts, starting superficially and working through to
cysts placed deeper within the liver parenchyma. This
approach is best suited to patients with Gigot type I disease.
The resulting decrease in liver volume can lead to a significant improvement in symptoms for the majority of patients
(57,58).
For patients with more severe parenchymal involvement,
classified as Gigot types II and III, fenestration alone is rarely
successful. A combination of hepatic resection with fenestration may, however, offer alleviation of symptoms through a
reduction in liver volume and mass (5961). The procedure
typically involves a non-anatomical resection of either the
right or left hemi-liver with fenestration of accessible cysts on
the remnant side. The preservation of hepatic parenchyma is
crucial when planning the resection. The procedure can be
technically challenging as the hepatic anatomy is distorted by
the cysts. The absence of landmarks predisposes to injury of
the remnant liver inflow or outflow. The major vasculo-biliary
structures are often compressed between adjacent cyst walls,
novel treatments
Medical treatments have in the past had little role in the treatment of PCLD. There are reports of a reduction in cyst volume using the somatostatin analog octreotide. The effect is
thought to be due to a direct reduction of fluid secretion by
cholangiocytes (72). In one recent clinical trial, the treatment
summary
Benign cystic lesions of the liver are being increasingly recognized due to improvements in and wider availability of radiological techniques. They only require treatment if they produce
symptoms or if there is a diagnostic uncertainty. Treatment is
usually in the form of percutaneous aspiration, aspiration
sclerotherapy or surgery. Surgical treatment ranges from fenestration of the cyst wall, cystectomy, or liver resection. These can
be performed as open or laparoscopic procedures according to
the surgeons expertise. PCLD may rarely require liver transplantation. As yet there are no randomized or case control
studies comparing different treatment options. Therefore,
treatment decisions have to be based on level 3 evidence (the
case report or small case series) and the experience of the
treating physician.
305
key points
The vast majority of benign cystic lesions of the liver do
not require treatment. Rarer forms of these lesions may have
an element of diagnostic uncertainty. Indications for
treatment are
acknowledgments
The authors would like to acknowledge and thank Dr
David White, Consultant Radiologist, University Hospital
Aintree, Liverpool, for contributing the images reproduced in
this chapter.
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34
308
layer for impaired vital exchanges with the host and decreased
endocyst pressure (1). Among the various causes suggested,
pericyst thickening and the penetration of bile between the pericyst and cyst wall and inside it are of concern for the surgeon.
The pericyst, initially composed of very thin connective
lamina, subsequently tends to become thicker (up to 1 cm or
more), sclerose, and calcify. The process of cyst expansion
causes compression of hepatic parenchymal structures, in turn
engulfed into the pericyst. Large vessels are compressed and
displaced while remaining, however, patent for a long time.
Similarly, bile ducts remain patent and may open into the pericyst, between it, and the parasite wall. This phenomenon
occurs frequently, unlike the rare frank rupture of the cyst with
effusion of the cyst contents into a large duct and the main bile
duct. This is of the utmost importance for surgery, since on the
one hand its appearance causes major changes in the cyst and
pericyst development, and on the other it favors the development of postoperative complications such as biliary fistulas.
Bile filtration in the virtual interstitium between the pericyst
and the chitinous membrane can form a perivesicular biloma
with loss of direct contact of the cyst with the pericyst, a
decrease in the mother cyst pressure and membrane rupture.
At the same time, the appearance of bile is preliminary to
cyst infection.
Whatever the cause, endogenous vesiculation should be
considered as an initial attempt at survival by the primary parasite. Subsequently the neoformed hydatid material packed
into the cystic cavity tends to show signs of stress and to degenerate extensively with varying consistencies akin to: fruit jelly,
putty, plaster, dry clay, or pus (Fig. 34.2). At the same time, the
fibrous pericyst becomes thicker and calcium deposits appear
as increasingly extended and confluent granules and laminae,
forming in some cases a continuous thick shell. These degenerative aspects have been considered as corresponding to the
parasites death, which is not. Viable hydatids are most often
found within this degenerate material (2).
Protoscoleces and brood vesicles generated by the germinal
layer can penetrate the chitinous membrane through fissures
and then tend to advance into the pericyst (3). Alternatively,
there may be germinal islets trapped between the lamellae of
the syncytial layer. Once the germinal elements penetrate the
pericyst, they may grow inside and then project toward the
liver parenchyma as diverticular protrusions surrounded by
their own thin pericyst: exogenous vesiculation (Fig. 34.3). In
their cavity, they contain growing cysts, favored by easy
exchanges through the thin neoformed pericyst and behave as
the mother cyst. As there is no connection with the inner
surface of primary pericyst they cannot be detected or even
suspected with the most careful examination after emptying
(Fig. 34.4). The exogenous cyst, while growing, can pull away
from the mother cyst and this results in the commonly
BC
P
DC
thin residual septum (sand-glass-like cyst), or with the collapse of separating septum, the two cavities communicate
through a more or less wide operculum (sacculations).
As for the presence and frequency of ectogenic vesiculation, the
phenomenon is either ignored or largely underestimated (59),
because of the preference for conservative operations which
do not allow their identification, and because in all reported
series the recurrence rates of clear and multivesicular cysts are
calculated together, thus leading to an under-reporting of the
real incidence of recurrence in multivesicular cysts. However,
ectogenic vesiculation is recognized in about 30% of radical
operations for multivesicular cysts (10,11). Once this phenomenon was identified and quantitatively assessed, its importance was recognized beyond just biological and pathological
interest. Consequently, in a large number of patients in whom
procedures performed including no removal of the pericyst,
this could not be considered effective: actually, only the cyst
was resected. Viable, vital parasite foci remained, bound to
lead to disease progression. This was incorrectly considered a
recurrence attributed to implantation from accidental dissemination of the operating field or reinfection. The latter interpretations, already unconvincing, have lost credibility, based
on the observation that the findings of ectogenic vesiculation,
compared with the incidence of recurrence in series of conservative surgery, interestingly enough, were similar, at about
30%. This was furthermore confirmed by the fact that the
so-called recurrences were practically absent in series of radical
surgery (1214).
(A)
(B)
(C)
(D)
Figure 34.2 Cyst features (total pericystectomy specimens). (A) Multivesicular cyst; (B) yellow-colored cystic membrane for biliary infiltration; (C) calcific cyst of
jelly-like necrotic contents and intense biliary infiltration; (D) calcific coarctate cyst of chalk-colored contents and dry clay consistency.
309
(A)
(B)
(C)
(D)
Figure 34.3 Exogenous vesiculation: microscopic appearance. (A) Brood capsules and protoscoleces contained in a protrusion of germinal layer within the cuticle;
(B and C) intrapericyst exogenous vesiculation hydatid membranes within the pericyst of primary cyst; (D) extrapericyst exogenous vesiculation encircled by a
new pericyst and protruding in the liver parenchyma adjacent to the mother cyst.
(A)
(B)
(C)
(D)
Figure 34.4 Intra- and extrapericyst exogenous vesiculation. Macroscopic appearance in four total pericystectomy specimens. (A and B) Within the pericyst of
open cysts viable daughter cysts are observed, separated from the mother cyst cavity; (C and D) clusters of pedunculated pseudodiverticula, non-communicating
with the mother cyst cavity, covered with a thin pericyst and containing daughter cysts.
310
diagnosis
Hydatid cyst of the liver may be asymptomatic for years, sometimes for decades. Diagnosis may be accidental, based on an incidental clinical exam that detects swelling when the cyst is located
in a palpable abdominal area or, in the case of hepatomegaly,
subsequently assessed with other examinations. Liver hydatidosis
may be an incidental finding in a plain radiograph of the hepatic
region when the cyst is calcified, during a chest radiograph for a
raised hemidiaphragm or during US examination performed for
other reasons such as gallstones. In children, large hepatic
swellings from hydatid cysts are accompanied by evident deformities of the chest involving the last ribs and arches. Apart from
a sensation of pressure, a cyst of the liver may cause deep-seated
pain at the chest base because of diaphragmatic pleural or peritoneal reactive process. Dyspepsia, possibly from reflexes originating in the periductal nervous network, is not unusual.
Cholestasis from major bile duct compression may be responsible for fever, also of high grade. Liver function tests remain
normal for a long time.
Diagnosis is established using several investigations.
Conventional radiology may show a raised hemidiaphragm. In
calcific cysts, high-density roundish shadows are readily
visualized (Fig. 34.5).
Diagnostic Imaging
Ultrasonography (US)
Ultrasound is the preferred first-line imaging method for
hydatid liver cysts. It is non-invasive, low-cost and reproducible, thus suitable for postoperative follow-up or during
medical therapy. US supplies precise information on the size,
number, location, and vascular and biliary relationships of
the cyst as well as on its structure. Cysts are staged according
to the content patterns. Based on several studies and classifications (1518), liver hydatid cysts can be divided into six
types:
(A)
(B)
Figure 34.5 Plain radiographs. (A) Partial en brioche image of diaphragm profile; (B) calcific image pathognomonic of hydatid cyst.
311
(A)
(B)
Figure 34.6 US image. (A) Total detachment of parasite membrane from pericyst; (B) multivesicular hydatid cyst: rosette sign.
(A)
(B)
Figure 34.7 CT image. (A) Univesicular cyst; (B) water-snake sign of membrane detachment.
(A)
(B)
Figure 34.8 CT image. (A) Multivesicular cyst: honeycomb or rosette sign; (B) calcific cyst of segment VII in contact with the caval vein and causing intrahepatic duct dilation stasis.
312
(A)
(B)
Figure 34.9 (A) MRI coronal T1-weighted sequence after DTPA gadolinium injection with visualization of a cyst, about 2 cm in diameter, of segment IV at the
level of portal vein bifurcation (in the same patient a bulky hydatid cyst of segments VII, VIII, and V is present); (B) same technique in another patient. Inferior
caval vein compression with marked stenosis caused by a bulky cyst of right hemiliver.
Angiography
Hepatic artery angiography, inferior caval vein, and hepatic
vein venography have been progressively abandoned following
the introduction of US and CT-angiography. They may be still
of some use in the case of huge cysts to define their relationships with the main parenchymal vessels.
Percutaneous cholangiography is contraindicated in liver
hydatidosis because of the risk of perforation of the cystic wall
and dissemination of hydatid contents. Endoscopic retrograde
cholangiopancreatography (ERCP) can be considered the most
suitable procedure for the characterization of the common bile
duct and the biliary relationships and communication of the
cyst. It allows pre- or postoperative papillotomy and bile duct
clearing (2325). Perioperative cholangiography through the
remnant of the cystic duct may be of great use to detect the site
of cystobiliary fistulas.
Radioisotope Imaging
Scintigraphic imaging of the liver has been practically abandoned as a preoperative exam. Its use is presently restricted to
monitor postoperative liver function.
Serology
The hydatid cyst secretes and exposes numerous immunomodulatory molecules to the hosts immune system. These
molecules modulate both the innate and the adaptive arms of
the immune response and appear to target cellular and
humoral response. Several techniques for biologic diagnosis
and follow-up of human cystic hydatidos are used and there
are significant differences in specificity and sensitivity among
various tests (26). The diagnostic value of hydatidosis with
immunoelectrophoresis ranges between 91% and 94%. Immunoelectrophoresis can be used for post-treatment followup (27). Sensitivities for enzyme-linked immunosorbent assay
(ELISA) vary from 64% to 100% depending on the antigens
complications
During its development, hydatid cysts of the liver may undergo
a number of complications, some of them clinically dramatic.
Infection
Infection of the cystic cavity and its contents is an ill defined
and frequently asymptomatic complication (33). It is most
likely caused by the penetration of bile into the cavity. Together
with the contents, the mother membrane can be destroyed and
consequently the altered escavated pericystic wall loses its
function of delimiting the infectious process which reaches the
hepatic parenchyma. Clinical course and related treatment are,
in this case, those of a hepatic abscess (34,35).
Rupture
Frank rupture (major communication) into the bile ducts
should be distinguished from simple biliary communication
(minor communication). Minor communications are usually
asymptomatic, revealed intraoperatively by a yellowish staining of the cystic content and the finding of biliary leakage in
the residual cavity. The true incidence of minor communication is ill defined; and the reported rates range between 28.6%
and 70% (36,37). The risk of biliary cyst communication has
been reported to be higher in patients with multiple cysts, in
patients to multilocular and degenerated cysts, and in patients
with cysts near the biliary bifurcation (38). Cyst diameter
313
(A)
(B)
Figure 34.10 Residual surfaces after removal of deep or vasculobiliary cysts: dissected and preserved vascular and biliary elements are indispensable for the survival
and function of parenchymal structures adjacent to the cyst. (A) The caval vein (c) and right hepatic vein with branchings are well visualized; (B) vasculobiliary
network of hilar origin distribution.
314
In turn, hepatic venous cysts are divided into right (VII and
VIII), median (IV), left (II); hilar cysts are divided into
right (V), anterior median (IV), and posterior (I), left (II and/
or III) (Fig. 34.11).
Clearly, there may be some overlap between locations. For
example, right hepatic cysts may extend to the midright lobe
and left hepatic cysts may be located across the hilum. Obviously, these possibilities do not affect the principles on which
the classification is based.
treatment
The desired goals of treatment of liver hydatidosis include
complete elimination of the parasite, prevention of recurrent
disease, achieved with minimum mortality. In spite of other
proposed techniques, surgery remains the first-line treatment.
There is, however, considerable disagreement about the surgical technique to be adopted. The major issue of debate is
whether complete removal of the pericyst is necessary for the
proper care of the disease. The focused concepts about the
7
2
5
3
6
Univesicular (sterile), clear cysts, lacking of the pericyst, can be safely treated by conservative surgery.
Multivesicular (fertile) cysts at different developmental stage should be treated by radical surgery
because of the risk of exogenous vesiculation and
because of high rates of postoperative complications.
approaches
Access must be generous for two main reasons: first, because of
the frequent presence of adhesions of the protruding cyst to
adjacent structures and organs, in particular the diaphragm.
Second, because of the need for extended liver mobilization to
control the vessels and exploit the liver flexibility to reduce the
cavities or residual surfaces after pericyst removal. The bilateral subcostal approach, possibly extended depending on the
location and size of the cyst(s), to the right as far as the midaxillary line, to the left as far as the lateral end of the rectus muscle, and medially upward as far as the xiphoid process of the
sternum (mercedes incision) is the classic approach for liver
surgery and hence for the surgical treatment of liver hydatidosis. Median laparotomy may be adequate for cysts located in
the left lobe, when the right liver is known to be unaffected.
The thoraco-abdominal approach is a no longer used, except
in case of hydatid cysts involving the right lung base.
Intraoperative General Concerns
Protection of the operating field is mandatory before the
planned operation on the cyst or before the cyst is emptied. A
cautious approach is to apply protection before liver dissection, and when the cyst is protruding from the liver surface
and adhering to the adjacent structures and organs. Isolation
of the peritoneal and/or pleural cavity to limit the access to the
operative field is achieved with dry gauze, preferred by the
authors, or soaked in a parasiticidal or hypertonic saline solution, not unanimously considered harmless. During prior
emptying of the cyst the gauze pads should be placed around
the site of puncture by the trocar. When emptying the cyst, a
large caliber trocar is connected with an aspirator by a similarly large non-collapsible tube. As soon as the cyst pressure is
relieved and the protruding pericyst tends to collapse, two of
its folds are grasped and raised with Allis or ovum forceps. The
amount emptied depends on the contents: it will be practically
complete in univesicular cysts, more or less partial in multilocular cysts where the hydatid material is abundant and
dense. If the pericyst wall is opened with electric cautery, direct
emptying is completed through a large tube with a frontal
315
316
relationships with the hepatic ducts and biliary communication should be carefully evaluated. In fact, it becomes evident
only after emptying and removal of membrane. The extent of
pericyst resection is based on how much of it is protruding or
how close it is to the hilar and adjacent major vasculobiliary
structures. A pericyst margin adequate for subsequent suturing should be considered. Resection is performed with electric
cautery and the help of Allis forceps on the residual margin;
particular attention should be paid to adjacent structures at
risk (Fig. 34.12). The analogy of the method with the dome
saillant resection proposed by Lagrot in the 1950s (69) and
still used (70) is only apparent because here it is limited to
clear cysts with a thin and soft pericyst after wide-field exposure, complete liver mobilization, control of hilar and caval
structures. All these measures enable the resection of ample
pericyst surfaces up to two-thirds of it, while suturing of residual margins exploits the flexibility of the liver once free of
its ligaments.
The control of bile leaks is very important. Bile transudation
may occur on the resection margins from small orifices, which
must be sutured to prevent bile collection within the cavity. As
for the search for major communications, the induction of
biliary hypertension by compression of the distal hepatic pedicle over the duodenum, squeezing the gallbladder at the same
time, may be useful. Then even minimal communication is
evidenced by a drop or flow of bile. The use of dyes must be
considered pointless because the site of the leak is always recognizable after having cleansed the residual cavity with a pad.
However, these are not the typical patterns of univesicular
cysts. Once the residual cystic wall has been controlled, closure
Radical Procedures
Radical procedures include major hepatic resection and total
pericistectomy. Hepatic resection since ever has not been considered the principal technique to resort to when treating liver
hydatidosis. The notable development of liver resective surgery in more recent years has not changed this trend so that
the rate of hepatic resections rarely exceeds 10% (76,77). Technically these resections are similar to those performed for
other indications, except for the possible extension of the cyst
beyond the anatomical limits of the hemiliver or sector to be
removed and the biliary relationship on which the indication
was based (Fig. 34.13). The first occurrence may involve difficult pericyst dissection from vasculobiliary structures supplying territories to be preserved. Furthermore, resections are
adopted in case entire sectors, lobes, or hemilivers are destroyed
by the cyst(s) and interruption of main bile ducts would make
their repair questionable because of a very high risk of serious
cholerrhagia. With the exception of these particular cases the
general policy should be to avoid liver resection in order to
spare as much health hepatic parenchyma as possible.
Wedge resections and liver transplantation should be mentioned in passing. Actually while the former might find an
occasional indication in case of minute marginal anterior
cysts, the use of liver transplantation should be considered to
the utmost anedoctical (78).
(A)
(B)
(C)
(D)
Figure 34.13 Right hepatectomy extended to segment IV and caudate lobe. (A) Bulky cyst mass; (B) the residual surface is sutured; (C) surgical specimen; (D) the
gallbladder is packed with hydatid material.
317
318
Figure 34.16 Total open pericystectomy. Cautious full depth incision of pericyst with a lancet on the cavity bottom allows access to vessel dissection from
several directions, even in the case of very thick cysts.
319
320
Figure 34.19 Exploration and cleansing of biliary tract. Through papillosphincterostomy the spoon for stones or a probe can be carefully advanced
to identify the biliary breach and specify the type of communication, whether
lateral or terminal, with the cyst cavity.
key points
Medical Therapy
Benzimidazole carbamates (mebendazole and albendazole)
are antihelminthic drugs that affect the parasite viability,
mainly, by impairing its glucose uptake. Mebendazole was
introduced first (102), but albendazole became the drug of
choice because of its better absorption and better clinical
results (103). These results are achieved after long treatment (104). Adverse events of this treatment have been
reported in about 10% of patients treated (105). General
complaints are headache, nausea, anorexia, vomiting, abdominal pain, and itching. A transient increase in liver enzymes
may be observed in the first weeks of treatment. For clinical
practice, albendazole should be administered in a dose of
10 mg/kg twice daily during a meal in four 1-month cycles
with a 15-day rest, or 10 to 12 mg/kg/day continuously for
3 months. It should not be associated with drugs that reduce
gastric acidity (106). Factors affecting the efficacy of benzimidazoles have not been well defined, but it is known that
penetration of drug across the cyst walls depends on the
nature of the cyst. Young cysts without thick, fibro calcified
pericyst are more sensitive to drugs (107,108).
It is difficult to understand how the drug could overcome
the barrier of a dense fibrotic or calcific pericyst, up to 0.5 cm
thick, and kill the hydatid material packed into the cavity.
Moreover, it is hardly believable that exogenous vesiculations
within the pericyst might be reached by the drug. Recurrence
following albendazole therapy occurs in at least 20% to 30% of
responsive cases (108,109), to which a further 20% of patients,
considered negative in whom no change was visualized, should
be added. Preoperative albendazole treatment has been suggested in order to lower cyst viability. However, contrasting
outcomings have been reported possibly because viability tests
on the surgical specimen cannot be considered conclusive as
confirmed by the development of parasites from culture of
cystic fluid shown to be negative on direct microscopy (110).
Although no conclusive data on the efficacy of perioperative
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5. Bourgeon R, Catalano H, Guntz M. La pE9rikystectomie dans le traitement des kystes hydatiques du foie. J Chir 1961; 81: 15374.
6. Belli L, Del Favero E, Marni A, Romani F. Resection versus pericystectomy in the treatment of hydatidosis of the liver. Am J Surg 1983;
145: 23942.
7. Moreno Gonzales E, Jovez Navalon JM, Landa Garcia JI, et al. Surgical
management of liver hydatidosis. 10-year experience with 269 patients.
It J Surg Sci 1985; 15: 26773.
8. Debesse B, Dujon A. La pE9rikystectomie au plus prE8s dans le traitement du kyste hydatique du foie. Ann Chir 1987; 41: 64651.
9. Moreno Gonzales E, Rico Selas P, Bercedo Martinez J, et al. Results of
surgical treatment of hepatic hydatidosis: current therapeutic modifications. World J Surg 1991; 15: 25463.
10. Tagliacozzo S, Daniele GM, Pisano G. Pericistectomia totale per echinococco epatico. Arch Atti Soc It Chir 1979; 1: 657712.
11. Tagliacozzo S, Daniele GM, Pisano G. Total pericystectomy for hydatid
disease of the liver. 6B0 World Congr Coll Int Chir Dig, Lisbona 1980,
abst SP503.
12. Magistrelli P, Masetti R, Coppola R, et al. Surgical treatment of hydatid
disease of the liver. A 20 year experience. Arch Surg 1991; 126: 51823.
13. Moreno Gonzales E, Rico Selas P, Martinez B, et al. Results of surgical
treatment of hepatic hydatidosi: current therapeutic modifications.
World J Surg 1991; 15: 25463.
14. Aydin U, Yazici P, Onen Z, et al. The optimal treatment of hydatid cyst
of the liver: radical surgery with a significant reduced risk of recurrence.
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42. Valle-Sanz YD, Lorente-Ramos RM. Sonograaphic and computer tomographic demonstration of hydatid cysts communication with the biliary
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43. Bilsel Y, Bulut T, Yamaner S, et al. ERCP in the diagnosis and management of complications after surgery for hepatic echinococcosis 2003;
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44. Sozuer EM, Ok E, Arslan M. The perforation problem in hydatid disease. Am J Trop Med Hyg 2002; 66: 5757.
45. Abdel Hameed AA, Abu Aisha H. Uneventful intraperitoneal rupture of
a hepatic cyst: a case report Trop Geogr Med 1987, 39: 802.
46. Barros JL. Hydatid disease of the liver. Am J Surg 1978; 135: 597600.
47. Marcos Sanchez F, Turabian Fernandez JL, Caballero Gomez F, et al.
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323
35
overview
Primary sclerosing cholangitis (PSC) is a chronic, progressive
disease characterized by inflammation and fibrotic strictures
of the biliary tree. Strictures are usually multi-focal, with 75%
of patients demonstrating both intra- and extrahepatic duct
involvement. Only 10% of patients have isolated extrahepatic
duct involvement (13). The incidence of dominant strictures
accounting for the majority of symptoms is approximately 45%
and most (up to 80%) of these occur at or near the hilum (4).
PSC is not only associated with inflammatory bowel disease
(IBD) in 70% of cases, most commonly ulcerative colitis, but
also occurs in the setting of autoimmune diseases such as
ankylosing spondylitis, celiac sprue, autoimmune pancreatitis,
thyroiditis, and others. The overall risk of developing PSC in
patients with ulcerative colitis approaches 10%, for patients
with Crohns disease the risk is lower, approximately 2%. As
with inflammatory bowel disease there is an approximate
2:1 male to female predominance and most patients present in
young adulthood or middle age (5,6).
diagnosis
Patients with PSC usually present with signs of cholestasis
including right upper quadrant abdominal pain, jaundice,
pruritis, and/or abnormal serum liver studies. Some IBD
patients are diagnosed during routine screening for liver disease revealing elevated liver function tests particularly an elevated serum alkaline phosphatase (2,6). In the absence of
alternative etiologies of cholestatic liver disease, the diagnosis
is usually confirmed with high-quality imaging of the biliary
tree utilizing endoscopic retrograde cholangiography (ERC),
or more recently, magnetic resonance cholangiography
(MRC). Both methods effectively demonstrate the characteristic beads-on-a string strictures (Fig. 35.1) of PSC making
diagnosis possible in over 95% of cases using image criteria
alone (3). ERC offers the ability to perform concurrent intervention, with the disadvantage of the low (38%) but welldefined incidence of complications related to this invasive
procedure. MRC is diagnostic only, but has the advantage of
minimal risk. MRC is also superior for visualization of ductal
anatomy proximal to dominant strictures, and the two modalities may be used in complimentary fashion. Percutaneous
transhepatic cholangiography (PTC) and intervention can
also be utilized where the expertise exists, but PTC is notoriously difficult in patients with the altered ductal anatomy
inherent to PSC.
Regardless of imaging modality, detailed knowledge of a
patients ductal anatomy is essential prior to any surgical intervention. Liver biopsy should be obtained at the time of diagnosis to assess the hepatic parenchyma for the presence and
degree of fibrosis, which can alter treatment plans. Colonoscopy
should also be performed to identify patients with subclinical
324
natural history
The natural history of primary sclerosing cholangitis is variable but generally involves progression from cholestasis to
biliary cirrhosis and ultimately hepatic failure leading to liver
transplant or death. Many more patients are being diagnosed
in the asymptomatic stage as screening for IBD patients with
serum liver studies has become routine. PSC generally follows
an insidious course and some patients remain asymptomatic
for many years. However, others progress rapidly or present
initially with high-grade obstruction, cirrhosis, or cholangiocarcinoma. The median time from diagnosis to death or need
for liver transplantation is 12 to 18 years. Liver failure and
cholangiocarcinoma are the leading causes of death, in order
of frequency (6). The Mayo Clinic developed a mathematical
model to stratify patients risk, which has recently been
updated. It utilizes data on patient age, total bilirubin level,
aspartate aminotransferase level, presence of variceal bleeding,
and serum albumin level to predict survival and assign a Mayo
Risk Score (8). This can be used to prioritize treatment plans
for individual patients. Unfortunately, surgical treatment for
inflammatory bowel disease such as proctocolectomy for ulcerative colitis does not alter the natural course of PSC and patients
may even present years after successful treatment for IBD.
cholangiocarcinoma
Cholangiocarcinoma (CCA) develops in 10% to 30% of
patients with PSC, and the incidence of CCA increases with
the length of follow-up (510 years). The incidence of 10% at
5 years correlates with an increased risk of 160-fold over the
general population. It is an ominous finding as the majority of
patients have unresectable disease at the time of diagnosis and
an overall median survival of only 5 to 11 months. A high
index of suspicion is warranted, as just over half of patients
with CCA related to PSC are diagnosed concurrently or within
1 year of their initial presentation (9,10).
The diagnosis of cholangiocarcinoma in PSC can be challenging. Imaging techniques such as CT, MR, and positron
emission tomography have proven largely unreliable in distinguishing benign from malignant biliary strictures. The majority (approximately 80%) of CCAs in PSC occur at the liver
hilum, corresponding with the most frequent location for
dominant strictures in this disease. Brushings and/or biopsies
for cytology taken at the time of ERC have only up to 43%
sensitivity in detecting malignancy (11). Recently, advanced
cytologic techniques that identify chromosomal abnormalities
including digital image analysis (DIA) and fluorescence in situ
hybridization (FISH) have shown promise, but further study is
warranted before widespread application is possible (12).
(A)
(B)
Figure 35.1 Cholangiograms (A and B) demonstrating the characteristic beads on a string strictures of PSC.
medical treatment
The inflammation and strictures of primary sclerosing cholangitis are thought to be immune-mediated and various
immunosuppressive medications have been used in an attempt
to slow the progression of PSC. However, numerous prospective randomized trials have failed to identify an agent that
slows progression or improves outcome in patients with
PSC (6). The most extensively studied drug, ursodeoxycholic
acid, has been shown anecdotally to improve bile acid transport and have immuno-modulatory effects. However, despite
initial encouraging studies showing improvement in serum
liver studies and histologic findings on liver biopsy in PSC
patients, no definitive improvement in survival or outcome
has been observed in two large randomized trials (16,17). The
National Institute of Health has sponsored a multicenter trial
endoscopic management
Endoscopic treatment involving balloon dilation to relieve
symptomatic obstruction has become first-line treatment for
benign dominant biliary strictures in primary sclerosing cholangitis. Stents were routinely employed in the past but have
fallen out of favor due to studies identifying an increased risk
of bacterial cholangitis with their use (19,20). Dominant strictures are defined as common bile duct or common hepatic
duct stricture with a cross-sectional diameter of <1.5 mm and/
or a hepatic duct stricture with a diameter <1.0 mm within
2 cm of the hepatic duct bifurcation (21). Dilation of dominant strictures relieves symptoms, improves serum liver studies, and can produce durable improvement in imaging
findings. Most patients require multiple interventions for adequate biliary drainage (20).
The effect of endoscopic treatment on disease progression
and survival is controversial. Two studies by Stiehl et al. and
Baluyut et al. demonstrated improved overall survival and
transplant-free survival with repeated endoscopic dilation,
compared to that which would be predicted using the Mayo
mathematical model. The incidence of cholangiocarcinoma
developing during the follow-up period in the two series was
3% and 8%, respectively (Table 35.1) (21,22).
surgical management
Surgical resection for primary sclerosing cholangitis was the
only therapeutic option for patients with dominant strictures
before the development of advanced endoscopic techniques
and liver transplantation (2325). The fact that most of the
dominant strictures in PSC occur at or near the hepatic bifurcation makes resection and biliary-enteric drainage feasible
and effective therapy (26). However, morbidity and mortality
are high in patients with advanced disease and cirrhosis. Liver
transplant is the treatment of choice for these patients and PSC
has become a leading indication for transplantation. However,
although advancements in endoscopy and transplantation have
made resection of dominant strictures in PSC less common,
there is still a role for this approach in select patients.
325
1 year
3 year
5 year
97%
87%
87%
86%
74%
83%
77%
59%
92%
89%
85%
83%
95%
95%
10 year
CCA
8%
3%
8%
60%
0
0
1 year
3 year
5 year
85%
93%
59%
89%
46%
95%
92%
82%
3 year
5 year
10 year
85%
95%
60%
87%
76%
83%
36%
67%
52%
60%
12%
57%
326
summary
Primary sclerosing cholangitis is a chronic, stricturing disease
of the bile ducts leading to progressive cholestatic liver disease
and a dramatic increase in risk for cholangiocarcinoma. Dominant strictures are common and usually involve the hepatic
bifurcation. Medical therapy is ineffective in preventing progression of disease or improving outcomes. Optimal management of symptomatic noncirrhotic patients with dominant
strictures has been somewhat controversial. Endoscopic therapy palliates symptoms and is relatively low risk and outcomes
seem to be improved over mathematical predictions. However,
the risk of cholangiocarcinoma remains in endoscopically
treated patients and close follow-up is necessary. Surgical
resection of the extrahepatic biliary tree also improves survival
over predicted, and the primary site for the development of
cholangiocarcinoma is removed.
Therefore, a treatment strategy for symptomatic, noncirrhotic
patients with PSC should involve a multi-disciplinary approach.
High-quality imaging and a high index of suspicion for cholangiocarcinoma with appropriate screening measures are essential
after diagnosis. Initially, endoscopic dilation of seemingly benign
dominant strictures should be undertaken. Recurrent or suspicious lesions should be strongly considered for resection due to
the risk of CCA. The surgical approach should involve resection
of the extrahepatic biliary tree including the hepatic bifurcation
with hepaticojejunostomy. PSC patients that progress to cirrhosis are best treated with orthotopic liver transplant.
references
1. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995;
332: 92433.
2. Zyromski NJ, Pitt HA. Primary sclerosing cholangitis. In: Cameron JL, ed.
Current Surgical Therapy, 9th edn, Philadelphia: Mosby/Elsevier, 2008:
43842.
3. LaRusso NF, Shneider BL. Primary sclerosing cholangitis: summary of a
workshop. Hepatology 2006; 44: 74664.
4. Bjornsson E, Lindquist-Ottosson J, Asztely M, et al. Dominant stricture in
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327
328
36
329
surgical management
Although, many studies have suggested improved survival in
patients with early gallbladder cancer with radical surgery
including en bloc resection of gallbladder fossa and regional
lymphadenectomy, its role for those with advanced gallbladder
cancer remains controversial. First, patients with more
advanced disease often require more extensive resections than
early stage tumors, and operative morbidity and mortality
rates are higher (24). Second, the long-term outcomes after
resection, in general, tend to be poorer; long-term survival
after radical surgery has been reported only for patients with
limited local and lymph node spread. Therefore, the indication
of radical surgery should be limited to well-selected patients
based on thorough preoperative and intra-operative staging
and the extent of surgery should be determined based on the
area of tumor involvement.
Surgical resection is warranted only for those who with
locoregional disease without distant spread. Because of the
limited sensitivity of current imaging modalities to detect
metastatic lesions of gallbladder cancer, staging laparoscopy
prior to proceeding to laparotomy is very useful to assess the
abdomen for evidence of discontinuous liver disease or peritoneal metastasis and to avoid unnecessary laparotomy. Weber
et al. reported that 48% of patients with potentially resectable
gallbladder cancer on preoperative imaging work-up were
spared laparotomy by discovering unresectable disease by laparoscopy (25). Laparoscopic cholecystectomy should be
avoided when a preoperative cancer is suspected because of
the risk of violation of the plane between tumor and liver and
the risk of port site seeding.
330
outcomes
Although advances in surgical technique and improvement in
perioperative care allow us to perform radical resection for
patients with gallbladder cancer safely, the outcomes for those
with advanced cancer remain disappointing. The 5-year survival rates for patients having radical surgery ranged from 0%
to 51%, most of them fall in 20% to 30% (Table 36.1). Nodal
status and histological margin have been reported as predictive factors of survival after radical resection for this group of
patients throughout the literature. For example, Behari and his
colleague reported that positive node was associated with
incomplete resection and none of the patients with N1 disease
survived beyond 5 years (30). Endo and his colleague reported
in their analysis of 55 patients who underwent complete resection, a 77% 5-year survival for patients without nodal involvement, 33% for those with single lymph node involvement, and
0% for those with two or more lymph nodes involvement (35).
These findings suggest that radical resection should not be
performed for patients with gross lymph nodes involvement
or extensive tumor infiltration to adjacent structure on perioperative evaluation, both of which make complete resection
with histological negative margin unlikely.
adjuvant therapy
Because of its propensity to spread to regional lymph nodes at
early stage and high rate of locoregional recurrence, adjuvant
chemotherapy and/or chemoradiation therapy seems a rational therapeutic option for gallbladder cancer. Traditionally
5-FU based chemotherapeutic regimen has been used with or
without combination of chemoradiation. However, there are
few data to support its efficacy. The rarity of gallbladder cancer
and further limitation of patients who can undergo complete
resection make the randomized trial difficult to conduct. To
date, there is only one randomized trial examining the efficacy
of adjuvant chemotherapy for gallbladder cancer. This study
palliative care
Most patients with gallbladder cancer present with advanced,
incurable disease and many are not candidates for surgical
resection. The median survival of patients with advanced
gallbladder cancer who are deemed inoperable ranges between
2 and 4 months (6,9,40) and palliation of symptoms should
be the primary goal. Symptoms and conditions associated
with incurable gallbladder cancer include jaundice, cholangitis, pain, and gastrointestinal obstruction. For obstructive
jaundice or gastrointestinal obstruction, palliative intervention may be required. The common procedure for biliary
obstruction due to gallbladder cancer is a segment III
bypass (41). In their series of 41 consecutive segment III
bypass for patients with advanced gallbladder cancer, Kapoor
and his colleagues reported 87% success rate with 12% mortality and 51% morbidity rate (42). Because of poor survival,
biliary stent is a preferred option for most of the patients. It
can be placed via either percutaneous transhepatic route or
endoscopic approach with minimal morbidity. Intestinal
bypass should be performed only in patients who have symptomatic obstruction.
Systemic chemotherapy and radiation therapy have, in general, little impact on unresectable gallbladder cancer. Multiple
Year
2000
2002
2003
2007
2008
2009
N
58
38
24
39
631
72
Stage
III/IVa
III/IVab
III/IVaa
IIc
III/IVaa
IIc
28/25%
33/17%
28/0%
34%
3951/2224%
22%
Note
Multi-institutional study
331
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surgery for gallbladder cancer: a 20-year experience. J Gastrointest Surg
2004; 8(2): 18390.
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pancreatic diseases. Eur J Ultrasound 2003; 16(3): 14159.
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37
Extrahepatic cholangiocarcinoma
Yuji Nimura
preoperative managements
Staging of Cholangiocarcinoma
Recent developments in diagnostic modalities have changed
the preoperative staging system, with invasive techniques
being replaced by non-invasive diagnostic procedures. Extracorporeal ultrasonography (US) is first used to detect biliary
dilation proximally to a possible biliary lesion, and magnetic
resonance cholangiopancreatography (MRCP) is performed
to demonstrate gross anatomy of the biliary tree and the variation of the intrahepatic bile ducts. Surgical anatomy and the
extent of the cancer along the involved intrahepatic segmental
ducts also have to be clarified in patients with hilar cholangiocarcinoma (Fig. 37.4A). Multi-detector row CT (MDCT) is
helpful not only to assess the depth of invasion and longitudinal extension of cholangiocarcinoma but also to find lymph
node and distant organ metastases. Furthermore multiplanar
reformation (MPR) images provide more useful information
about complex structures at the hepatic hilus and display
the entire length of the involved bile duct, and show ductal
thickening and intraductal masses (Fig. 37.4B). Also volume
333
8c
8a
8a
4b
4b
8b
8c
8b
4c
4c
2
3a
7b
7a
3b
6c
3a
2
3b
7a 7b
5c
5c
6b 5b
6c
4a 5a
4a
5a
5b
6a
6a
6b
Figure 37.1 Cholangiographic anatomy of the intrahepatic subsegmental bile duct. Numerals refer to Couinauds segments. 3a, Superior branch; 3b, inferior
branch; 4a, inferior branch; 4b, superior branch; 4c, dorsal branch; 5a, ventral branch; 5b, dorsal branch; 5c, lateral branch; 6a, ventral branch; 6b, dorsal branch;
6c, lateral branch; 7a, ventral branch, 7b, dorsal branch; 8a, ventral branch; 8b, lateral branch; 8c, dorsal branch.
curative hepatobiliary resection (2936). These invasive diagnostic procedures are carried out during the preoperative
period of biliary drainage.
1r
1r
1ls
2
A
U
P
P
1li
1c
Figure 37.2 Surgical anatomy of the hepatic hilus, including the biliary and
portal branches of the caudate lobe. U, Umbilical portion of the left portal
vein; P, right posterior branch; A, right anterior branch; 1ls, superior branch of
the left caudate lobe; 1li, inferior branch of the left caudate lobe; 1r, branch of
the right caudate lobe; 1c, branch of the caudate process; 2, left lateral posterior branch; 3, left lateral anterior branch; 4, left medial branch.
334
EXTRAHEPATIC CHOLANGIOCARCINOMA
Round ligament
Round ligament
S4
S3
S4
P3
B3
P4
B4
S3
S4
P3
B3
P4
B4
B2
P2
LHD
Round ligament
P4
B4
B2
P2
LPV
B3a
P3
B3b
B2
P2
LHD
LHD
LPV
LPV
(A)
S3
(B)
(C)
Figure 37.3 Schema of the infraportal variation of the anterior branch of the left lateral section (B3). (A) Normal anatomy, (B) infraportal B3 joining B4,
(C) supraportal B3d (superior branch) and infraportal B3b (inferior branch).
(A)
(B)
(C)
Figure 37.4 (A) MRCP shows biliary stricture at the hepatic hilus. A possible diagnosis is hilar cholangiocarcinoma separating the hepatic confluence. (B) Coronal
images of multiplanar reformation (MPR) show a soft tissue tumor at the hepatic confluence separating the right and left hepatic duct (arrow). (C) The soft tissue
tumor separates the confluence of the right anterior and posterior sectional ducts (arrow).
(A)
(B)
Figure 37.5 Volume rendered (VR) images of the hepatic artery (A) and portal vein (B). 3D images can be obtained. (A). Irregular encasement is demonstrated on
the right hepatic artery (arrow). (B) The left portal vein is obstructed and the right portal vein is involved (arrow). P, right posterior sectional branch; 7d, paracaval
branch of the segment 7.
335
costs in shortening the period of postoperative antibiotics treatment and hospital stay.
operative procedures
Pancreatoduodenectomy for Mid-third and
Distal Cholangiocarcinoma
PD and pylorus-preserving pancreatoduodenectomy (PPPD)
have been used as the standard operation not only for pancreatic cancer but also for distal cholangiocarcinoma. Although
the details of this surgical procedure are presented in the chapter of pancreatic cancer, an important part of the procedure as
related to cholangiocarcinoma is presented to avoid an overlap
of description.
PD versus PPPD
PPPD is preferably used in biliary tract cancer surgery to preserve the important organs as much as possible. Also, as the
risk of peripyloric lymph node metastasis is low in extrahepatic
B4b
B2
B1
B3
P
B4a1
(A)
B4a2
(B)
Figure 37.6 (A) PTBD tube cholangiography in a supine position. A tip of the PTBD catheter (arrow) is introduced from the right anterior sectional duct into the
left hepatic duct across the hepatic confluence occupied by the tumor to drain bile from the future remnant hepatic lobe. Another PTBD catheter (arrow head) is
placed in the right posterior sectional duct. A: right anterior sectional duct, P: right posterior sectional duct, L: left hepatic duct. (B) PTBD tube cholangiography
in a right anterior and cranioanterior oblique position. Selective cholangiography of the left hepatic duct clearly demonstrates each segmental duct and the
expected resection line can be defined at the confluence of the left medial segmental duct proximally to the confluence of the caudate lobe branch. B1: caudate lobe
branch, B2: lateral posterior branch, B3: lateral anterior branch, B4a: medial inferior branch, B4b: medial superior branch.
Before
After
Figure 37.7 Volumetric changes of the liver sections before and after right trisectional portal vein embolization. Hypertrophy of the left lateral section is observed
after portal vein embolization.
336
EXTRAHEPATIC CHOLANGIOCARCINOMA
cholangiocarcinoma, PPPD is advisable as appropriate surgery
for distal cholangiocarcinoma.
Extent of Lymph Node Dissection
Lymph node metastasis, perineural invasion, surgical resection
margins, and pancreatic invasion are prognostic factors after
curative resection for middle and distal cholangiocarcinoma (4651). Therefore regional lymph node dissection is necessary, including the nodes in the hepatoduodenal ligament and
along the common hepatic and superior mesenteric arteries.
Proximal Extension of Resection
In cases of distal cholangiocarcinoma with proximal extension
close to the hepatic confluence, the proximal bile duct is carefully dissected while detaching the portal bifurcation and the
left hepatic duct is transected on the left extremity of the hilar
plate along the right wall of the umbilical portion of the left
portal vein (UP). At the resected margin of the left hepatic
duct, the openings of the resected segmental ducts (B2, B3,
and B4) are identified according to their anatomical variation.
On the right extremity of the hilar plate, the right hepatic
artery is carefully skeletonized in Rouvieres sulcus and the
right posterior sectoral duct is carefully divided with a negative margin. Next, the right anterior sectoral duct is divided.
The caudate lobe branches are sometimes identified and
divided according to their anatomical variation (Fig. 37.8).
Hepaticojejunostomy
After resecting the proximal bile duct, each individual sectional or segmental bile duct should be anatomically identified and sutured side by side to complete the hepaticoplasty
and to minimize the number of hepaticojejunostomies with a
Roux-en-Y jejunal limb. A running suture of 5-0 PDS is preferably used for both posterior and anterior wall anastomosis.
4
3
A
1
P
LH
HA
M
P
RH
Figure 37.8 Hilar bile duct resection. The right and left sectional or segmental ducts and caudate lobe branches are identified and divided with free margins.
Numerals refer to Couinauds segments. A, anterior sectional duct; P, posterior sectional duct; RHA, right hepatic artery; MHA, middle hepatic artery; LHA, left
hepatic artery.
337
338
Figure 37.9 The right posterior segmental and subsegmental ducts are identified
at the resected margin of the right posterior sectional duct. P6, posterior inferior portal branch; P7, posterior superior portal branch; B6a, ventral biliary
branch; B6bc, dorsal and lateral biliary branch; B7, posterior superior biliary
branch; RHV, right hepatic vein..
EXTRAHEPATIC CHOLANGIOCARCINOMA
caudate lobe from the IVC. At the cranial part of this procedure, the distal end of the RHV is divided and closed at the
confluence of the IVC.
Next, liver transection is started from the right edge of the
attachment of the round ligament and progressed dorsally
along the right edge of the UP and the portal branches for the
left medial section (S4) are ligated and divided. During this
procedure, the lumen of the divided portal branches must be
carefully observed not to overlook portal thrombi at the bifurcation if the right trisectional PE has already been carried out.
When medial branches of the left portal vein are divided, the
demarcation is observed more clearly along the right edge of
the falciform ligament. Then liver transection is advanced cranially along the demarcation and reaches the distal end of the
MHV at the confluence of the LHV or the IVC. And the MHV
is divided and closed at the confluence. Finally the left lateral
sectional duct is exposed and isolated cranially close to the UP
and divided with a free resection margin, and the right trisection of the liver, caudate lobe and the extrahepatic bile duct are
removed en bloc.
Anatomic Right Trisectionectomy
Anatomic right trisectionectomy is a more extensive hepatectomy than traditional right trisectionectomy and this more
aggressive procedure is indicated for more advanced hilar
cholangiocarcinoma which involves not only the right hepatic
duct and the left medial sectional duct but also the confluence
of the left medial and lateral sectional ducts (52).
The actual surgical procedure is slightly different from that
of traditional right trisectionectomy in dividing all the portal
branches for the left medial section (S4), including the main
superior and inferior branches and the dorsal branches which
ramify from the dorsal aspect of the UP. By progressing this
procedure, the UP is gradually turned counterclockwise to
expose the left lateral sectional duct more proximally on the
Figure 37.10 All left medial branches of the portal vein are divided to turn the umbilical portion of the vein and to expose the left lateral sectional duct more
proximally and left laterally to the vein. B2: lateral posterior branch, B3: lateral anterior branch, B4, P4: medial branch, P4c: dorsal branch, RPV: right portal vein.
339
discussion
Figure 37.11 The left lateral sectional or segmental ducts ( ) are resected
left dorsally to the umbilical portion of the left portal vein. In this case, right
hepatopancreatoduodenectomy with portal vein resection and reconstruction
(arrow) are performed. P, pancreas; RL, round ligament.
340
Recent improvement in preoperative staging system and managements of difficult biliary cancer patients, as well as technical developments in hepatobiliary surgery have increased the
rate of potentially curative resection and decreased postoperative morbidity and mortality (13,14,3640,4244). Although
preoperative BD has recently not been used prior to PD, the
value of preoperative BD before cholestatic liver resection has
not been clarified by RCTs (28).
As the HPD is the ultimate surgery for the visceral organs,
unexpectedly high morbidity and mortality have been
encountered (63); however, recent progress in surgical techniques and perioperative management for biliary cancer
patients with difficult preoperative complications improved
the outcome of this surgery and an increasing number of
operations and 5-year survivors have been reported not only
from aggressive surgeons in Japan but also from the United
States (6468). It is expected that an increasing number of
patients with locally advanced cholangiocarcinoma will be
considered for difficult surgeries employing HPD with or
without vascular resection, which should be justified by
improved outcome (6972).
Recent retrospective analysis of the impact of future liver remnant (FLR) volume and preoperative BD on postoperative hepatic
insufficiency and mortality rates revealed that preoperative BD
did not appear to improve perioperative outcome in patients
with FLR 30% and PVE is likely to offer little benefit (73).
According to the continued and utmost efforts of aggressive
hepatobiliary surgeons, favorable results of PD and hepatectomy have been reported and prognostic factors after curative
resection of extrahepatic cholangiocarcinoma have been
revealed (2227,42,4651).
Although preoperative BD followed by PE has been used
prior to major hepatectomy for biliary cancer patients with
obstructive jaundice in many centers all over the world, it may
be difficult to clarify the value of this strategy by RCTs.
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50. Cheng Q, Luo X, Zhang B, et al. Distal bile duct carcinoma: prognostic
factors after curative surgery. A series of 112 cases. Ann Surg Oncol 2007;
14: 12129. (Category III) (Grade C).
51. Murakami Y, Uemura K, Hayashidani Y, et al. Pancreatoduodenectomy
for distal cholangiocarcinoma: prognostic impact of lymph node metastasis. World J Surg 2007; 31: 33742. (Category III) (Grade C).
52. 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: 2832. (Category III)
(Grade C).
341
342
38
background
ultrasound
ct scanning
For detailed information about potential causes of obstructive
jaundice, a high-quality, contrast-enhanced CT scan is often
necessary. CT scanning can give important information about
the pancreas (often obscured by bowel gas on ultrasound
scanning). Heads of pancreas tumors, that often present with
obstructive jaundice, are normally visible on targeted, enhanced
CT scans of the pancreas (14,15).
The degree of biliary dilatation and the site of any caliber
change in the biliary tree can provide additive information
about the tumor. Segmental intra-hepatic dilatation of the bile
ducts can suggest cholangiocarcinoma.
Lymphadenopathy can cause malignant biliary obstruction
and when this occurs this tends to be at the porta hepatis. This
is normally well seen on CT scans with the opportunity to get
information about a possible site of primary tumor. Large
colonic masses or widespread lymphadenopathy with splenomegaly may suggest a possible cause of the malignancy.
The importance of CT scanning is that of diagnosing the
primary tumor, as well as providing information for staging
and operability.
CT scanning should ideally be performed prior to any endoscopic intervention of the biliary tree (ERCP) as the complication of pancreatitis can interfere with accurate staging of
the disease.
While CT may give a good indication of the site of biliary
obstruction and the cause, detailed views of the biliary tree are
better obtained with MR scanning.
mr scanning
Magnetic Resonance Imaging (MRI scanning) is increasingly
important in providing good imaging of the biliary tree (13).
343
endoscopic assessment
Endoscopic Intervention
The anatomy of the biliary tree allows good access to the biliary system with an endoscope. The bile ducts drain, via the
common bile duct, through the ampulla of Vater and sphincter
of Oddi into the second part of the duodenum.
This allows an accessible port of access to the biliary system
by use of an endoscope designed to sit opposite the ampulla
within the duodenum.
The use of endoscopy in the management of malignant biliary obstruction can be in the diagnosis, staging, and therapy of
the disease.
ercp
Endoscopic Retrograde Cholangio-Pancreatography (ERCP)
is an endoscopic method of accessing the biliary tree. ERCP is
performed using a side-viewing endoscope, passed normally
to the second part of the duodenum, sitting opposite the
ampulla of Vater (Fig. 38.4).
344
(A)
(B)
Figure 38.3 (A) EUS cholangio. (B) A Eus Ca Panc (arrow indicates the pancreatic tumor).
345
complications of ercp
The reason to limit the use of ERCP for therapy rather than diagnosis, unlike most other modalities of endoscopy, is the risk profile.
Because of the anatomy of the biliary tree, and the distal portion of the common bile duct passing through the head of the
pancreas, the main risk of ERCP is that of acute pancreatitis.
A lot of effort has been put into reducing the risk as much as
possible. This includes the improved training of ERCP endoscopists, as well as the development of guidance suggesting that
a fewer number of endoscopists perform ERCP to increase the
numbers performed by each individual. The technical changes
of wire-guided cannulation are also thought to reduce pancreatitis risk as wire cannulation of the pancreatic duct should
result in lower rates of ERCP-induced pancreatitis than opacification with contrast (18).
Rates of pancreatitis have been quoted very variably as 1% to
30% (1822); however, the recent large volume British Society
of Gastroenterology (BSG) audit of ERCP practice in the
United Kingdom reported pancreatitis rates of 1.5% with an
overall complication rate of 5.1% (23).
Other ERCP complications are those for standard endoscopy, namely bleeding and perforation. Another risk following
stenting of the ampulla is the risk of cholangitis (24); however,
346
direct cholangioscopy
A technique that has developed for the assessment of intrabiliary pathology is that of direct, per oral cholangioscopy.
Whereas traditional ERCP provides detailed information
about intra-biliary pathology, this is normally part of a contrastenhanced radiological cholangiogram performed with the assistance of an endoscope rather than direct vision. Strictures may
be misclassified as malignant rather than benign, particularly
with the relatively poor yield of biliary brushings (25,26).
Direct cholangioscopy provides the user the opportunity to
see directly into the biliary tree to the second- or third-order
ducts. A clearer impression about the nature of a stricture, be
it benign or malignant can be obtained and the cause of the
stricture can be biopsied as well as brushed, and this can be
done under direct vision, thereby improving the yield of diagnostic histology to about 80% (27,28).
The original cholangioscopy via ERCP scopes, were the
mother and baby scopes that required two operators to use
with one controlling the duodenoscope (mother) and the second
operating the smaller cholangioscope (baby). The baby scope
passed through the working channel of the duodenoscope.
As well as being clumsy, irrigation and visualization were
poor and newer technologies have enabled improved and
constant irrigation improving cholangioscopic views.
347
348
radiotherapy
Brachytherapy
Intraductal radiotherapy, brachytherapy has been used in a
small number of studies in an attempt to improve survival in
patients with nonresectable cholangiocarcinoma.
A retrospective study comparing brachytherapy to stenting
alone did show some survival benefit, that didnt achieve statistical significance (p = 0.06) in patients with type II or III
tumors treated with brachytherapy, but this was associated
with more stent changes and longer hospital stays. The authors
felt that the benefit was limited to those with type II or III
tumors treated within 10 months of diagnosis (86).
A more recent study looking at external beam radiotherapy
in conjunction with expandable metal stents in patients with
cholangiocarcinoma, showed longer survival in those than in
stents alone (10.6 vs. 6.4 months, p < 0.05) and longer stent
patency than metal stents alone (9.8 vs. 3.7 months, p < 0.001);
hilar strictures
Unilateral Versus Bilateral
The more difficult scenario is in strictures that affect the bifurcation of the common hepatic duct, the hilar strictures. These
are commonly caused by cholangiocarcinomas and if extend
beyond the hilum a decision has to be made about the best
approach to drainage (Fig. 38.12).
While the optimal drainage is achieved by bi-lobar drainage,
this can prove technically difficult, and the great danger in this
group of patients is in failing to drain an opacified area. This
has been shown in various series to increase morbidity and
mortality due to cholangitis (80,81).
Adequate palliation of jaundice is likely to be obtained with
drainage of 30% of the liver volume and this can normally be
achieved through unilobar stenting (8285).
Due to these problems, in some centers PTC is preferred to
ERC as at PTC the obstructed area is targeted first and this can
easily be drained.
349
photodynamic therapy
The greater majority of patients with cholangiocarcinoma do
not undergo resection (88). The disease has a particularly poor
prognosis, especially if the disease is advanced with a median
survival time of 62 days if there is bilateral intrahepatic disease (81). Photodynamic therapy (PDT) has emerged as a
promising new modality of treatment for patients who do not
undergo resection.
PDT uses the combination of two non-toxic moieties; light
and a photosensitizing chemical, which when combined
together produce a cytotoxic effect. The photosensitizer tends
to accumulate in proliferating tissue. This tissue is then illuminated with light of a wavelength appropriate to the absorption
spectrum of the photosensitizer. A photochemical reaction
generates cytotoxic reactive oxygen species resulting in apoptosis or necrosis of tumor cells. PDT may also cause thrombosis
in tumor blood vessels and induce a tumor-specific immune
reaction with more distant effects from the site of illumination.
Photofrin (Axcan Pharma Inc.) has been the most widely
used photosensitizer in this application and is a complex mix
of compounds derived from hematoporphyrin. It is activated
at a wavelength of 630 nm. The depth of necrosis obtained is 4
to 6 mm.
The technique of ERC-PDT involves the prior administration of Photofrin at a dose of 2 mg/kg, optimally 48 hours
before the procedure. A cylindrical laser diffuser fiber is
positioned across the malignant stricture through a standard cannula. Concurrent oxygen administration (4 l/min)
optimizes the PDT effect. A light dose of 180 to 200 J/cm is
delivered. Stents, preferably plastic, are inserted after the
Refer to
gastroenterology/
hepatology
Jaundiced patient
Non-obstructed
biliary system
Biliary ultrasound
Obstructed biliary
system
Cross sectional
imaging (CT/MR)
Other imaging
Hepatobiliary MDT
meeting review
Operable
Resection
perioperative
biliary drainage
Inoperable
Life expectancy
<4 months
Life expectancy
4 months
ERC/PTC and
plastic stent
ERC/PTC and
metal stent
350
conclusions
The management of biliary malignancy can be a complex
issue. There are various treatment options that are appropriate
and the choice of optimal treatment may depend on local
expertise.
We have found that in patients with proximal biliary neoplasia, the risks of cholangitis are higher than in other groups,
particularly when the biliary system has been previously
instrumented. Our group strongly advocates that patients with
a proximal biliary malignancy should be transferred to the
regional specialist center for a review of the imaging and an
appropriate method of biliary decompression to be arranged
and performed there. Local data suggest that this reduces the
rate of cholangitis in this cohort of patients.
We have found that the drainage of biliary disease can be
optimized with the use of SEMS as opposed to 10 F plastic
stents and that patients can still be operable following this.
Carefully sited SEMS can allow biliary drainage and a welldecompressed system without interfering in the surgical field.
We have also started using fully covered SEMS which have
proved safe to remove up to 3 months following deployment.
references
1. Ishizaki Y, Wakayama T, Okada Y, Kobayashi T. Magnetic resonance cholangiography for evaluation of obstructive jaundice. Am J Gastroenterol
1993 Dec; 88(12): 20727.
2. Pavone P, Laghi A, Passariello R. MR cholangiopancreatography in malignant biliary obstruction. Semin Ultrasound CT MRI 1999 Oct; 20(5):
31723.
3. Vaishali MD, Agarwal AK, Upadhyaya DN, et al. Magnetic resonance cholangiopancreatography in obstructive jaundice. J Clin Gastroenterol 2004;
38(10): 88790.
351
352
88. Shaib YH, Davila JA, Henderson L, McGlynn KA, El-Serag HB. Endoscopic
and surgical therapy for intrahepatic cholangiocarcinoma in the United
States: a population based study. J Clin Gastroenterol 2007 November/
December; 41(10): 9117.
89. Harewood GC, Baron TH, Rumalla A, Wang KK, Gores GJ, Stadheim LM,
et al. Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma.
J Gastroenterol Hepatol 2005; 20(3): 41520.
90. McCaughan JS Jr., Mertens BF, Cho C, Barabash RD, Payton HW. Photodynamic therapy to treat tumors of the extrahepatic biliary ducts. A case
report. Arch Surg 1991 January 1, 1991; 126(1): 1113.
91. Ortner M-AEJ, Liebetruth J, Schreiber S, et al. Photodynamic therapy of
nonresectable cholangiocarcinoma. Gastroenterology 1998; 114(3): 53642.
92. Rumalla A, Baron TH, Wang KK, et al. Endoscopic application of photodynamic therapy for cholangiocarcinoma. Gastrointest Endosc 2001;
53(4): 5004.
93. Berr F, Wiedmann M, Tannapfel A, et al. Photodynamic therapy for
advanced bile duct cancer: Evidence for improved palliation and extended
survival. Hepatology 2000; 31(2): 2918.
94. Ortner MEJ, Caca K, Berr F, et al. Successful photodynamic therapy for
nonresectable cholangiocarcinoma: a randomized prospective study.
Gastroenterology 2003; 125(5): 135563.
95. Zoepf T, Jakobs R, Arnold JC, Apel D, Riemann JF. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am
J Gastroenterol 2005; 100(11): 242630.
96. Witzigmann H, Berr F, Ringel U, et al. Surgical and palliative management
and outcome in 184 patients with hilar cholangiocarcinoma: palliative
photodynamic therapy plus stenting is comparable to R1/R2 resection.
Ann Surg 2006 August 2006; 244(2): 2309.
353
39
354
presentation
The clinical triad of abdominal pain, mass, and jaundice is seldom seen in adults (3,25). Clinical symptoms in most cases are
intermittent and nonspecific resulting in delayed diagnosis.
Also the majority of these patients do not have consistent
abnormalities in liver function tests (LFTs) (27). Abdominal
pain and recurrent cholangitis are the most common presentation (3,2830). The abdominal pain usually mimics that of
calculus cholecystitis and many patients do have gallstones
either in the cyst and/or in the gallbladder. This might lead to
misdiagnosis of calculus cholecystitis and or choledocholithiasis with biliary ductal dilatation. Subsequently, a number of
these patients who genuinely have cystic dilatation of the biliary tree end up treated inadequately by simple cholecystectomy and or common bile duct (CBD) exploration or
occasionally treated by biliary enteric bypass (31).
In areas where incidence of choledochal cysts is relatively
high, it is prudent to consider choledochal cyst in the differential diagnosis in patients who present with biliary colic, recurrent cholangitis, and evidence of dilated biliary tree (32,33).
However, in areas where incidence of choledochal cysts is rare,
this might represent a real-diagnostic dilemma requiring careful management of these patients at a specialist unit to ensure
correct and adequate treatment tailored to each individual.
Other presentations include those related to complications
that might develop secondary to cystic dilatation of the biliary
tree such as calculi, recurrent hepatic abscesses, recurrent pancreatitis, bleeding, cyst erosion into surrounding structure,
cirrhosis, portal hypertension, and cholangiocarcinoma
(6,34). Such presentations may obscure the primary problem
and may increase the complexities of treatment (32,35).
Indeed, studies in adults have shown that nearly 80% of them
present with one or more of these conditions (5,6,27).
diagnosis
Correct diagnosis of true cystic dilatation of the biliary tree in
adults depends mainly on the use of imaging studies and some
times can be quite challenging. In indeterminate cases, careful
evaluation for anomalous pancreaticobiliary ductal confluence may be useful.
II
IVa
IVb
III
(A)
(B)
Figure 39.2 (A) MRCP image demonstrating segmental dilatation of the intra-hepatic biliary tree in the right lobe of the liver (Type V). (B) ERCP image demonstrating segmental dilatation of the intra-hepatic biliary tree in the right lobe of the liver (Type V).
355
complications
The most common complication associated with choledochal
cysts is stones in the gallbladder, within the cysts or in the pancreatic duct (6). The calculi in the cysts are of the type seen in
biliary stasis (47). In choledochal cysts the calculi can be mistaken for choledocholithiasis in a dilated bile duct secondary
to obstruction. The main distinguishing features are nondilated proximal and intra-hepatic biliary radicles in the case
of type I cysts and non-dilated intervening ducts in the case of
type IV cysts.
Biliary strictures are another recognized complication associated with adult choledochal cysts. This is most often related
to earlier surgical intervention but also can occur secondary
to chronic inflammation or rarely related to congenital
etiology (47,48).
Cirrhosis and liver abscesses are often associated with longstanding biliary obstruction and recurrent cholangitis (48,49).
Some patients develop portal hypertension due to compression of the portal vein by a large choledochal cyst or more
often secondary to biliary cirrhosis (50).
Pancreatitis is a well-recognized complication related to
choledochal cysts. Incidence (1070%) has been reported in
the literature by several authors (3,51,52).
The pathophysiology of pancreatitis in these patients is not
well understood but most authors believe that it is due to activation of pancreatic enzymes associated with biliary reflux
especially in patients with APBDC (51,53).
Choledochal cysts are associated with an increased risk of
developing cholangiocarcinoma and gallbladder tumors (5456).
The risk is about 20 times higher than that in the general population ranging from 2.5% to 30% (3,5658). The risk is age
related: 0.7% in children under the age of 10, 6.8% in patients
11 to 20 years of age, and 14.3% in patients over the age of
20 years (57). Carcinoma occurs not only in the cyst wall but
also in the remainder of the hepatobiliary and pancreatic
tree (57,59). Therefore, long-term follow-up is indicated in all
(A)
treatment
Management of choledochal cysts in adults should be performed at specialist unit and tailored according to each patients
circumstances. Cyst type and more important patients general
health, presenting symptoms and risk of developing complications related to the choledochal cysts are major factors that
should be considered when deciding upon which type of treatment to be adapted.
Total cyst excision when possible remains the gold standard
treatment for choledochal cysts. This has been recommended
by many investigators because of lower incidence of both early
and late postoperative complications. Therefore, this approach
has gained popularity worldwide (10,27,33,60,61). In choledochal cysts types I and IVb involve complete excision of the
bile duct from the confluence of the hepatic ducts proximally
up to the pancreaticobiliary junction distally. Cholecystectomy
at the same time is a necessity, as the gallbladder usually arises
from or adheres to the cyst wall and may contain stones or
occasionally even tumor. Reconstruction of the biliary-enteric
communication in these patients is usually achieved by
Roux-en-Y hepaticojejunostomy or less commonly by hepaticoduodenectomy. For type IVa choledochal cyst, the extrahepatic component should be treated in the same way as for
types I and IV cysts. The management of the intra-hepatic
component depends on the severity of the disease and extent
of involvement. This could range from percutaneous drainage
through stricture dilatation and stone removal to partial hepatectomy (Fig. 39.4) or liver transplantation (3).
More radical surgery is required if malignancy is confirmed
on preoperative or fresh frozen biopsies. This might involve
(B)
Figure 39.3 (A) MRCP image demonstrating intra- and extra-hepatic bile duct dilatation (Type IVa). (B) ERCP image demonstrating intra- and extra-hepatic bile
duct dilatation (Type IVa).
356
Figure 39.4 Intra-operative view following surgical resection of type IVa choledochal cyst seen in Figure 3A,B. Surgery involved left hepatectomy, total
excision of the bile duct and cholecystectomy.
(A)
situations where the intensity of fibrosis precludes safe dissection to allow total cyst excision, it is advisable to follow the
approach described by lilly et al. (63). In this technique, the
most densely adherent portion of the cyst wall is retained on
the hepatoduodenal ligament, removing only the less adherent
portion. The mucosal lining of the retained cyst wall should be
ablated by diathermy to minimize the risk of malignant transformation in that segment of the cyst.
Simple cystenterostomy, which was used to be commonly performed in the past, should no longer be considered a therapeutic option due to a high incidence (3050%) of late complications
such as cholangitis, anastomotic stricture, stone formation, biliary cirrhosis, and, worst of all, malignancy (5,33,56,6062,64).
Therefore, these patients with previous inadequate choledochal cyst excision should, if appropriate, undergo further
revision surgery to reduce recurrent symptoms and the risk of
developing malignancy.
Treatment for type V cysts (Carolis disease) is still controversial. Hepatic resection is safe and effective for part of type V
cysts (Fig. 39.5A,B) (10,65). For the type V cysts with diffuse
intra-hepatic cholangiectasia and frequent recurrent cholangitis resulting in hepatic cirrhosis, liver resection is rarely feasible in which cases liver transplantation may be the only
effective treatment (66).
Type II and III cysts are rare lesions. Type II cysts may be
treated by cyst excision and primary ductal reconstruction or
reconstruction using Roux-en-Y hepaticojejunostomy while
Type III cysts, also known as choledochocele, may be excised
trans-duodenal following which both biliary and pancreatic
ducts are anastomosed to duodenum (64). Small lesions (type
III cysts) may be treated by sphincteroplasty or possibly by
endoscopic sphincterotomy (67,68).
All patients with choledochal cysts including those who had
complete choledochal cyst excision and more important those
(B)
Figure 39.5 (A) Demarcation of right anterior sector (segments 5 and 8) following extra-hepatic division of the right anterior sectoral hepatic artery and portal
vein. (B) Intra-operative view following segmental (central) liver resection (segments 5 and 8) for localized intra-hepatic segmental dilatation of the biliary tree
seen in Figure 2A,B.
357
summary
Diagnosis and treatment of adult choledochal cysts can be quite
challenging. Therefore, management of these patients should be
carried out at specialist units. Choledochal cysts rarely present
for the first time in adulthood. However when they do, the presentation is variable and most often due to presence of associated
disease. Also they can be totally asymptomatic.
The appropriate treatment strategy should be selected based
on the type of the cyst and more important on the individuals
general health and presenting symptoms. Total cyst excision
and Roux-en-Y hepaticojejunostomy are the current recommended surgical options world wide for type I and IV choledochal cysts while for type V cyst (diffuse Carolis disease)
with frequent recurrent cholangitis, liver transplantation
should be considered. Patients with previous cyst drainage
procedures should undergo revisional surgery if appropriate
to reduce recurrent symptoms and the risk of developing
malignancy. Conservative treatment might be the most appropriate strategy in asymptomatic individuals with poor general
health and significant co-morbidities. All patients with choledochal cysts including those who had complete choledochal
cyst excision should be kept under long-term surveillance.
key points
Choledochal cysts are increasingly diagnosed in adult
population
Etiology of choledochal cysts remains speculative
Adults with choledochal cysts most commonly present
with complications related to their choledochal cysts
Choledochal cysts are associated with an increased risk of
developing cholangiocarcinoma and gallbladder tumors
MRI is widely held as the imaging modality of choice for
choledochal cysts
Patients with choledochal cysts should be managed at a
specialist unit to ensure correct and adequate treatment
tailored to each individual
Total cyst excision when possible remains the gold standard treatment for choledochal cysts
references
1. Gigot JF, Nagorney D, Farnell M, Moir C, Ilstrup D. Bile duct cysts: a
changing spectrum of disease. J Hepato-Biliary-Pancreatic Surg 1996;
3(4): 40511.
2. Lenriot JP, Gigot JF, Segol P, et al. Bile duct cysts in adults: a multi-institutional retrospective study. French Associations for Surgical Research. Ann
Surg 1998; 228(2): 15966.
3. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease. A changing pattern of presentation. Ann Surg 1994;
220(5): 64452.
358
50. Nunez-Hoyo M, Lees CD, Hermann RE. Bile duct cysts. Experience with
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51. Okada A, Nakamura T, Higaki J, et al. Congenital dilatation of the bile
duct in 100 instances and its relationship with anomalous junction. Surg
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52. Swisher SG, Cates JA, Hunt KK, et al. Pancreatitis associated with adult
choledochal cysts. Pancreas 1994; 9(5): 6337.
53. Todani T, Urushihara N, Watanabe Y, et al. Pseudopancreatitis in choledochal cyst in children: intraoperative study of amylase levels in the
serum. J Pediatr Surg 1990; 25(3): 3036.
54. Todani T, Tabuchi K, Watanabe Y, Kobayashi T. Carcinoma arising in the
wall of congenital bile duct cysts. Cancer 1979; 44(3): 113441.
55. Tsuchiya R, Harada N, Ito T, Furukawa M, Yoshihiro I. Malignant tumors
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58. Shi LB, Peng SY, Meng XK, et al. Diagnosis and treatment of congenital
choledochal cyst: 20 years experience in China. World J Gastroenterol
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59. Kimura K, Ohto M, Saisho H, et al. Association of gallbladder carcinoma
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60. Rush E, Podesta L, Norris M, et al. Late surgical complications of choledochal cystoenterostomy. Am Surg 1994; 60(8): 6204.
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62. Tan SS, Tan NC, Ibrahim S, Tay KH. Management of adult choledochal
cyst. Singapore Med J 2007; 48(6): 5247.
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1979; 149(1): 3642.
64. Powell CS, Sawyers JL, Reynolds VH. Management of adult choledochal
cysts. Ann Surg 1981; 193(5): 66676.
65. Madariaga JR, Iwatsuki S, Starzl TE, et al. Hepatic resection for cystic
lesions of the liver. Ann Surg 1993; 218(5): 6104.
66. Sans M, Rimola A, Navasa M, et al. Liver transplantation in patients with
Carolis disease and recurrent cholangitis. Transpl Int 1997; 10(3): 2414.
67. Zheng LX, Jia HB, Wu DQ, et al. Experience of congenital choledochal
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68. Akkiz H, Colakoglu SO, Ergun Y, et al. Endoscopic retrograde cholangiopancreatography in the diagnosis and management of choledochal cysts.
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359
Benign biliary strictures are largely due to trauma or inflammation. Most traumatic biliary strictures result from iatrogenic operative injuries. In addition to causing strictures
iatrogenic operative injuries may lead to other types of biliary
abnormalities such as loss of continuity of the biliary tract and
fistula. Inflammatory strictures are due to pancreatitis and less
commonly sclerosing cholangitis, septic cholangitis, and
inflammatory pseudotumors. Today it is usually possible to
treat most inflammatory strictures by endoscopic stenting.
Consequently the focus of this chapter will be on iatrogenic
biliary injury.
360
period when all cholecystectomies were performed by laparotomy to 0.47% in the latest period of the study 1996 to 2001
when most procedures were laparoscopic (9). To summarize it
is likely that the incidence of biliary injury during laparoscopic
cholecystectomy is higher than it was when cholecystectomies
were performed by laparotomy but how much higher is uncertain. Clearly, ongoing good population studies defining the
incidence of this problem are needed.
Figure 40.1 A classification of laparoscopic injuries to the biliary tract. The injuries Type A to E are illustrated. Type A injuries originate from small bile ducts in
the liver bed that or from the cystic duct. Type B and C injuries almost always involve aberrant right hepatic ducts. The notations >2 cm and <2 cm in Type E1 and
Type E2 indicate the length of common hepatic duct remaining. The corresponding Bismuth classification numbers are given when possible as B1-5. Note that
Types A and D do not exist in the Bismuth classification, which is a classification of bile duct strictures rather than injuries. Note that B,C and E5 injuries would
be classified as B5. They are separated in our classification because of the increase incidence of B and C injuries in the laparoscopic era.
Figure 40.2 Type A (left) and Type D injuries (right) are much more common in the laparoscopic era and were given separate categories in our classification. The
Type A injury figure demonstrates extravasation of contrast from the liver bed of the gallbladder due to injury to a bile duct in that location. The Type D injury
figure demonstrates an injury which was incompletely repaired over a t-tube (arrow). There is extravasation of contrast from the common bile duct when T tube
is injected. A percutaneous drain (arrowhead) was inserted to drain postoperative bilomas. The injury healed without further treatment.
although this was not borne out in a Cochrane review of randomized trials (18) (evidence level 1a). However, in the latter,
conclusions were drawn from a total of four bile duct injuries
among 438 patients (0.9%) (18). Acute inflammation causes
thickening of tissues, increases friability and vascularity, and
promotes adhesions. These factors obscure normal anatomical
relationships (Fig. 40.3A) and increase difficulty of exposure
and dissection. The inflammatory mass may effectively obliterate the triangle of Calot and hide the cystic duct (19) (Fig. 40.3B).
Severe inflammation is more likely to be encountered when
the time between onset of symptoms and surgery for acute
cholecystitis is greater than 72 hours (20,21), when the white
blood cell count is greater than 18,000 cells/cu mm (20,22), or if
the patients age is over 60 years (20,23,24). The Tokyo Severity
361
the cystic duct with the common hepatic duct and consequently there is great potential for injury (27). Aberrant right
hepatic duct injuries are more common in laparoscopic than
open cholecystectomy.
Parallel Union Cystic Duct
The parallel union cystic duct (Fig. 40.3D) occurs in about
20% of individuals. It was a well-described risk factor for biliary injury in the era of open cholecystectomy and continues to
be a risk factor today.
Aberrant Position of Cystic Duct Termination
The cystic duct may insert into the biliary tree at any point
from the right hepatic duct to the termination of the common
bile duct. Insertion into the right hepatic duct is very uncommon but exposes this duct to injury.
Congenital Adhesions Between the Gallbladder
and Common Hepatic Duct
Such adhesions are prominent in some individuals. They
obscure the triangle of Calot and may fix the common hepatic
duct to the side of the gallbladder. In some cases the Pouch of
Hartmann may actually lie over and to the left of the common
bile and common hepatic ducts (Fig. 40.3E).
Triangle
of Calot
(A)
(D)
(B)
(C)
(E)
(F)
Figure 40.3 Conditions which predispose to the deception that the common bile duct is the cystic duct especially when the infundibular techniques is used.
(A) Situation in which the infundibular technique is effective. There is mild inflammation. The triangle of Calot is open and the funnel shape of the junction
between the gallbladder and cystic duct (heavy line) is readily apparent. (BF) Conditions which may give a misleading funnel shape (heavy lines) due to concealment or obliteration of the triangle of Calot. In these cases the common bile duct is dissected by a surgeon who thinks it is the cystic duct widening to become the
gallbladder. (B) Severe acute cholecystitis. (C) Severe chronic inflammation. (D) Parallel cystic duct insertion. (E) Congenital bands. (F) Large impacted stone.
362
(A)
(B)
(C)
(D)
(E)
(F)
Figure 40.4 Patterns of biliary injury due to misidentification. (A). The classical type E injury in which the common duct is divided between clips at point x. The
ductal system is later divided again to remove the gallbladder either at point y1 producing E1 or E2 injuries, or at point y2 producing E3 or E4 injuries. (B) Variant
of Type E injury which leads to bile leakage into the operative field and thereby an increased chance of recognition before the entire injury evolves. (C) Variant of
Type E injury leading to clipping but not excision of the duct. This injury also causes intraoperative bile leakage, except when cystic and common bile ducts are
both occluded, as shown in the inset. D,E, and F represent variants of injury to aberrant right hepatic duct, producing Type B or Type C injuries. The injuries shown
in D, E, and F correspond to the injuries shown in A, B, and C, but affect the aberrant right duct.
363
common bile duct as the cystic duct and will prevent excisional
injuries of bile ducts, if the cholangiogram is correctly interpreted. Unfortunately, operative cholangiograms are sometime misinterpreted. The most common misinterpretation is
the failure to recognize that when only the lower part of the
biliary tree is seen, the common bile duct rather than the cystic
duct has been incised and cannulated. IOC is not effective at
detecting aberrant right ducts, which unite with the cystic duct
before joining the common duct. The aberrant duct appears to
be the cystic duct visually and on cholangiograms, especially
since some nonaberrant right-sided ducts usually fill
(Fig. 40.6). Since it is not unusual to obtain only partial filling
of the right hepatic ducts by IOC this is taken as a normal
pattern. Another drawback is that an incisional injury of the
(A)
Cystic plate
Figure 40.5 The critical view of safety. The triangle of Calot is dissected free
of all tissue except for cystic duct and artery and the base of the liver bed is
exposed. When this view is achieved, the two structures entering the gallbladder can only be the cystic duct and artery. It is not necessary to see the common
bile duct.
(B)
Figure 40.6 (A) Intraoperative cholangiogram which was interpreted as normal with only a wisp of dye entering right hepatic ducts. Note stone at ampulla.
(B) Postoperative ERCP in same patient done to remove stone. Note retrograde filling of aberrant right hepatic duct, made stenotic by clips. Note how the point
of union of the aberrant duct with the common hepatic duct looks like a cystic duct- common duct junction. Problem successfully treated by stenting.
364
Common
hepatic duct
Cystic duct
Common
bile duct
(A)
(B)
Figure 40.7 Cause of bile duct injury in top down cholecystectomy in the face of severe inflammation with obliteration of triangle of Calot which draws the side
of the common hepatic duct to the side of the gallbladder. (A) Real anatomical situation. (B) Apparent anatomical situation is shown by heavy line. The surgeon
sees the anatomy bounded by the heavy line as the gallbladder and the cystic duct and as the gallbladder is excised top-down (arrow) the common hepatic duct is
transected. Vascular injuries are also common with this mechanism of injury.
365
III
IV
Sg 6,7
LHD
Sg 5,8
II
Figure 40.8 Intraoperative photo (left) and diagram (right) showing transection of multiple hepatic ducts during open cholecystectomy by the fundus down technique in a very inflamed gallbladder. The right anterior sectional duct (Sg 5,8), the right posterior sectional duct (Sg 6,7) and the left hepatic duct (LHD) were
transected in this high E4 injury.
366
Equipment
Laparoscopic equipment must be regularly maintained. Focal
loss of insulation on cautery instruments can result in arcing
and thermal injuries to bile ducts or bowel.
technical problems
Injury to a Bile Duct in the Course of Dissection
Avoidance depends on the principles of careful dissection and
experience, as well as recognition of circumstances in which
the potential hazard in continued dissection may outweigh the
benefit of completing a cholecystectomy. Also the author recommends not using the top-down technique in the face of
severe inflammation either in open or laparoscopic surgery.
Failure to Obtain Secure Closure of the Cystic Duct
Tips of clips should be noted to project beyond the cystic duct.
Pre-formed ligature loops should be used for closure of the
cystic duct if the cystic duct is thick, rigid or wide. Two loops
should be applied on the side of the cystic duct to be retained.
Thermal Injuries
Cautery should be used with great care in the porta hepatis.
Low cautery settings are essential, characteristically 30 W or
less. Attempts to stop hemorrhage by blind application of cautery clamps, or clips are very unwise. Brisk bleeding requires
conversion. Adhesions should be divided sharply or with minimum application of power.
Tenting Injuries
The injury is avoided by not lifting the gallbladder forcefully
when applying clips to the cystic duct. It is recommended that
the surgeon sees that a length of cystic duct will remain below
the clip closest to the common bile duct end of the cystic duct
before applying that clip.
367
368
1 and 6 weeks after the primary operation when local inflammation may be expected to be great. In these patients percutaneous tubes are inserted to relieve obstruction from affected
segments, to drain subhepatic collections and control sepsis.
Repair is performed when inflammation has settled, usually
about 3 months after the last operation. This delayed approach
is sometimes used even when the patient is referred within the
first week, especially in complex injuries and those in which
either a thermal etiology or a concomitant ischemic injury is
suspected (14,16). Immediate repair may also be undertaken
when the injury is diagnosed months after surgery, for instance,
after failure of stenting of a stenosis or late failure of a biliaryenteric anastomosis.
Preoperative Preparation
The complete extent of the injury must be diagnosed preoperatively. Failure to do so may result in exclusion of bile ducts from
the repair. The percutaneous transhepatic tubes placed to
assure biliary drainage from all liver segments also serve as
guides to the position of the injured ducts at surgery (Fig. 40.10).
Our policy is to perform conciliation between CT and PTC
studies to be sure that all ducts in the liver are accounted for.
Operative Technique
Success depends upon fulfilling six principles of repair, i.e., to
construct anastomoses, which are well vascularized, tension
free, mucosa-to-mucosa, widely patent, precisely constructed,
and that drain all parts of the liver. Most experts in this field
recommend hepatico-jejunostomy in preference to either
choledocho-choledochotomy or choledocho-duodenostomy,
since a tension free anastomosis is always possible with hepaticojejunostomy. Whenever possible, we prefer to construct
side-to-side anastomoses to avoid dissection behind bile ducts,
which may affect their blood supply (37). Often the anastomosis
Figure 40.10 An E4 injury in which the confluence of the right and left hepatic
ducts has been resected. Note the wide separation of the ducts indication a
very high injury. Also note multiple clips. Preoperative placement of percutaneous transhepatic tubes facilitated identification of anatomy at surgery.
Step 1
for a median of 4.9 years is a 4.5% rate of poor outcomes requiring interventional treatment but no requirement for operative
re-repair (37).
Comparison among surgical series is difficult because of
lack of standard reporting variables and effect of differences in
the severity of injuries treated in different series. Injuries above
the confluence involving several bile ducts have a worse prognosis than injuries of the common hepatic duct and the proportion of severe injuries in a series will affect outcome.
Reporting of treatment failure is not uniform. Length of follow-up is another obvious variable affecting outcome and is
not uniform among series. Several authors have reported that
quality of life (5254) and lifespan (8) are adversely affected by
a biliary injury.
Step 2
C. Core or lift
liver off right
Portal pedicle
Gallbladder
plate
A. Identify left
duct by HeppCouinaud
technique
D. Open bile
duct on
anterior surface
(A)
(B)
Figure 40.11 (A) Technique for identifying isolated right ducts. Step 1: Finding and dividing cystic plate to expose right pedicle. (B) Technique for identifying
isolated right ducts. Step 2: Elevating right portal pedicle, identifying and incising right duct.
369
370
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30. Fletcher DR, Hobbs MS, Tan P, et al. Complications of cholecystectomy:
risks of the laparoscopic approach and protective effects of operative
cholangiography: a population-based study. Ann Surg 1999; 229: 44957.
31. Flum DR, Dellinger EP, Cheadle A, et al. Intraoperative cholangiography
and risk of common bile duct injury during cholecystectomy. JAMA 2003;
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32. Hugh TB, Hugh TB. New strategies to prevent laparoscopic bile duct
injury--surgeons can learn from pilots. Surgery 2002; 132: 82635.
33. Way LW, Stewart L, Gantert W, et al. Causes and prevention of laparoscopic bile duct injuries: analysis of 252 cases from a human factors and
cognitive psychology perspective [see comment]. Ann Surg 2003; 237:
4609.
34. Heistermann HP, Tobusch A, Palmes D. [Prevention of bile duct injuries
after laparoscopic cholecystectomy. The critical view of safety]. Zentralblatt fur Chirurgie 2006; 131: 4605.
35. Yegiyants S, Collins JC, Yegiyants S, Collins JC. Operative strategy can
reduce the incidence of major bile duct injury in laparoscopic cholecystectomy. Am Surg 2008; 74: 9857.
36. Lillemoe KD, Martin SA, Cameron JL, et al. Major bile duct injuries during laparoscopic cholecystectomy. Follow-up after combined surgical and
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biliary injuries using a policy of side-to-side hepatico-jejunostomy. Ann Surg
249: 42634, 2009
38. Hepp J. Hepaticojejunostomy using the left biliary trunk for iatrogenic
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40. Mercado MA, Chan C, Orozco H, et al. Long-term evaluation of biliary
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41. Laurent A, Sauvanet A, Farges O, et al. Major hepatectomy for the treatment of complex bile duct injury. Ann Surg 2008; 248: 7783.
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41
introduction
About 10% to 15% of the adult Western population has
gallstones (1,2). This equates to 7.5 million Britons and
20 million Americans with gallstones, with between 1% and
4% a year developing symptoms (2,3). Cholecystectomy is not
recommended in asymptomatic patients (4). However, symptomatic gallstone disease is one of the most common conditions in the United Kingdom requiring surgery (5,6). Up to
35% of patients with gallstones will ultimately become symptomatic, requiring cholecystectomy (7). In England, 49,077
cholecystectomies were performed between April 2005 and
March 2006 (3). It is estimated that over half a million cholecystectomies are performed each year in the United States (5).
Gallstones are seen in all age groups but incidence increases
with age, with over one-third of the population over the age of
70 years affected (3,5). The development of gallstones is a multifactorial process, but has been shown to be associated with family
history, pregnancy, obesity, rapid weight loss (such as after bariatric surgery), hemolytic anemias, parenteral nutrition, loss of
bile salts (as seen in terminal ileitis and after terminal ileal resection), and diabetes mellitus (via the metabolic syndrome) (8).
with radiation to the right lower chest or the lower pole of the scapula. This can be explained by the origin of the gallbladder from
the lower thoracic segments, and transmission of visceral sensation through splanchnic nerves to the lower thoracic spinal cord.
Some pain afferents may travel within the right phrenic nerve
and peritoneum below the right diaphragm, accounting for the
radiation of pain to the right shoulder tip. The pain of biliary
colic often has a slower periodicity than ureteric colic, lasting
between 30 minutes and 2 hours, but sometimes persisting for
up to 8 hours. Although it is a commonly held belief that the
consumption of fatty food is likely to provoke an attack, there is
little evidence to support this (6). The pain may resolve spontaneously but often requires parenteral analgesia and anti-emetics.
Acute Cholecystitis
This is characterized by the presence of right upper quadrant or
epigastric pain lasting for more than 8 hours, accompanied by
systemic signs of infection such as fever and leukocytosis. The
condition arises after impaction of a stone in the neck of the
gallbladder or cystic duct, leading to sustained high pressure in
the gallbladder. This leads to a reduction in the blood flow to
the mucosa with subsequent ischemic injury (6). As a result of
this, a chemical cholecystitis develops with inflammatory infiltrate and edema of the gallbladder wall. In the first 48 hours it
is unusual for bacterial infection to occur but the incidence of
infection after 1 week is in the order of 70% (6). Traditionally
patients were admitted to hospital for a period of intense medical therapyanalgesia, intra-venous fluid rehydration and
broad-spectrum antibiotics, with cholecystectomy deferred for
6 to 12 weeks (12). This used to be common practice across the
United Kingdom. In one survey, 88% of surgeons reported
routinely managing patients in this manner (13). However, it
has been shown that early surgery (laparoscopic or open) is
preferable to delayed surgery and is not associated with any
additional morbidity or mortality (1214). Laparoscopic
cholecystectomy, widely accepted as the gold standard of
treatment, has been shown to be safe and effective in acute
cholecystitis, with shortened length of hospital stay (15).
empyema
classification of gallstones
There are three common types of gallstone.
1. Cholesterol (20%)
2. Bile Pigment (5%)
3. Mixed (75%)
Gallstones are responsible for a wide range of clinical problems. The most common of these are biliary colic (56%) and
acute cholecystitis (36%) (11).
Biliary Colic
This arises when a gallstone impacts in the neck of the gallbladder leading to obstruction of the cystic duct. Sustained
gallbladder contraction, produces a rise in pressure within the
gallbladder, leading to the pain perceived as biliary colic (6).
This is typically centered in the right upper quadrant, or epigastrium,
373
Liver
XXX
Increased cholesterol
Decreased bile salt
secretion
obstructive jaundice
Gall
bladder
Bile
supersaturated
with
cholesterol
Nidus for
gallstone
formation
Cholesterol
gallstone
mucocele
In this situation the obstructed gallbladder remains free of
infection. Although the mucosa remains inflamed, it continues
to function, absorbing water from bile and secreting mucus. The
gallbladder fills with clear or bile-stained mucus. The patient
will often report an episode of severe pain, consistent with
cholecystitis. The symptoms may resolve partly, but there will be
some persisting right upper quadrant pain and tenderness.
374
acute cholangitis
Acute cholangitis results when bacterial infection develops
within a partially or completely obstructed biliary system.
Stasis leads to an increase in the resident bacterial flora, which
are often found when gallstones are present in the biliary tract.
Classically the condition presents with Charcots Triad of
symptomsright upper quadrant pain, rigors, and jaundice.
Ascending infection of the biliary tree can lead to septicemia
and multiple hepatic abscesses. One-fifth of patients presenting with cholangitis have a bacteremia, with gram negative
organisms mainly responsible (26). Treatment is with broad
spectrum antibiotics, such as second generation cephalosporins or ciprofloxacin. ERCP is performed at an early stage
allowing both confirmation of the diagnosis and decompression of the bile ducts. Biliary stents can be placed to encourage
further drainage prior to definitive treatment.
acute pancreatitis
Gallstones are responsible for up to 60% of all cases of pancreatitis. Between 4% and 8% of patients with gallstones will
develop acute pancreatitis due to migratory stones (27). Small
stones, with mean diameter of 4 mm, are more likely to cause
pancreatitis than larger stones (28).
The condition develops when a small gallstone, traveling from
gallbladder to the bowel, impacts in the biliopancreatic duct
mirrizi's syndrome
Percutaneous Cholecystostomy
In critically ill or high-risk patients with biliary sepsis, percutaneous cholecystostomy allows decompression of the
inflamed gallbladder, with resolution of sepsis. Patients can
then undergo definitive surgery once their overall condition
has improved. A retrospective review of 55 patients treated by
percutaneous transhepatic cholecystostomy reported successful biliary drainage in 98%, with 95% of patients recovering
well (43). Percutaneous cholecystostomy can be performed
under ultrasound or fluoroscopic guidance. The gallbladder
can be entered using the Seldinger technique with tract dilatation and catheter placement via guide wire or by means of the
direct trocar technique (44). The choice of tract depends on
the anatomy and whether stone extraction is planned. The
transhepatic route is associated with less risk of bile leakage,
but the transperitoneal approach is preferable for stone
removal through a larger tract (43).
This occurs when a gallstone, impacted in the neck of the gallbladder, causes inflammation to the surrounding tissue
thereby compressing the adjacent bile duct. The stone induces
fibrosis leading to obliteration of the cystic duct. Ongoing
inflammation results in adherence of the gallbladder to the
common hepatic duct, causing partial obstruction and jaundice. Mirrizis syndrome has been classified into two types. In
type 1, there is no communication between the gallbladder
and the bile duct. In type 2, the gallstone has eroded into the
bile duct, resulting in a cholecystcholedochal fistula.
biliary dyspepsia
This represents a set of vague abdominal symptoms which
have been attributed to gallstones. These include non-specific
upper abdominal pain, nausea, belching, and food intolerance.
These symptoms have been found to occur with equal
frequency in patients with or without gallstones (34). In fact,
symptoms other than typical biliary colic are rarely due to
gallstones (6). Cholecystectomy in these situations is often
ineffective with up to 30% of patients continuing to suffer
dyspeptic symptoms (35,36).
375
376
Figure 41.4 A window is created behind the cystic duct and artery.
of the procedure for bleeding and bile leaks, as are the cystic
duct and artery clips. The area can be gently irrigated with
saline and then suctioned. The camera is moved to the top port
and the gallbladder is grasped via the umbilical port and delivered. The linea alba can be closed with absorbable sutures and
the skin with steristrips or sutures.
Future Developments
Advances in surgical technology and innovation have made
possible the advent of 2 port (53) and single port laparoscopic
cholecystectomy (54) and the development of NOTESnatural orifice transluminal endoscopic surgery (55). This will allow
the surgeon to undertake major intraperitoneal surgery without the need for skin incisions, with access to the peritoneal
cavity via the mouth (via the stomach), the rectum and the
vagina, using flexible endoscopes. There is, to date, no research
published on resections in humans but the first transvaginal
cholecystectomy in a porcine model was carried out in 2005
(55). Progress in this area is likely to be rapid since the set up of
working groups, dedicated to advancing the concept (56).
377
key points
10% to 15% of the adult Western population have gallstones. Between 1% and 4% of patients a year develop
symptoms.
Cholecystectomy is not recommended for asymptomatic
gallstones (4)Grade A.
Cholecystectomy is recommended for all patients with
symptomatic gallbladder stones and CBDS (except where
surgery is considered inappropriate). Grade A.
Laparoscopic cholecystectomy is the gold standard of
treatment for symptomatic gallstone disease (45)Grade A.
Laparoscopic cholecystectomy is safe and effective in the
management of acute cholecystitis (12,14))Grade A.
Cholecystectomy during the index admission for cholecystitis is recommended (12) Grade A.
Symptomatic patients with suspected ductal stones should
undergo stone extraction where possibleGrade B.
ERCP is not recommended solely as a diagnostic test, it
should only be done in patients for whom an intervention
is planned. Grade B
Biliary sphincterotomy and endoscopic stone extraction are
recommended for patients with bile duct stones post
cholecystectomy.
Biliary stenting should only be used as a sole treatment in
patients with limited life expectancy or very high-surgical
risk. Grade A.
Patients with ductal stones undergoing laparoscopic
cholecystectomy may be managed by laparoscopic common bile duct exploration at the time of surgery, or
undergo peri-operative ERCP. Transcystic and transductal
exploration of the common bile duct are both recommended approaches for removal of stones. Grade A.
In patients with bile duct stones that have not been extracted,
short term use of a biliary stent is recommended, followed
by further endoscopy or surgery. Grade B.
If duct clearance is not achieved by minimally invasive
methods then open surgical exploration is recommended
as an important treatment option. Grade B.
378
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selective ERCP and endoscopic treatment of bile duct stones before
laparoscopic cholecystectomy. Gastrointest Endosc 1999; 50(2): 2008.
25. Martin DJ, Vernon DR, Toouli J. Cochrane Database of Systematic Review
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26. Leung JW, Ling TK, Chan RL, et al. Antibiotics, biliary sepsis and bile duct
stones. Gastrointest Endosc 1994; 40(6): 71621.
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30. Neoptolemos JP, Hall AW, Finlay DF, et al. The urgent diagnosis of
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for clearance of bile duct stones. Gastrointest Endosc 2001; 53(1):
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379
introduction
The most frequent type of pancreatic adenocarcinoma,
pancreatic ductal adenocarcinoma (PDAC), accounts for more
than 85% of all pancreatic malignancies (1). Other malignant
pancreatic tumors include intraductal papillary mucinous carcinomas, mucinous cystadenocarcinomas, acinar cell cancers,
as well as endocrine cancers. These rare tumors will not be discussed in this chapter. PDAC is characterized by late presentation, aggressive local tumor growth, early lymphogenic and
hematogenic spread, and poor prognosis.
epidemiology
PDAC is the tenth most common type of cancer in the United
States and the United Kingdom but accounts for the fourth
and sixth most frequent type of cancer-related death in these
countries (24), respectively. Due to its aggressive nature, the
number of new cases per year (an estimated 37,680 in the U.S.
in 2008 and 7,632 in the UK in 2005) almost equals the number of deaths per year (34,290 in the U.S. and 7315 in the UK)
(36). PDAC has an overall median survival of less than
6 months and one of the lowest overall 5-year survival rates of
any malignant disease with 0.4% to 5% (7,8). Furthermore,
these dismal figures seem to have improved little compared to
the 1950s (5). The incidence rate peaks between 65 and
75 years of age (9) and only 15% to 20% of patients initially
present with localized disease suitable for potential curative
surgical resection.
380
Influence on risk
Dietary fiber
Fruit/vegetables
Vitamin C
Low fat low cholesterol
Grilled/smoked meat
Low sugar
Fish
Tea
Coffee
Alcohol
No proven benefit
No proven benefit
Potential benefit
No proven benefit
Potential risk
No proven benefit
No proven benefit
No proven benefit
No proven risk
No proven risk
3, C
2b, C
3, D
2b, B
3, C
2b, B
2b, B
2b, B
2b, B
3, C
References
(12,248,249)
(250)
(12,251)
(15,14)
(252254)
(254256)
(15,14)
(257,258)
(25,31,259)
(25,31,260,34)
381
Gene
Not known,
BRCA2 (617%,
(57,56,55))
40%
2. Hereditary forms of CP
Hereditary pancreatitis
PRSS1
SPINK1
CFTR
40%
STK11
36%
CDKN2A
17%
BRCA1/2
38%
MLH1, MSH2,
MSH6, PMS2
<5%
APC
<5%
TP53
<5%
Cystic fibrosis
FBOC
HNPCC
FAP
LiFraumeni
<5%
Familial pancreatic cancer syndrome (FPC), hereditary pancreatitis and cystic fibrosis as well as hereditary tumor syndromes with PDAC association are listed.
The causative genes are listed as well as the cumulative risk to develop PDAC the age of 70. Abbreviations: DIOS, distal intestinal obstruction syndrome; COPD,
chronic obstructive pulmonary disease; STK11, serine-threonine protein kinase 11; PDAC, pancreatic ductal adenocarcinoma; FPC, familial pancreatic cancer;
BRCA1/2, breast-cancer gene 1/2; PRSS1, Protease Serine 1; SPINK1, serine protease inhibitor Kazal-type 1; CFTR, cystic fibrosis transmembrane regulator;
FAMM, familial atypical multiple mole melanoma syndrome; MPCS, melanoma pancreatic cancer syndrome; CDKN2A, cyclin-dependent kinase inhibitor 2A;
HNPCC, hereditary non-polyposis colon cancer; FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli; FBOC, familial breast and ovarian
cancer syndrome; MLH1, MutL homolog 1; MSH2/6, MutS homolog 2/6; PMS2, postmeiotic segregation 2; TP53, tumor protein 53.
Following the initial suspicion of a pancreatic malignancy after taking the patients history and conducting a
thorough physical exam, a laboratory work-up and a transabdominal ultrasound are the first steps to be taken. Laboratory values should include amylase and lipase, cholestasis
parameters (GT, direct and indirect bilirubin, alkaline
phosphatase), the transaminases ALT and AST, a blood
count to evaluate tumor anemia, coagulation parameters,
and the tumor marker carbohydrate antigen 19-9 (CA199). None of these parameters are specific for pancreatic
cancer and none can be used as a screening tool. The
tumor-associated antigen CA19-9 specifically has been
tested in two large studies and found to be ineffective as a
screening tool in asymptomatic patients because of its low
positive predictive value (72,73). Furthermore, controversies exist regarding the correct cut-off value for CA19-9.
382
However, in the context of suspected pancreatic malignancy, CA19-9 remains a valuable adjunct since in combination with computed tomography (CT) a positive
predictive value of 99% can be achieved when levels are
over 120 U/ml (74). In addition, high levels of CA19-9
(over 150 U/ml) were shown to serve as an indicator for
irresectability with a positive predicitive value of 88% and
might justify further staging procedures (75). Finally,
CA19-9 can be used as a parameter of therapeutic response
and as an indicator of recurrence in patients
with PDAC.
Transabdominal ultrasonography is a fast and cost-effective
measure and provides valuable information. The presence of
ascites, hepatic metastasis as well as dilated intrahepatic and
extrahepatic bile ducts can be evaluated with high accuracy,
whereas the visualization of the primary tumor is achieved
Age
Symptoms
a
Low
<50
Pain only
Medium
<50
High
>50
>50
Pain plus
Loss of appetite/loss of
weight/fatigue
Pain onlya
Pain plus
Loss of appetite/loss of
weight/fatigue
Work-up
US if pain
persists
US, (CT)
US, EUS,
(CT)
Epigastric pain that radiates to the back and persists at night should trigger
further investigations independent of age.
Abbreviations: US, abdominal ultrasound; EUS, endoscopic ultrasound; CT,
computed tomography.
M1
N0
N1
N0/N1
0
IA
IB
IIA
III
IIB
IIB
IIB
III
IV
383
Borderline
Local irresectability
Distant metastasis
Venous involvement
Splenic vein
Portal vein-SMV confluence
(short segment)
Arterial involvement
Superior mesenteric artery (SMA)
(not circumferential)
()
(short segment)
(circumferential/long
segment)
(encasement)
(pylorus or
antrum)
Coeliac axis
Common hepatic artery
Gastroduodenal artery
Involvement of neighboring organs
Duodenum
Stomach
Colon
Spleen
Kidney / adrenal gland
Spine
Distant metastasis
: must be absent. : must be present. : may or may not be present (in brackets the maximum extent of involvement). For locally irresectabe tumors: one
-criterion is enough to classify the tumor as locally irresectable. Abbreviations: SMV: superior mesenteric vein.
History
physical exam
Labs
transabd. US
MDCT or
MRI/MRCP or
EUS
(ERCP)
(PET)
(diag. laparoscopy)
Resectable
Borderline
Locally
irresectable
Metastatic
disease
Figure 42.1 Preoperative diagnosis pathway in patients with pancreatic cancer. The aim is to determine surgical respectability. Abbreviations: US, ultrasonography;
MDCT, multidetector-computed tomography; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreaticography; EUS, endoluminal
ultrasound; ERCP, endoscopic retrograde cholangiopancreaticography; PET, positron emission tomography.
384
latter are difficult to extract during surgery and may harm the
bile duct (Evidence grade IV; recommendation D).
management
Management of PDAC depends on the clinical tumor stage
(Fig. 42.2):
1. Patients with resectable tumors should undergo surgery as soon as possible followed by adjuvant chemotherapy.
2. Patients with borderline tumors should undergo
exploration and resection if possible. If resection
is not possible the decision to perform a (double) bypass operation (gastrojejunostomy and/or
hepaticojejunostomy) must be made. The patient
can then either be enrolled in a neoadjuvant treatment protocol to achieve respectability or undergo
palliative care.
3. Patients with locally advanced, unresectable tumors
can be enrolled in a neoadjuvant treatment trial or
be treated palliatively.
4. Patients with distant metastasis should be offered
palliative treatment.
The rational to perform surgical resection whenever possible is the vastly improved prognosis and quality of life following a macroscopic complete (R0/R1) removal of the tumor
(see below). It should be mentioned that age should not be a
contraindication for surgery since several studies have demonstrated comparable outcomes between young and old patient
cohorts (evidence grade 4, recommendation D) (121123).
surgical resection
The objective of surgical management of PDAC is the macroscopic complete resection of the primary tumor, complete regional lymphadenectomy, and reconstruction of the
gastrointestinal tract. Depending on the localization of the
tumor this goal can be achieved either by left (distal) pancreatectomy, pancreatoduodenectomy (PD) or by total
pancreatectomy. A standard PD (KauschWhipple operation) (124) involves resection of the pancreatic head, the
duodenum, the distal common bile duct, the distal stomach, the gall bladder, and regional lymph nodes. A variant of
this standard PD procedure preserves the stomach and is
thus termed pylorus-preserving pancreatoduodenectomy
(ppPD, Traverso-Longmire operation) (125). Resections as
well as the extent of lymphadenectomy (standard and
extended) have been defined in order to allow for better
comparison of data (126,127). For details concerning the
surgical resection procedures see the chapter on pancreatic
resection in this book.
Standard Versus Pylorus-Preserving
Pancreatoduodenectomy
The question whether standard or pylorus-preserving pancreatoduodenectomy (PD vs. ppPD) is superior in the treatment of PDAC has been a matter of debate for some time. The
main areas of concern were the oncological completeness of
the ppPD procedure as well as the potential physiological side
385
II
Borderline
Laparotomy
III
Local
irresectability
IV
Metastatic
disease
Histology
Histology
-CT/US/EUS: biopsy
-CT/US/EUS: biopsy
Resection
-PD
-ppPD
Irresectable
-Left resection
Neoadjuvant
(R)CTx
Palliative CTx
supportive care
-total pancreatecotmy
Adjuvant CTx
(Double bypass)
Resectable
Neoadjuvant
(R)CTx
Palliative CTx
supportive care
Laparotomy
Irresectable
Figure 42.2 Treatment of PDAC dependent on clinical tumor stage. Abbreviations: CTx, chemotherapy; RCTx, radio-chemotherapy; EUS, endoluminal
ultrasound; US, ultrasound; PD, pancreaticoduodenectomy; ppPD, pylorus-preserving pancreaticoduodenectomy.
386
Several studies have investigated whether pancreaticogastrostomy might be superior to the traditional pancreaticojejunostomy. A recent meta-analysis of three randomized
controlled trials and 13 nonrandomized observational studies
found no significant differences between the two procedures
regarding overall postoperative complications, pancreatic fistula, intra-abdominal fluid collection, or mortality when analyzing the randomized controlled trials (136). On the contrary,
analysis of the 13 nonrandomized observational studies
showed significant results in favor of pancreaticogastrostomy,
a result which was most likely due to publication bias. Therefore, neither pancreaticogastrostomy nor pancreaticojejunostomy seems to be superior in reconstruction after PD (evidence
grade Ia; recommendation A).
Further areas of research concern technical aspects of the
pancreaticojejunostomy. Specifically the question whether the
anastomosis should be performed with invagination (end of
the pancreas invaginated into either the end or the side of the
jejunum) or whether a duct-to-mucosa approach leads to less
pancreatic fistulas has been investigated. All have been proven
to be safe and feasible with no clear advantage of one over the
other (137,138). Similarly, the use of anastomotic stents has
failed to affect fistula rates (137,139).
neoadjuvant treatment
Currently, no randomized controlled trial comparing neoadjuvant therapy (radiochemotherapy or chemotherapy alone)
with direct resection for locally advanced pancreatic cancer
exists. A number of phase I/II trials or retrospective studies,
however, have demonstrated that neoadjuvant treatment is
safe and may result in down-sizing in a number of cases resulting in resection rates as high as 51% for tumors that deemed
unresectable at presentation (160162). These patients might
benefit from the improved prognosis of an R0/R1 resection,
although data to confirm this notion are lacking. Due to the
lack of evidence, however, neoadjuvant treatment for pancreatic cancer should be confined to clinical trials.
In this context, it should be pointed out that specialized,
high-volume centers have markedly improved resection rates
compared to low-volume centers (over 50%), i.e., patients that
might be classified as unresectable in one hospital might
undergo successful resection at a specialized center (163,164).
387
Group
1
2
3
4
5
6
7
Lymph nodes
Right cardial
Left cardial
Along the lesser curvature of the stomach
Along the greater curvature of the stomach
Suprapyloric
Infrapyloric
Along the left gastric artery
9
10
11
12
12h
12a1
12a2
12p1
12p2
12b1
12b2
12c
13
13a
13b
14
14a
14b
14c
14d
15
16a1
16a2
16b1
16b2
17a
17b
16
17
18
Figure 42.3 Japanese Pancreatic Society lymph node groups (140). Only the lymph node groups relevant for pancreatic surgery are shown in the figure, while the
table lists all abdominal lymph node groups. 13 and 17 are first-order lymph nodes. 6, 8, 12 and partly 9 are second-order lymph nodes. 10, 11, 15, 16, 18 and partly
9 are third-order lmyph nodes. Abbreviations: SMA, superior mesenteric artery; IMA, inferior mesenteric artery. Opaque numbers indicate posteriorly
positioned lymph nodes.
388
Year
Low-volume
High-volume
Low-volume
High-volume
References
19941998
19941999
19921995
19881998
19841991
19981995
19841995
19841993
19881993
19901995
<5
<1
<1
1
<10
<3
<20
15
1
<5
25
>16
>5
10
>81
>6
20
>11
>4
>20
16
16.3
16
9.5
21.8
14.4
14.2
12.9
19
19
0.86
3.8
4
3.3
4
3.4
1.8
5.8
2.2
1
(165)
(170)
(169)
(172)
(173)
(174)
(167)
(175)
(168)
(176)
389
Grade B
814 days or einsertion > POD 7
14
Present
Grade C
>14 days or reinsertion >POD 14
21
Present
Grade B
Often well
Yes/no
Negative/positive
Usually yes
Grade C
Clinical condition
Specific treatmenta
CT/US findings
Persistent drainage
>3 weeks
Reoperation
Ill appearing/bad
Yes
Positive
Yes
No
No
Yes
No
No
No
No
Yes
No
Possible
Yes
Yes
Grade A
Grade B
Well
Grade C
Late, severe, intra-/extraluminal
Partial (peripheral) or total parenteral nutrition, antibiotics, enteral nutrition, somatostatin analog and/or minimal invasive drainage; bFor the definition of
mild and severe PPH see text. Abbreviations: delayed gastric emptying (DGE) (261), postoperative pancreatic fistula (POPF) (195), and postpancreatectomy
hemorrhage (PPH) (200). CT, computed tomography; US, ultrasound; POD, postoperative day; NPO, nothing by mouth.
390
Time of onset, localization, and severity allow an exact classification of PPH into three grades and thus define further
diagnostic and therapeutic measures (Table 42.7).
postoperative treatment
In addition to the management of complications, standard
postoperative treatment should include nutritional support
which is vital since many patients suffer from tumor cachexia
going into the surgery and the return of normal bowl function
may be delayed because of postoperative complications like
DGE. However, early total parenteral nutrition after pancreatic
resection was associated with an increased risk of complication
(204). Enteral feeding is recommended after pancreatic resection whenever possible, however, early initiation of enteral
feeding via an intraoperatively placed jejunal feeding tube after
Whipple resections resulted in significantly higher rates of
DGE as compared to patients not receiving early enteral nutrition in one study (267). Another study evaluating continuous
enteral feeding to cyclic enteral nutrition after ppPD showed
significant benefits for the latter with earlier commencement of
normal oral diet and shorter hospital stay (205).
Increasingly, components of fast-track surgery are
applied to pancreatectomized patients including early
postoperative mobilisation, oral diet, and modern forms of
analgesia (206). Intraoperatively placed drains for example
can be removed on the second postoperative day if inconspicuous to avoid bacterial contamination of the abdominal cavity (207,208).
The benefit of prophylactic application of somatostatin analogs to prevent pancreas-specific complications has been controversial with some studies arguing for and some against it. A
recent meta-analysis of 10 randomized trials including
1918 patients showed no benefit of somatostatin analogs to
reduce mortality, but did show a significant reduction in morbidity in the treatment group (209). The external validity of
the analysis was, however, limited by the lack of any standardized definition for pancreatic fistulas between different trials
(see above). As a result a meaningful subgroup analysis was not
possible to elucidate which patients benefit from prophylactic
application. Therefore, currently, prophylactic use of somatostatin analogs cannot be recommended indiscriminately.
adjuvant treatment
Two recent randomized controlled trails (CONKO-1 (210);
ESPAC-1 (211)) as well as one meta-analysis (212) have
demonstrated a significant benefit of adjuvant chemotherapy on outcome following pancreatic cancer resection compared to observation. Therefore, all patients undergoing
curative resection should receive adjuvant chemotherapy
(evidence grade 1b, recommendation A). The current data
suggest that tumor-specific risk factors like grading or
T-stage as well as age (even >80) are no contraindication for
adjuvant chemotherapy (210,211). Poor postoperative performance status should be regarded as only a relative contraindication since in the trial of Oettle et al. even patients
with Karnofsky index 50 were included (210). Currently,
both 5-FU/folic acid (211) and gemcitabine (210) chemotherapy schemes are accepted after curative resection. A
direct comparison of gemcitabine with 5-FU/folinic acid
was recently conducted in the randomized, multicenter
ESPAC-3 trial (270). Both groups had comparable overall
survival rates after a median of 34.2 months of follow-up.
While the treatment-related serious adverse events were significantly more frequent in the 5-FU/folinic acid group
compared to gemcitabine, this did not translate into a difference in overall quality of life, which was comparable between
the two groups. Based on the data from the currently available studies, adjuvant chemotherapy should be initiated
within 6 weeks of surgery and be applied for 6 months.
Table 42.8 lists all available randomized controlled trials of
adjuvant treatment after resection of pancreatic carcinoma.
Furthermore, based on subgroup analysis of the CONKO-1
trial (210), patients receiving a gemcitabine-based adjuvant
chemotherapy demonstrated a significantly longer disease-free
survival compared to observation alone after R1 resection of
pancreatic cancer. Therefore, even in the setting of an R1 resection postoperative chemotherapy has been proven beneficial
(evidence grade 1b, recommendation A).
In contrast, the evidence for a combination of radiochemotherapy with chemotherapy is less clear, although this
treatment is common in the United States (213). Most adjuvant trials have been underpowered and the randomized
controlled ESPAC-1 (211) trial as well as one meta-analysis
(212) failed to show any benefit for radiochemotherapy
( Table 42.8). Radiochemotherapy actually seemed to have a
detrimental, albeit nonsignificant, effect on outcome.
Therefore, currently, radiochemotherapy cannot be recommended as adjuvant treatment for PDAC outside trials (evidence grade 1b, recommendation A). Shortly data of the
randomized controlled CAPRI trial (combination of radio-,
chemo- and immunotherapy) (214) should be available to
see if the promising data from previous reports on this
combination can be confirmed (215).
391
392
19942000
19982004
20002007
19861992
19841987
Chemotherapy
ESPAC-1a
CONKO-1
ESPAC-3
Takade et al.
Bakkevold et al.
Year
Comparison
CTx vs. no CT
2x2 factorial design
2x(20 Gy in
10 fractions+500 mg/m2
5FU/FA days 13)
(20 mg/m2 FA+425 mg/m2
5FU days 15) x 6 cycles
CTx vs. OBS
6 cycles of gemcitabine every
4 weeks. Each cycle consisted
of 3 weekly infusions of i.v.
gemcitabine 1000 mg/m2
followed by a 1-week pause.
Treatment
17.7
10.4
12.8
12.4
30.6%
24.3%
24.2
29.6
34%
20.5%
estimated
overall 3-year
survival
13.4
6.9
23.0(fluorouracil)
vs. 23.6
(gemcitabine)
39.7
30.0
Overall 2-year
survival rate
20.1
15.5
Median survival
(months)
Table 42.8 Randomized Controlled Trials for Adjuvant Treatment after Resection for Pancreatic Cancer
0.94 (0.811.08)
p=0.39
(262)
Significant survival benefit in
gallbladder cancer patients.
No difference in 158 eligible
pancreatic cancer patients.
No difference in 48 eligible
ampullary cancer patients
(263)
Significant increase in median
survival (23 vs. 11 mo,
P1/40.02) in 60 pancreatic and
ampullary patients combined
(Continued)
(211)
Ref.
Conclusion
Hazard ratio
(95% CI), p-value
19982002
19741982
RTOG 97-04
GITSG
2x (20 Gy in 10
fractions+25 mg/kg 5FU/FA
days 15)
Treatment
RCTx +
gemcit. vs.
RCTx + 5FU
RCTx vs. No
RCTx
RCTx vs. No
RCTx
Comparison
20.0
10.9
20.5
16.9
17.5
12.6
15.9
17.9
Median survival
(months)
42%
15%
31%
22%
3-year survival
35.7
23.2
28.5
41.4
Overall 2-year
survival rate
Hazard ratio
(95% CI), p-value
Non-significant decrease in
survival for RCTx (P=0.053) in
289 patients.
Conclusion
(266)
(265)
(264)
(211)
Ref.
Trials addressing chemotherapy (CTx) and radiochemotherapy (RCTx) are listed. aThe ESPAC-1 trial had a factorial 2x2 design, meaning that patients were initially randomized into one of the four groups: observation,
chemotherapy, radiochemotherapy, or a combination of both. Comparisons were made between (1) patients receiving chemotherapy (chemotherapy alone or radiochemotherapy + chemotherapy) and those not
receiving it (observation or radiochemotherapy only) or (2) patients receiving radiation therapy (radiochemotherapy or radiochemotherapy + chemotherapy) and those not receiving it (observation or chemotherapy
alone). Abbreviations: OBS, observation; NN, not reported.
19871995
EORTC
Radiochemotherapy
19942000
ESPAC-1a
Year
Table 42.8 (Continued) Randomized Controlled Trials for Adjuvant Treatment after Resection for Pancreatic Cancer
393
prognosis
Curative surgical resection in patients with PDAC is the single
most important factor influencing survival and the quality of
life (216). Advanced age (>80 years) is no contraindication for
resection which can be performed with similar mortality and
morbidity rates and offers the same advantages than in the
young (217). Although mortality rates for pancreatic surgery
decreased significantly in the last years (see above) the overall
5-year survival rate for all patients with PDAC remains dismal
(around 5%) (7,8). This number can be explained in part by
the low incidence of resectable PDAC at presentation, but
might also reflect a failure of adequate treatment. A recent
nationwide study in the United States including over
9,500 patients with early, potentially resectable (stage I,
T1/2N0M0) PDAC demonstrated that 71% of these patients
did not undergo resection, mostly because they were not
offered surgery (218).
Following curative resection and adjuvant chemotherapy,
patients have a 5-year survival rate of 20% to 25% and a
median survival of 17 to 28 months (181,201,210,211,217,219
223). Even after 5 years, recurrence does occur meaning that
true long-term survivors are rare (224,225). These numbers,
however, compare favorable to the devastating prognosis of
patients with inoperable, locally advanced, or metastatic disease that have a median survival of 8 to 12 and 3 to 6 months,
respectively (226). In certain subgroups (R0 resection, negative lymph node status, and specialized center), the 5-year survival might actually be as high as 40% (227).
Multiple pre-, intra-, and postoperative factors influencing
prognosis have been studied, but consistently negative resection margins (R0), negative lymph node status (N0), favorable
tumor grading, primary tumor size under 2 cm, and absence
of perineural invasion have been identified as favorable prognostic markers. Tumor size under 2 cm seems to improve
median survival dramatically from an average of 14 months to
35.5 months and significantly improves 5-year survival
(201,228232). Similarly, a positive lymph node status (N1)
has been demonstrated to be a negative prognostic factor
(181,233235), a finding confirmed by data from the ESPAC-1
trial (211,212). Finally, poor tumor grading significantly worsens median as well as overall survival in a number of studies
(181,223,236), as does perineural invasion (237239), although
in the latter case a significant association could not be verified
in other studies (231,240).
Similarly, the results concerning the influence of microscopic tumor-free resection margins (R0) on prognosis have
been ambiguous. While a number of studies have demonstrated a significant improvement in median as well as 5-year
survival following R0 resection as compared to R1 resection
(181,227,236,241) others have failed to confirm this association (240,242244). This observation is confirmed by data
from the ESPAC-1 trial in which only tumor grade and lymph
node status were identified as significant prognostic factors
(245). The reason for this apparent disparity is that the pathological handling and reporting of pancreatic specimens vary
widely between different institutions and guidelines concerning this matter have not been standardized (246). Consequently, the rate of R0 resections dropped from 86% to 24%
394
conclusion
All patients with PDAC should be evaluated for potential surgical resection given the improved prognosis and quality of life
following resection compared to palliative treatment only. In
case of questionable local respectability determined by the
radiologist, an experienced pancreatic surgeon should evaluate the radiographic images to determine whether a tumor is
resectable or not. Surgery can nowadays be carried out with
low mortality and acceptable morbidity rates at high-volume
specialized centers. Extended resections are justified if this
results in macroscopic complete resection of the tumor. Surgical resection as the mainstay of treatment should be complemented by adjuvant chemotherapy in order to improve
survival in patients suffering from PDAC.
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43
401
402
palliation of pain
(A)
(B)
Figure 43.2 Coronal section of a representative CT scan showing a metallic endostent providing adequate relief of duodenal obstruction from a pancreatic
head cancer (A). Plain film radiography demonstrating the long-term patency of palliative metallic biliary and duodenal stents which can be deployed serially as
combined or separate endoscopic procedures (B).
403
Table 43.1 Randomized Trials of Operative Versus Nonoperative Palliation of Malignant Biliary Obstruction
Study
Year
Shepherd et al.
Surgery
Stent
Andersen et al.
Surgery
Stent
Smith et al.
Surgery
Stent
Overall
Surgery
Stent
1988
No. of patients
Treatment
failure (%)a
Major complications
(%)
25
23
8
9
56
30
8
43
25
25
4
4
20
36
8
52
101
100
7
5
29
11
2
36
151
148
7
5
32
18
4
40
1989
2004
Table 43.2 Randomized Trials of Operative Versus Nonoperative Palliation of Malignant Gastroduodenal Obstruction
Study
Year
Mehta et al.
Laparoscopic GJ
Stent
Fiori et al.
Open GJ
Stent
Overall
Surgery
Stent
2006
404
No. of patients
14
13
93
85
57
0
9
9
89
100
11
0
23
22
91
91
39
0
2004
80
7.
60
8.
40
p = 0.0001
9.
20
10.
0
0
12
15
18
21
24
27
30
33
36
11.
Months of survival
12.
13.
14.
15.
16.
17.
summary
Based on the existing clinical evidence, we advocate operative
biliary decompression, gastric bypass, and chemical splanchnicectomy for all patients who undergo laparotomy without
an indwelling metallic biliary stent and are found to have
locally unresectable pancreatic carcinoma in the periampullary region. Even though this has not been studied directly, the
durability of operative palliation should influence patients
quality of life positively by decreasing the need for reinterventions and future hospitalizations. Symptomatic patients with
preoperatively confirmed locally unresectable cancer or metastatic disease can be palliated reliably with nonoperative techniques. Such patients should be offered surgical palliation only
when nonoperative procedures are unsuccessful and they have
a reasonable life expectancy. To take advantage of the longterm benefits of surgical palliation, operative bypass procedures must be performed with acceptable morbidity.
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introduction
A cystic tumor of the pancreas is a radiographic finding that
has a broad histologic differential. This differential includes
non-neoplastic pseudocysts, benign neoplastic cysts (serous
cysts), pre-malignant cysts (mucinous cysts), and cystic lesions
with invasive carcinoma (Table 44.1) (1). The current ability to
determine the histologic diagnosis of these lesions without
resection is improving but limited (2,3). Serum testing, radiographic imaging, endoscopic ultrasound, cyst fluid cytology,
and cyst fluid marker analysis (CEA) have a combined overall
accuracy of approximately 70% to 85% (4). This diagnostic
limitation can make treatment decisions difficult: resection
may provide the only form of cure in those patients with highrisk mucinous cysts or very early invasive disease; however,
resection has a major morbidity rate of approximately 20%
and mortality rate of 2% to 10%. Resection of benign cysts will
expose the asymptomatic patient to all the risks of resection
without identified benefit.
As cross-sectional imaging improves this diagnostic and
treatment dilemma will become more common. The
increased use of high-quality cross-sectional imaging has
resulted in an increasing number of patients identified with
small (<3 cm) asymptomatic cysts, and the ability to determine histology in these patients is even more difficult (57).
The natural history of these small, incidentally discovered
lesions is unknown. Even in a patient with a small and
asymptomatic pre-malignant cyst (mucinous) the future risk
of progression to malignancy has not been determined with
respect to both frequency and duration. The decision to
resect a small, asymptomatic mucinous lesion, particularly in
someone who is elderly or with significant comorbidities,
must take into account the fact that the natural history of
that lesion is unknown.
clinical scenariospresentation
and diagnostic evaluation
The clinical scenarios below are from three patients with cystic
lesions of the pancreas treated at our institution over the past
5 years. The presentation and diagnostic evaluation are presented. Treatment decisions and rationale are provided in the
last section of this chapter.
Scenario 1. Otherwise healthy 66-year-old female who
underwent CT imaging of the abdomen for left lower quadrant abdominal pain. Symptoms resolved without treatment
and imaging revealed no evidence of diverticulitis or other
left abdominal/pelvic pathology. Imaging did reveal 4.5 cm
cystic lesion in pancreatic tail (Fig. 44.1). Review of CT
revealed imaging characteristic of serous cystadenoma
(microcystic, central calcification). No further diagnostic testing
was performed.
407
The more common clinical problem with serous cystadenoma is local growth and the subsequent development of
symptoms such as pain or jaundice. The presence of symptoms (pain) appears to be related to the size of the lesion as
studies describing patients with larger tumors tend to have a
greater percentage of patients with symptoms. Compagno and
Oertels study in 1978 of 34 cases of serous cystadenoma
reported an average tumor diameter of 10.8 cm, and 71% were
symptomatic (11). In a previous report from our institution
the average tumor diameter of patients with resected serous
lesions was 4.9 cm, and 35% were symptomatic (14).
Because the exact size at which a serous lesion will become
symptomatic is unknown, and because the growth rate of
serous cystadenomas has not been defined, the appropriate
management of the young patient with an asymptomatic serous lesion is yet to be determined. Tseng et al. reported a
growth rate of 0.6 cm/year for patients with serous cystadenoma (15). In Tsengs report, serial radiography was obtained
Kloppels classification
Epithelial tumors
Non-epithelial tumors
Pseudotumors
Serous cystadenoma
Mucinous cystadenoma
Cystadenocarcinoma
Intraductal papillary mucinous
tumor
Pseudopapillary and solid tumor
Teratoma
Acinous cystadenocarcinoma
Adenosquamous carcinoma
Mucinous cystic adenocarcinoma
Cystic islet cell tumor
Vascular tumor
Lymphangioma
Hemangiopericytoma
Leiomyosarcoma
Lymphoma
Single cyst
Polycystic disease
Exclusively pancreatic
With hepatorenal disease
Von HippelLindau disease
Figure 44.1 Cystic lesion in the tail of the pancreas (arrow) in otherwise
healthy 66-year-old female.
408
Figure 44.2 Cystic lesion in the tail of the pancreas (solid arrow) and dilated
main pancreatic duct (broken arrow) in an otherwise healthy 63-year-old
female.
Figure 44.3 Cystic lesion in the body of the pancreas (arrow) in an otherwise
healthy 60-year-old female.
(A)
a variety of names including mucinous ductal ectasia, papillary carcinoma, and villous adenoma. Because of the lack of a
unifying diagnosis, older reports evaluating mucinous cysts of
the pancreas may actually represent a combination of both
IPMN and mucinous cystic neoplasm (MCN) which is a distinct histopathologic entity.
Grossly, IPMNs are characterized by ductal dilatation and
mucin production (Fig. 44.5). IPMN is considered a whole
gland process; however, radiographically apparent disease
may be evident in the main pancreatic duct alone, the
branch ducts alone, or both. Microscopically, IPMN lesions
are characterized by papillary projections of columnarlined epithelium with varying degrees of dysplasia (Fig.
44.5). Mucin is typically abundant both within the cytoplasm of the lining epithelial cells as well as within the acellular fluid matrix. Current nomenclature (WHO) divides
these lesions into the categories of adenoma, borderline (lowgrade dysplasia), high-grade dysplasia (carcinoma in situ),
and carcinoma.
(B)
Figure 44.4 Gross and microscopic characteristics of serous cystadenoma. Arrow notes central scar.
BD
PD
(A)
(B)
Figure 44.5 Gross and microscopic characteristics of main duct IPMN. Abbreviations: PD, pancreatic duct; BD, bile duct.
409
PD
Cyst
(A)
(B)
Figure 44.6 Gross and microscopic characteristics of MCN. Abbreviation: PS, pancreatic duct.
410
diagnostic evaluation
High-quality cross-sectional imaging is essential for the evaluation of patients with cystic lesions of the pancreas. Multidetector CT (MdCT) allows thin section scanning of the
pancreas and has become the most common method for assessing pancreatic cysts (28). MdCT has the ability to provide excellent visualization of septa, mural nodules, and calcifications.
MdCT also allows excellent visualization and characterization
of the pancreatic parenchyma. Evaluation of the parenchyma
adjacent to the cyst is critical as we have recently reported on
several patients with pancreatic adenocarcinoma who presented with isolated small retention cysts adjacent to a radiographically occult malignancy (14). MRCP also provides
excellent characterization of cyst morphology (4). MRCP
may also allow for the ability to diagnose branch duct IPMN
through identification of communication between the cyst
and the pancreatic duct (29).
Endoscopic evaluation with endoscopic ultrasound (EUS)
has played an increasingly important role in the evaluation of
pancreatic cysts. In general, endoscopy with or without endoscopic retrograde cholangiopancreatography (ERCP) has a
limited role in the evaluation of pancreatic cysts; however,
these tests may have indications in the evaluation of suspected
IPMN. Endoscopic ultrasound (EUS) with or without cyst
aspiration is highly operator dependent, but the information
gained from EUS by an experienced gastroenterologist can be
very valuable. EUS can provide detailed images of the cyst wall
as well as internal cyst architecture and can be used to perform fine needle aspiration biopsy. The fluid obtained by EUS
FNA can be used both for cytologic analysis as well as for
various tumor marker analyses.
The diagnostic utility of cyst fluid analysis has been studied
extensively (4,3032). A variety of tumor markers including
CA19-9, CEA, CA15-3, M1 mucin, and amylase have been
evaluated. The most consistent results have been reported for
cyst fluid CEA levels. In a prospective study by Brugge et al. of
112 patients with cystic lesions, an elevated cyst fluid CEA level
(>192 ng/ml) was the best predictor of a mucinous lesion and
accurately identified these lesions in 79% of cases (3). Elevated
CEA levels and the presence of extracellular mucin have been
shown to have a positive predictive value for mucinous lesions
as high as 85% (4,33,34). The degree to which the cyst fluid
CEA level is elevated has not been found to be predictive of
malignancy within mucinous cysts. Serous cystadenomas and
retention cysts have been shown to have almost uniformly
undetectable cyst fluid CEA levels (4,34,35).
The ability of cyst fluid cytology to differentiate between
serous versus mucinous cysts as well to identify malignancy
within the mucinous sub-group is limited. Most studies have
shown accuracy rates of cyst fluid cytology in the range of 50%
and thus cytology is probably inferior to cyst fluid CEA alone
in discriminating between serous and mucinous cysts (3).
treatment recommendations
Because of the frequent inability to determine histology without resection, and because of the unknown natural history of
some cystic sub-types, many authors have recommended routine resection of all pancreatic cysts (2,37,38). These authors
argue that because the preoperative distinction between
benign and malignant is unreliable, and because the potential
adverse consequences of not resecting a pre-malignant or
malignant cyst are significant, all medically fit patients should
undergo resection. Although this approach provides a guarantee to patients that no pre-malignant or malignant lesions will
be observed, it exposes patients with benign lesions to the risks
of pancreatectomy.
Several recent reports, including a study from our own institution, have recommended a more selective approach to resection (3941). Proponents of this approach argue that with
current imaging techniques, and with an improved understanding of the various histologic entities, a group of patients
can be identified who have an extremely low risk of malignancy. Most reports evaluating this approach have recommended non-operative management (radiographic follow-up)
for selected patients with small, incidentally discovered cysts
of the pancreas that do not have a solid component or other
concerning clinical or radiographic features of malignancy
411
412
summary
In summary, many institutions are now reporting a selective
approach to resection in patients with cystic lesions of the
pancreas. Routine resection of all pancreatic cysts is currently
impractical, and given the large numbers of patients being
identified with <2 cm lesions this approach would result in a
mortality rate that is much higher than the rate of malignancy.
Most studies that have advocated a selective approach have
reported the radiographic characteristics of main duct dilatation, a solid component, cyst size, and symptoms to be associated with treatment recommendations. In the absence of these
findings we feel that radiographic follow-up is warranted. In
the young patient with a small mucinous tumor the additional
factors are the likelihood of progression to malignancy and the
patient anxiety about radiographic follow-up. No data are
available for the former.
Efforts should be made to improve the ability to distinguish
histopathologic sub-types without resection. The current
challenges are to improve the sensitivity and specificity for the
identification of mucinous sub-type, to better characterize the
progression of IPMN and mucinous cystic tumors, and to
develop better methods for identifying the presence of in situ
or invasive disease in these patients. Continued improvements
in cross-sectional imaging and endoscopic techniques, and
further investigation into markers in the serum and cyst fluid,
should allow better stratification of mucinous sub-types.
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3. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of
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4. Brugge WR, Lauwers GY, Sahani D, et al. Cystic neoplasms of the pancreas.
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10. OMalley VP, Cannon JP, Postier RG. Pancreatic pseudocysts: cause,
therapy, and results. Am J Surg 1985; 150: 6802.
11. Compagno J, Oertel JE. Microcystic adenomas of the pancreas (glycogenrich cystadenomas): a clinicopathologic study of 34 cases. Am J Clin
Pathol 1978; 69: 28998.
12. Compagno J, Oertel JE. Mucinous cystic neoplasms of the pancreas with
overt and latent malignancy (cystadenocarcinoma and cystadenoma).
A clinicopathologic study of 41 cases. Am J Clin Pathol 1978; 69: 57380.
13. Matsumoto T, Hirano S, Yada K, et al. Malignant serous cystic neoplasm
of the pancreas: report of a case and review of the literature. J Clin Gastroenterol 2005; 39: 2536.
14. Allen PJ, DAngelica M, Gonen M, et al. A selective approach to the resection of cystic lesions of the pancreas: results from 539 consecutive
patients. Ann Surg 2006; 244: 57282.
15. Tseng JF, Warshaw AL, Sahani DV, et al. Serous cystadenoma of the pancreas: tumor growth rates and recommendations for treatment. Ann Surg
2005; 242: 4139.
16. Kloppel G, Solcia E, Longnecker DS. World Health Organization International Classification of Tumors. Berlin: Springer, 1996.
17. DAngelica M, Brennan MF, Suriawinata AA, et al. Intraductal papillary
mucinous neoplasms of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg 2004; 239: 4008.
18. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 2004; 239: 78897.
19. Salvia R, Fernandez-Del CC, Bassi C, et al. Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann Surg 2004; 239:
67885.
20. Sahani DV, Saokar A, Hahn PF, et al. Pancreatic cysts 3 cm or smaller: how
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21. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic
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22. Chari ST, Yadav D, Smyrk TC, et al. Study of recurrence after surgical
resection of intraductal papillary mucinous neoplasm of the pancreas.
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23. White R, DAngelica M, Tang L, et al. The fate of the remnant pancreas
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pancreas: clinicopathological features, prognosis, and relationship to
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(M1 antigens) in cyst fluid for the diagnosis of cystic lesions of the
pancreas. Int J Cancer 1997; 74: 28690.
32. Hammel P, Levy P, Voitot H, et al. Preoperative cyst fluid analysis is
useful for the differential diagnosis of cystic lesions of the pancreas.
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36. Goh BK, Tan YM, Yap WM, et al. Pancreatic serous oligocystic adenomas:
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consequences. Langenbecks Arch Surg 1998; 383: 5661.
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413
45
introduction
Pancreatic endocrine tumors are benign or malignant epithelial
tumors that show evidence of endocrine cell differentiation.
Pancreatic endocrine tumors are uncommon, representing
<5% of pancreatic tumors in surgical series (1,2). Clinically
silent endocrine tumors have been detected in 0.3% to 1.6% of
unselected autopsies in which only a few sections of the pancreas were examined, and in up to 10% of autopsies the whole
pancreas was systematically investigated both grossly and
microscopically. Most tumors from these series are small (less
than 1 cm), in elderly patients (mean age of 70 years), and
benign (clinically silent microadenomas).
Pancreatic endocrine tumors can be broadly classified as
functional or non-functional. Despite changing trends, the
majority of clinically relevant pancreatic endocrine tumors are
functional (3). The proportion of non-functioning tumors, in
series of islet cell neoplasms, has varied over time, ranging
between 15% and 53% of cases (47). While the definition of
non-functional has been inconsistent in many reports,
increased use of more sophisticated imaging modalities has
allowed clinically silent intra-abdominal masses to be identified incidentally and many series report an increased incidence
of non-functioning neoplasms (8,9). Overall, the reported
35% to 50% incidence of non-functioning endocrine tumors
suggest that non-functional tumors are at least as common as
insulinomas and more common than all of the remaining pancreatic endocrine tumor types (2).
Functional endocrine tumors of the pancreas are peptidesecreting neoplasms leading to clinical presentation with a
defined syndrome related to the effects of an abnormally elevated plasma peptide level. These peptides may or may not
occur naturally in the pancreas and a given tumor may secrete
multiple peptides. It is on the basis of the primary functional
peptide hormone secreted that each tumor is named; e.g., gastrinoma, insulinoma.
Non-functioning islet cell tumors are pancreatic neoplasms
with endocrine differentiation in the absence of a clinical syndrome of hormone hyperfunction. Despite the presence of
hormones in tumor cells at immunohistochemistry, many of
these tumors lack evidence of increased serum hormonal levels. Tumors releasing increased amounts of hormone in the
blood stream without evidence of a hyperfunctional syndrome
are also often reported as non-functioning tumors. Several
explanations can be given for why these non-functioning
tumors are hormonally silent. One reason is that the principal
hormone secreted by the tumor may cause no specific clinical
signs, although it is released in excess. In some situations, the
tumor makes a functionally inert hormone, which is recognized by an antibody directed against a functional hormone.
As the specificity of antibodies improves, such false positives
should disappear. A second possibility is that the amount of
414
insulinoma
Insulinoma is a neoplasm that arises from the pancreatic insulin-producing beta-cells. Unlike other gastrointestinal endocrine tumors, which are malignant in more than 60% of cases,
90% of insulinomas are benign, solitary growths that occur
almost exclusively within the pancreatic parenchyma
(Table 45.1). They occur throughout the head, body, and tail of
the pancreas with equal frequency (14). Three percent are in
the uncinate and 2% to 3% are ectopic. Ectopic insulinomas
are usually found in the duodenal mucosa, the hilum of the
spleen, or in the gastrocolic ligament (13).
Pancreatic associated
primary (%)
Malignancy
rate (%)
Metastatic
rate (%)
Multicentricity (%)
Size
MEN-1 (%)
30
9599
100
100
68
60
516
82
50
>90
5080
31
>50
50
75
2040
10
24
20
10
Medium
Small
Large
Small
Large
1841
410
Rarely
4
Unknown
Gastrinoma
Insulinoma
Glucagonoma
Vi Poma
Somatostatinoma
Source: Adapted from Ref. (13).
Transabdominal
ultrasonography
CT
Angiography
26
11
40
15
59
26
17
43
50
60
36
44
35
54
44
75
53
64
26
47
Portal venous
sampling
94
77
63
89
MR imaging
Intraoperative
ultrasonography
Palpation
0
25
92
64
100
90
82
90
95
90
16
415
gastrinoma
416
90%
10%
Figure 45.2 Anatomic triangle in which gastrinomas are most often found.
Source: From Ref. (13).
417
Liver (%)
9
31
30
58
48
42
71
92
Ultrasound
CT
MR
SRS
Source: Adapted from Ref. (57).
418
Primary (%)
Liver (%)
5075
28
73
78
NA
62
NA
41
other studies, the investigators found that SRS was significantly more sensitive than conventional imaging studies and,
on a lesion-by-lesion basis, was even more sensitive than all
conventional imaging studies combined. The addition of all
conventional studies to SRS detected only three (4%) additional lesions found at exploration in three patients (45).
The potential benefit of endoscopic ultrasound for preoperative imaging is that it can visualize small tumors and may
help distinguish the primary tumor from lymph node and
liver metastases. In a study of 22 patients, EUS had a sensitivity
of 50%, 75%, and 63% for duodenal, pancreatic, and lymph
node gastrinoma, respectively (46). Currently, studies suggest
that EUS has a sensitivity of 50% to 75% and a specificity of
95% in the localization of gastrinomas (24,46).
Techniques such as portal venous sampling of gastrin and
angiography with intra-arterial injection of secretin with
venous sampling of gastrin have been shown to have good sensitivity for gastrinoma detection (Table 45.4) However, since
80% of gastrinomas are located in a relatively small anatomical
area, the gastrinoma triangle, performing a study that indicates a region that may harbor a tumor does not add much
information. Secretin angiography may be indicated for selection of patients that may benefit from an aggressive approach
(e.g., pancreaticoduodenectomy) for a locally advanced or
locally recurrent gastrinoma. A secretin angiogram may be
indicated to determine whether all tumor is localized within
the planned resection (37).
In our opinion, preoperative evaluation in patients with
gastrinoma should include
1. Endoscopy to evaluate for the presence of duodenal
gastrinoma,
2. Spiral CT scan to evaluate the pancreas, lymph
nodes, and liver (consider MR imaging if CT
is not adequate or further evaluation of liver is
needed), and
3. SRS for global evaluation of tumor extent.
Despite these tests, a significant percentage of patients will
not have their tumors detected before surgery. Therefore, a
thorough surgical exploration is indicated.
All patients with sporadic gastrinoma should undergo localization studies and be considered for exploratory laparotomy
for potential cure. Since gastrinomas are relatively indolent, it
has not been shown that resection of the primary tumor
extends survival. However, evidence suggests that resection of
primary gastrinoma decreases the incidence of liver metastases. Patients with liver metastases from gastrinoma will eventually die of disease. Therefore, it is reasonable to assume that
resection of the primary should prolong survival (37).
When exploring a patient for gastrinoma, a meticulous
intraoperative approach is necessary. Gastrinomas that were
previously missed have often subsequently been found to be in
the duodenal wall. Gastrinomas are located in more proximal
portions of the duodenum and the tumor density decreases
more distally (Fig. 45.3). Simple palpation through the bowel
wall without opening the duodenum will miss small duodenal
tumors. Endoscopic transillumination and extensive duodenotomy have been found to improve localization of duodenal
glucagonoma
Glucagonomas are usually large tumors (>5 cm) and occur
most often in the body and tail of the pancreas and are rarely
extrapancreatic (Table 45.1) (13,16). The incidence of glucagonoma is considerably less than insulinoma and gastrinoma
and is estimated to be one in 20 million to one in 30 million.
The exact incidence is unknown because glucagonomas may
Series
Sporadic
or MEN
S
S
S
S
MEN
MEN
S/MENa
No. with
tumor
found (%)
No.
diseasefree (%)
73
11
5
22
19
10
17
56 (77)
10 (91)
5 (100)
9 (41)
17 (90)
10 (100)
17 (100)
37 (50)
9 (82)
5 (100)
2 (9)
1 (5)
0 (0)
5 (30)b
419
420
vipoma
VIPoma syndrome characterized by watery diarrhea, hypokalemia, and achlorhydria (WDHA) was first described in 1958
by Vemer and Morrison (59). Vasoactive intestinal peptide was
first isolated from bovine intestine in 1970 and soon after it
was shown that extracts of peptides from tumor and plasma of
patients with WDHA produced similar symptoms in dogs
(13,60). The first report of a surgical cure was in 1978 when
excision of a VIPoma in a patient with WDHA syndrome completely relieved the symptoms as plasma VIP levels dropped to
normal (13). Since that time, 201 cases have been reported in
the literature (61).
VIPomas are predominantly in the pancreas (90%) and
extrapancreatic tumors are very rare, except in children (14).
Pancreatic VIPomas are usually solitary, small in diameter, and
in the body or tail of the pancreas 75% of the time (Table 45.1)
(61). Approximately 50% of pancreatic VIPomas are malignant and one-half of these are metastatic to the liver or regional
lymph nodes at diagnosis. Less than 5% of patients with
VIPoma of the pancreas have MEN-1 (14). The tumors have a
bimodal distribution which is related to histologic type. In a
study of 62 patients, 52 had pancreatic VIPomas and 10 had
extrapancreatic ganglioneuromas. The extrapancreatic sites
(adrenal, mediastinal, retroperitoneal) occur predominantly
in the pediatric population and demonstrate a less aggressive
course, with only a 10% rate of metastasis (61).
Diagnosis includes an evaluation of the diarrhea for a secretory nature. This can be confirmed with a trial of fasting for 48
to 72 hours, which will have no major effect on the diarrhea
due to VIPomas. The fecal content of potassium and sodium is
determined. The sum of twice the sodium plus the potassium
should equal isotonicity in a secretory diarrhea. All infectious
causes of diarrhea must be excluded. A fasting plasma VIP
level of more than 200 pg/ml is required to establish the diagnosis (14,62).
Spiral CT scanning should be used to localize VIPomas.
With small lesions, other modalities such as SRS or angiography may occasionally be necessary to help identify tumor location (63).
Surgical excision remains the only effective method of cure.
Preoperative restoration of extracellular volume status and
correction of electrolyte abnormalities must be accomplished.
The fluid and electrolyte imbalance should be reversed slowly
because of its chronic nature. Octreotide acetate is useful in
promptly inhibiting VIP secretion from the tumor and stopping the diarrhea (55) A careful surgical exploration including
evaluation of the retroperitoneum, both adrenal glands, and
the pancreas should be performed. Surgical therapy consists of
enucleation or pancreaticoduodenectomy for pancreatic head
tumors. Body and tail tumors are best managed by distal pancreatectomy. Complete resection of these tumors delivers full
symptomatic relief. If all apparent tumor cannot be resected or
if there is metastatic disease, surgical debulking remains a useful option. VIP levels are an excellent tumor marker for recurrence. If there is recurrence, repeat debulking may be a viable
and therapeutic option (64).
Survival of patients with malignancy and/or metastatic disease is disappointing. The average survival is approximately 1
somatostatinoma
421
Study (yr)
Jaundice (%)
Mass (%)
20
21
25
58
198291
194884
196078
194996
40
24
28
35
35
48
36
56
30
24
46
40
24
8
Study years
Multiple
No. (%)
25
11
19
10
13
20
73
14
34
196078
196383
194884
197385
198590
198291
195392
197296
198596
14 (56)
7 (64)
9 (47)
8 (80)
5 (38)
14 (70)
43 (59)
11 (79)
16 (47)
5 (20)
4 (36)
7 (37)
2 (20)
8 (62)
5 (25)
30 (41)
1 (14)
16 (47)
6 (24)
3 (16)
1 (5)
1 (7)
2 (6)
diagnosis
Since the clinical presentation of non-functioning islet cell
tumors is similar to other pancreatic neoplasms, the major
challenge is to distinguish this tumor from other forms of pancreatic neoplasia, especially from the much more common
ductal adenocarcinoma. Non-functioning islet cell tumors
tend to be larger than ordinary pancreatic adenocarcinomas at
the time of diagnosis. Viable portions of islet cell tumors are
typically well vascularized and often hypervascular relative to
the unaffected portion of the pancreas. As a result this neoplastic tissue usually undergoes an appreciable degree of
enhancement on images made with appropriate techniques of
intravenous contrast enhancement (74). Other morphologic
features that distinguish islet cell tumors include the lack of
422
Sex (M:F)
Vascularity
Degree of necrosis
Size
Enhancing capsule
Calcification
1.3:1.0
1.0:1.0
1.0:9.0
1.0:1.0
1.0:2.0
Hypovascular
Hypovascular
Hypovascular
Hypervascular
Hypovascular
Little
Much
Much
Variable
None
Small
Large
Large
Mod-large
Large
No
Variable
Yes
No
Yes
No
No
Yesperipheral
Yes (25%)internal
Yescentral
423
424
(A)
(B)
(C)
Figure 45.6 (A) CT scan of patient with cirrhosis and large non-functioning tumor of tail of pancreas (arrow). (B) Another image of the liver of the same patient
shows a cystic lesion in the liver (arrow), which was suspicious for metastatic disease. (C) Octreotide scan of the same patient. Top panel demonstrates two intense
areas of uptake in the left abdomen corresponding with the tumor and the spleen (arrowheads). In the bottom panel, the large cyst in the liver is visualized and
there is no uptake within this cyst in the liver (arrowhead). At operation, these findings were confirmed, no liver metastases were identified and the patient underwent a distal pancreatectomy with splenectomy.
without actual invasion. The large tumor bulk may cause near
obstruction of blood vessels via a compressive effect which can
be relieved by tumor resection. For instance, tumors in the tail
of the pancreas can compress the splenic vein leading to splenomegaly and even varices (Fig. 45.7A,B). Nevertheless, these
tumors can be frequently resected with negative margins. Similarly, tumors in the head of the pancreas can compress the superior mesenteric vein. Again, in the absence of known metastatic
disease, every attempt should be made at tumor resection.
Tumors in the head of the pancreas should usually be treated
by pancreaticoduodenectomy, while tumors in the body and
tail should be treated with distal pancreatectomy. Extension of
tumor from the pancreas into surrounding organs such as the
stomach and colon should be resected en bloc. If the tumor is
small (<2 cm) and located in the tail of the pancreas consideration should be given to distal pancreatectomy with splenic
preservation. In patients with significant co-morbid conditions or for small lesions in the head of the pancreas,
enucleation can be entertained.
With endocrine tumors, some authors have advocated that
surgical removal of involved lymph nodes should be performed
425
Study years
25
21
27
43
20
73
33
34
58
196078
194884
196584
195087
198291
195392
198388
198596
194996
>5d
10
6.2
5.1
44%
63%
58%
40
30
4.8
76%
52%
Survival allb
Curativec
42
6.8
100%
(actuarial 5-yr)
(actuarial 5-yr)
(actuarial 3-yr)
months (mean)
months (median)
yr (median)
(actuarial 3-yr)
(actuarial 5-yr)
(A)
(B)
Figure 45.7 (A) Large tumor in the tail of the pancreas with splenic vein obstruction and varices (arrows). This tumor was resected with negative margins.
(B) Intraoperative picture of varices encountered at the time of resection (arrows).
426
Type
25
3 (12)
4 (50)
11
2 (18)
Biliary bypass (N = 2)
Unknown (N = 1)
Double bypass (N = 3)a
Biliary bypass (N = 1)
Biliary bypass (N = 2)
11
2 (18)
Double bypass (N = 2)
73
12 (16)
20
7 (35)
Distal pancreatectomy (N = 9)
Pancreaticoduodenectomy (N = 3)
Distal pancreatectomy (N = 2)
Biliary bypass (N = 3)
Pancreaticoduodenectomy (N = 2)
Survival
7 yr (mean)
4.5 yr (mean)
1.5 yr (AWD)
8 yr (AWD)
13 mo (AWD)
26 mo (DOD)
4.5 yr (median)
16 mo (median)
a
Biliary and gastric bypass.
Abbreviations: AWD, alive with disease; DOD, dead of disease.
427
treatment: chemotherapy
Recommended chemotherapy for advanced islet cell tumors is
based on the results of a multicenter randomized trial. In this
trial, 105 patients were randomized to receive one of three regimens: streptozotocin plus fluorouracil, streptozotocin plus
doxorubicin, or chlorozotocin alone. Patients with either nonfunctioning or functioning islet cell tumors were included in
this study. Streptozotocin plus doxorubicin was superior to
streptozotocin plus fluorouracil in terms of the rate of tumor
regression, measured objectively (69% vs. 45%, p = 0.05,
respectively), and the median length of time to tumor progression (20 vs. 6.9 months, p = 0.001, respectively). Streptozotocin
plus doxorubicin also had a significant advantage in terms of
survival (median 2.2 vs. 1.4 years, p = 0.004) (97). This regimen
is now considered the standard treatment for advanced islet cell
tumors, but should be considered in the context of each individual patient, as some may have prolonged survival untreated,
and response to treatment is greater than the effect on overall
survival.
treatment: octreotide
Octreotide is a synthetic octapeptide with structure and activities similar to those of the native hormone somatostatin, but
with significantly longer half-life and duration of action that
the native substance. Octreotide has been reported to be effective in controlling the hormone-induced symptoms of patients
with functional islet cell tumors (100). Although rare reports
of tumor regression to octreotide have been published, the
drug has been primarily utilized to ameliorate the symptoms
from hormonal excess in patients with functional islet cell
tumors. In a study which included 13 patients with advanced,
incurable non-functional islet cell tumors, octreotide was
administered via subcutaneous injection. No patient experienced a major objective response. Of the 21 patients with
functional tumors, 15 demonstrated either a symptomatic
improvement or an objective decrease in hormone level.
Octreotide is useful in controlling symptoms due to hormonal
excess in functional islet cell tumors. There is no evidence that
octreotide would benefit patients with non-functional islet cell
tumors.
prognosis
Evans et al. (84) found that patients who underwent curative
resection of their primary tumor in the absence of metastases
had a 72% 5-year survival with a median survival of 6.8 years.
This was in sharp contrast to patients who presented with
428
conclusions
Clinically, there are similarities and differences between the
various functional endocrine tumors of the pancreas. These
tumors vary with regard to size, location, age distribution, sex
distribution, propensity for malignancy, and metastatic potential in accordance with the individual tumor type. The clinical
morbidity and mortality associated with the tumor are due to
peptide hypersecretion and not to tumor mass. In addition,
key points
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98.
99.
100.
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431
introduction
Although ductal adenocarcinoma is the most common malignant neoplasm of the pancreas, there are multiple unusual
tumors of the pancreas that surgeons must keep in mind. A
thorough history and physical exam and a high-resolution
dedicated pancreatic CT scan are crucial in differentiating
these rare tumors from the more commonly seen tumors. At
times, MRI/MRCP, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasound can aid in making the
diagnosis. Here, we discuss nine rare tumors of the pancreas
and their distinguishing features (Table 46.1).
432
Type of tumor
Percentage of
all pancreas
tumors
Demographics
Solid pseudopapillary
neoplasm
13%
Young females
<1%
Adenosquamous
carcinoma
Pancreatic lymphoma
<14%
<0.5%
Imaging
Prognosis
Resection
Resection
Better than
adenocarcinoma
Resection
Chemotherapy
radiotherapy.
Occasionally
resection
Worse than
adenocarcinoma
Better than
adenocarcinoma
Metastases to the
pancreas
Von HippelLindau
syndrome
<1%
Variable
Rare
M=F
Rare
Medullary carcinoma
?<5%
Well circumscribed
lesion or infiltrating lesion with
poorly defined
borders
Often hypervascular
spherical lesions
Cysts, adenomas, and
hypervascular
neuroendocrine
tumors
Common local
infiltration and
metastases
Similar to ductal
adenocarcinoma
Uncommon
Focal enlargement of
pancreas
Autoimmune
pancreatitis
Treatment
Steroid therapy
Similar to adenocarcinoma
Better than
adenocarcinoma if
positive for microsatellite instability
Good
Note: Autoimmune pancreatitis (also termed lymphoplasmacytic sclerosing pancreatitis) is not a neoplasm, but may be mistaken for a neoplastic process.
Figure 46.1 CT scan showing a large heterogenous mass in the tail of the
pancreas (arrow) with central calcification. The surgical specimen was
consistent with a solid pseudopapillary neoplasm.
433
Year
Number of patients
Wisnoski (12)
Seth (11)
Kitagami (16)
Holen (10)
2008
2008
2007
2002
672
14
115
39
56
57
59.6
60
Median survival
(month)
47
33
123
41
19
without resection (21). Obviously, a complete surgical resection is recommended for ASC whenever possible. While the
standard of care currently recommends adjuvant chemo- or
chemoradiation therapy for resected ASC patients, no trials
have proven a survival benefit in this patient cohort.
pancreatic lymphoma
Primary pancreatic lymphoma (PPL) is a rare disease,
representing less than 0.5% of all pancreatic tumors and less
than 2% of extra nodal non-Hodgkins lymphomas (NHL)
(22,23). PPL occurs more frequently in men than women and
usually presents in the 5th to 6th decade (median age 57.1
years) (24). The clinical presentation of PPL is often nonspecific. The most common presenting symptom is abdominal
pain (83%), followed by abdominal mass (58%), weight loss
(50%), jaundice (37%), acute pancreatitis (12%), small bowel
obstruction (12%), and diarrhea (12%) (25). The classic
B-symptoms of nodal NHL are seen in less than 2% of PPL
patients (27). Laboratory studies are often non-diagnostic.
Two different morphologic patterns of involvement are seen
on CT: a well-circumscribed mass or an infiltrating lesion with
poorly defined borders (27). Certain CT findings such as a bulky
head of pancreas tumor without significant dilation of the bile
duct or main pancreatic duct and enlarged lymph nodes below
the level of the renal vein suggest PPL over adenocarcinoma
(23,27). However, cytohistological examination of tissue,
obtained by image-guided fine needle aspiration (FNA) or
endoscopically guided FNA, is required to confirm the diagnosis
of PPL (24,28). Surgery is usually reserved for rare cases where
less invasive modalities fail to provide a tissue diagnosis.
The treatment of PPL has varied, due to the lack of prospective randomized studies to delineate management. Chemotherapy has been the mainstay of treatment with CHOP
(Cyclophosphamide, Adriamycin, Vincristine, Prednisone),
CVP (Cyclophosphamide, Vincristine, Prednisolone), and
MACOP-B (Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin) being used most commonly (26,29). Radiotherapy has been used variably, alone and
as consolidation after chemotherapy (26). Recently rituximab
has been used in combination with CHOP resulting in
improved response rates (30). Surgical resection for stage I and
II disease has been shown to increase cure rates and may be
used as part of multimodality therapy for resectable lesions
(31). In general, the outcomes for pancreatic lymphoma are
better than for ductal adenocarcinoma.
434
Figure 46.2 CT scan showing a large heterogenous mass involving the body
and the tail of the pancreas (arrow) in a 70-year-old male who had previously
undergone right upper lobectomy for lung adenocarcinoma. This mass was
found during a follow-up PET CT scan. The pathology specimen confirmed
the diagnosis of a metastasis from the lung primary.
Clinical setting
Colon
Melanoma
Recommended treatment
Survival benefit
Metastectomy
Metastectomy not recommended
Metastectomy in conjunction with
multimodality therapy
En bloc resection (typically pancreaticoduodenectomy)
Metastectomy if complete resection of all
intra-abdominal sites is possible
Improved survival
No survival benefit
May improve survival
Improved survival
Improved survival
435
medullary carcinoma
Initially described by Goggins et al. in 1998 as pancreatic
adenocarcinomas with DNA replication errors (RER+), medullary carcinomas of the pancreas are poorly differentiated carcinomas that have been frequently grouped with conventional
ductal carcinoma of the pancreas. However, they are
histologically distinct, described by syncytial growth pattern,
expanding tumor borders, and extensive necrosis (56).
Furthermore, they have unique genetic features and tumor
pathogenesis. Although not clearly known, up to 5% of
pancreatic cancers may be medullary variants. Clinically,
patients with these tumors present in the 6th and 7th decade of
life with a slight male to female predominance and most
patients have a family history of cancer in a first degree relative.
On a molecular level, medullary carcinomas of the pancreas
were initially reported to have a wild-type K-ras gene. However, later studies have not confirmed this as a universal finding. In addition, medullary cancers harbor microsatellite
instability (MSI) in about 22% cases as compared to a lack of
MSI in ductal adenocarcinomas (56). This suggested a distinct genetic pathway for medullary tumor development that
is different from pancreatic adenocarcinoma (57). MSI is
caused by mutations or methylation in such DNA repair genes
as MLH1 and MSH2 (and others), which can be inherited or
acquired (58).
Patients with MSI-positive medullary tumors are observed
to have better prognosis than those with ductal adenocarcinoma. Bunzo et al. examined the predictive value of MSI on
prognosis of pancreatic cancer and found that MSI-positive
tumors had significant longer survival times than their MSInegative counterpart (59,60). Such a beneficial association of
MSI positivity with prognosis has been observed in other types
of cancers including colorectal, gastric, and ampullary cancer.
The treatment for localized disease is surgical resection. The
optimal post-resection chemotherapy remains unknown,
although this tumors unique molecular profile suggests a role
for specifically targeted therapy.
436
Japanese criteria
Korean criteria
Histology
Serology
Involvement of other
organs
Not included
Response to steroid
therapy
Not included
Imaging
Mayo criteria
At least one of the following:
(1) Periductal lymphoplasmacytic
infiltrate with obliterative
phlebitis and storiform fibrosis
(2) Lymphoplasmacytic infiltrate
with storiform fibrosis showing
abundant (>10 cell/HPF)
IgG4-positive cells
Elevated serum IgG4 levels
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47
Acute pancreatitis
C. Ross Carter, A. Peter Wysocki, and Colin J. McKay
introduction
In the last 20 years, there are few disease processes where the
understanding and the approach to management have
changed more than that of acute pancreatitis. Acute pancreatitis presents a spectrum of disordered physiology, ranging
from a mild and rapidly resolving attack (80%) requiring
little more than analgesia and a short period of intravenous
fluid resuscitation, to an overwhelming system illness characterized by multi-organ dysfunction refractory to aggressive
resuscitation. Various clinical and biochemical scoring systems (14) have been used in an attempt to differentiate
between mild or severe acute pancreatitis, but out-with the
study environment, management is reactive aimed at normalizing altered physiology or the management of local
complications.
The majority of patients with severe early organ dysfunction will have pancreatic necrosis on CT scan. There is an
association between the development of necrosis and the
severity of organ dysfunction (5), although patients with
edematous pancreatitis may manifest clinical features of a
severe attack. Clinical practice has changed rapidly over the
last decades, and the previous focus on parenchymal necrosis
and particularly the role of prevention/treatment of infection
are now considered in a wider concept tending toward organ
support and less aggressive intervention. Most patients who
develop organ failure have evidence of this at the time of
admission or very shortly thereafter (6), and worsening or
persistent organ failure is associated with an adverse outcome,
and/or the development of late complications. There is no
evidence that aggressive early surgical intervention to address
the necrosis has a beneficial effect on outcome and indeed is
potentially harmful.
The majority of patients with acute pancreatitis will have a
mild clinical course and other than maintenance of fluid volume and analgesia, subsequent treatment is aimed at prevention of a further attack. Early definitive treatment of
cholelithiasis is recommended by cholecystectomy or endoscopic sphincterotomy as recurrent mild attacks are not
uncommon (7). The main focus of this chapter is on the 15%
to 20% of patients who present with severe disease and the
options and rationale for clinical management.
etiology
Pancreatic inflammation was first reported in association
with alcohol excess in 1878 by Freidrich, and 20 years later,
Opie proposed the bile reflux theory potentially underlying the most common cause of gallstones. A detailed
description of the pathophysiological mechanisms that are
thought to be involved in the initiation of an attack is
beyond the scope of this chapter. An attack may be initiated by obstruction of the duct either through passage of a
439
440
ACUTE PANCREATITIS
radiological assessment
Trans-abdominal ultrasound is often performed within
24 hours but in the absence of jaundice, this has little effect on
clinical management. Bowel gas and a restless patient often
compromise the examination and exclusion of cholelithiasis
may require a repeated examination in the recovery period.
Early post-admission CT may be appropriate where the diagnosis is in doubt or a complication suspected; however, as the
evolution of necrosis is not complete until at least 72 hours, in
some patients axial scanning is best delayed until this time.
Subsequent management and need for further radiological
assessment are determined by the clinical condition and the
trend of biochemical and organ failure scores.
management of necrosis
Until recently, sterile necrosis was considered to be a driver of
organ dysfunction, leading to a necrosectomy for patients
failing to progress after a few weeks. It was also considered
essential to identify the development of infection as early as
possible, leading to the popularization of protocol-driven
radiologically guided fine needle bacterial aspiration (40),
and pre-emptive necrosectomy following a positive result.
Current opinion is that outcome can be improved by the
avoidance of early major intervention, especially in patients
with organ failure, utilizing minimally invasive approaches to
sepsis control where possible. CT-guided fine needle aspiration no longer plays any role in our practice.
For many years most specialist centers have addressed all
collections utilizing a single surgical technique. This dogmatic
procedure-based algorithm failed to address the changing
requirements and risk profile with maturation of the collection. The indications for intervention vary with the dynamic
evolution of pancreatic/peri-pancreatic collections (41). In the
first 4 weeks, the solid necrotic phase, demarcation of devitalized tissue is incomplete and an attempt to remove the devitalized tissue often incomplete and associated with bleeding.
By about 8 to 10 weeks demarcation results in formation of a
walled off fluid collection containing a variable amount of
solid necrosis. In the early weeks, achieving control of sepsisdriven organ failure is the primary consideration, whereas following maturation when organ failure is rare and morbidity
low, indications include failure to thrive, SIRS, nutritional failure, gastric outlet obstruction, or pain.
The presence of proven infection within necrosis (bacteria or gas on CT) was previously seen as a mandatory indication for urgent debridement, as it was believed until
recently that recovery would only occur once the necrosis
was completely removed. The observation that drainage of
441
442
Necrosectomy
with closed
packing
Necrosectomy
with
scheduled
re-explorations
Necrosectomy
with closed
lavage
Necrosectomy
with
scheduled
re-explorations or
resection
Necrosectomy
with closed
lavage
Warshaw,
1998 (44)
140
(100%)
58b (1998)
140
255
(75%)
53 (1685)
340
29
(100%)
46
(100%)
57 (2887)
46
64
(56%)
29
53 (3081)
64
Mean age
in yrs
(range)
11/5/
16//
13/4/
14//
9//
Mean
AII/RS/
CT-SI
20
12 (131)
22
23
31
Timing of
intervention
from onset
(mean days)
27%
39%
55a
64
24%
13%
6%
Mortality
85
41
Survivors.
Median.
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; ITU, intensive therapy unit.
Beger, 2005
(43)
Gtzinger,
2002 (47)
Buchler,
2000 (46)
Bradley,
1999 (45)
Method
Unit, year
Number
of patients
in series
Number
with
infected
necrosis
(%)
mean 3 days
90%
preoperative
organ failure
ITU
preoperatively
78%
44%
Morbidity
51%
(median 1)
79%
(mean 2.2)
26%
17%
Reoperations
Mean
27 days
45%
(median
6 days)
ITU postoperatively
ACUTE PANCREATITIS
packing and planned re-operation are, however, sometimes required to control blood loss from the retroperitoneum following the development of an intraoperative
coagulopathy, a lavage system being created, following
correction of the coagulopathy, at the time of interval
pack removal.
With Closed Lavage
The Ulm group popularized the use of post-operative closed
lavage and this remains the most popular method for postoperative sepsis control following open debridement. Several
(46) large diameter tube drains are inserted in the lesser sac
and throughout the abdomen and the abdomen closed. Continuous lavage is then commenced, the aim being the continuous removal of devitalized necrotic material and bacteria. The
lavage is continued, for around 3 to 4 weeks on average, until
the return fluid is clear, and the patient has no residual signs of
systemic sepsis.
Minimally Invasive Approaches
A number of minimally invasive techniques have been developed over the last 15 years and these are often viewed as complimentary rather than exclusive. These will be initially
described and then the potential advantages/disadvantages
discussed.
Percutaneous Catheter Drainage (Table 47.2)
Interventional radiological drainage of abscesses has been
commonplace for many years. The major difficulty in the
acute pancreatitis patient is the tendency for these to
block, leading to recurrent sepsis. Utilizing simple drainage as the primary modality of treatment is possible, but
is extremely labor intensive and delayed surgical intervention
is commonly required.
Endoscopic Drainage (Table 47.3)
Transmural drainage of lesser sac collections was initially
performed for established pseudocyst. Baron first described
extending the role into the management of pancreatic abscess,
where the collections contained some solid component.
Endoscopic ultrasoundguided drainage can increase the
technical success rate and reduce the risk of bleeding. Small
diameter stent drainage could lead to incomplete drainage,
and the use of tract dilatation, multiple catheters, and intracystic lavage became commonplace. Seifert described the
performance of a necrosectomy through the endoscopic cystgastrostomy and this is becoming increasingly popular.
Potential advantages include that it can be performed without
a general anesthetic, potentially performed as a day patient
in suitable patients and the lack of an external drain, but
inadequate drainage and hemorrhage are potential hazards.
Percutaneous Necrosectomy (Table 47.4)
This combines minimally invasive drainage with closed postoperative lavage. A CT-guided radiological drain in inserted
ideally in the left flank to promote gravitational drainage. The
laparoscopy
Early attempts at laparoscopy attempted to mimic the open
debridement, but proved technically challenging and has been
superseded by the other surgical approaches. Laparoscopic
cystgastrostomy has been reported for the management of late
walled off necrosis. Initial descriptions involved intra-luminal
laparoscopy but the position of the collection relative to the
stomach is critical. Modification by performing a longitudinal
anterior gastrostomy and then addressing the posterior cystgastrostomy greatly simplified the procedure and allows a onestep approach to organized necrosis. The procedure requires a
well-formed cavity and complete separation of the necrotic
tissue, so is less appropriate for collections in an early stage of
the disease.
summary
The choice of primary procedure is determined by the relative importance of sepsis control and the stage of evolution
of the necrosis-associated peri-pancreatic collection. Optimal sepsis control is obtained by percutaneous necrosectomy but completion of the process takes some time and
requires multiple procedures. At the other end of the spectrum, where sepsis is not an issue but intervention demanded
through pressure effects or failure to thrive, a single procedure laparoscopic cystgastrostomy expedites completion of
treatment, particularly where a predominant solid component makes endoscopic clearance likely to require multiple
procedures.
Endoscopic cystgastrostomy has a role between these
extremes. In the septic patient, initial endoscopic drainage
is easy but maintenance of sepsis control often demands
repeated intervention and adjuvant radiological drainage.
A particular problem is that the first indication of a blocked
internal cystgastrostomy drainage system is a clinical escalation of sepsis whereas a blocked external drain is easily
recognized and addressed. Similarly large or para-colic collections are unsuitable. However, in the fluid-predominant
443
444
b
44 (2587)d
23/4/d
18//6c
/4/8
>4
>11c
10 (158)
7d
42
15
19
20
16
Successful
percutaneous
management
alone of those
with infected
necrosis
Number of
deaths in
series
1
14 Fr
catheter
dilated to
20 Fr
combined
with
irrigation
27
Median of
(18/60 mantwo
aged without
catheters
surgery)
per patient
(824 Fr)
with active
necrosectomy in
18 patients
b
a
(10/61)d
2
Average of
1.4 drains
per patient
(1012 Fr)
a
2
Average of 3 4
transperitoneal
catheters
per patient
(1028 Fr)
816 Fr
5
Technique
61
Szentkereszty,
2008 (54)
80
57 (1779)c
80
Bruennler,
2008 (53)
23
49
31
12 (231)
15b
59 (3678)
19
9 (148)
23
//8
Mean timing
Mean AII/ of intervention from
RS/CT-SI
for patients onset days
in series
(range)
/5/E
26
34
15
40 (1768)
25
Olh, 2006
(51)
Lee, 2007 (52)
53
32
Gouzi, 1999
(49)
Baril, 2000
(50)
56 (3171)
34
Mean age in
years (range)
Freeney, 1998
(48)
Author, year
Number of
patients in
series
Number with
infected
necrosis
managed
percutaneously
2 (19)c
37 (1260)c
0.1
15d
20
12
a
0.4b
17
3.3
Acute
operative
management
Average catheter of those with
infected
exchanges per
necrosis
patient (range)
1456
43
25152
Average
duration
of
drainage
(days or
range)
13
5
49
53 (3064)
56 (3880)
63 (3884)
62 (1868)
55 (3755)
Median age
in years
(range)
11 (2 SN)
0 (8 PA)
1 (1 SN, 1 RC)
Number with
infected
necrosis
/4/8
6 (212)
?24
8//6
42
1328
Timing of
intervention
from onset
(mean days)
12//9
Mean
AII/RS/
CT-SI
for
patients
in
series
Patients in
series cured
by endoscopic
treatment
alone
Technique
10 Fr strent
10 Fr stent
Transpapillary
stenting 10 Fr
stent 7 Fr
nasocyst
catheter
Transpapillary
stenting 10 Fr
stent 7 Fr
nasocyst
catheter
7 Fr, 10 Fr stents
15%
28
0.3
Number of
endoscopic
reinterventions
(average)
0
Number
of
deaths
in series
17
2496
Post-procedure
length of stay
(days)
Author, year
Number of
patients in
series
ACUTE PANCREATITIS
445
446
110
54(1889)
107
30 (1191)
a
a
51
58 (4180) 7 (2 PA)
56 (1885) 38 (9 SN)
47
23
28
/10/E
46b (2378) 6
24
Timing of
intervention
from onset
(mean days)
9//9
45 (3274) 10
Mean AII/RS/
CT-SI for
patients in
series
10
Number
with
infected
necrosis
28
Patients in
series cured by
retroperitoneal
necrosectomy
Without
laparotomy
21(19%)
>50
84c
64
42
38%
16
Median
ITU
Number post-operative preoperaof deaths length of stay
tively
in series
(days)
(number)
Carter, 2000
(33)
Risse, 2004
(59)
Connor,
2005 (60)
Mui, 2005
(61)
Shelat, 2007
(62)
Carter2007
Author, yr
Number of
patients in
series
Median
age in
years
(range)
43
Early
morbidity
3(16)
55%
Mean of
11 days
Mean of 0 days
a
3 (28)
ITU
post-operatively
(number)
2.3 (14)
2.5 (14)
Median
number of
reoperations
per patient
(range)
53 (2963)
52 (3466)
20
18
15
Gambiez,
1998 (64)
Horvath,
2001 (65)
Besselink,
2006 (66)
van
Santvoort,
2007 (67)
14 (1 SN)
18
13 (7 SN)
18 (17 SN)
Number
with
infected
necrosis
9//8
//8
//7
/3/E
/4a/E
Mean
AII/RS/
CT-SI
13 (7 with IPN)
40
Patients in
series cured by
lumbotomy
without
laparotomy
41 (15164) 11
48 (0181)
41 (2777)
14a
Timing of
intervention
from onset
(mean days)
13
Number
of
deaths
in series
100 (45240)
100 (43240)
62
70
Mean length
of stay (days)
Technique
2 (111)
1
2 percutaneous
drainages
2.6
Mean number
of reoperations
per patient
25
Morbidity
a
For entire reported series of patients with various diagnoses/treatments.
data not stated, ? limited/unclear data published
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; ITU, intensive therapy unit; ASIS, anterior superior iliac spine; IPN, infected pancreatic necrosis; SN, sterile necrosis.
36 (1648)
51 ()
46 (2680)
40
Fagniez,
1989 (63)
Median age
in years
(range)
Number of
patients in
series
Author,
year
ACUTE PANCREATITIS
447
(A)
(B)
(C)
(D)
Figure 47.1 (A) Early phase CT (48hrs) with head necrosis and peripancreatic edema. (B) CT at 6 weeks confirming extensive loss of parenchyma with early
demarcation and no evidence of infection. (C) CT at 7 weeks with extensive gas indicating infectionclinical sepsis addressed by percutaneous necrosectomy x3.
(D) CT at 12 weeks prior to discharge.
references
Figure 47.2
448
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21. Al Bahrani AZ, Abid GH, Holt A, McCloy RF, Benson J, Eddleston J et al.
Clinical relevance of intra-abdominal hypertension in patients with
severe acute pancreatitis. Pancreas 2008; 36(1): 3943.
22. Zhang WF, Ni YL, Cai L, et al. Intra-abdominal pressure monitoring in
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26. Abou-Assi S, Craig K, OKeefe SJ. Hypocaloric jejunal feeding is better
than total parenteral nutrition in acute pancreatitis: results of a randomized comparative study. Am J Gastroenterol 2002; 97: 225562.
27. Eatock FC, Chong P, Menezes N, et al. A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis. Am J Gastroenterol 2005; 100(2): 4329.
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48 Chronic pancreatitis
introduction
Chronic pancreatitis (CP) is a common disorder of the gastrointestinal tract with enormous social and personal impact. The
prevalence of CP is 10 to 30 per 100,000 population and it
affects about eight new patients per 100,000 population per
year in the United States (13). Autopsy series, however, suggest
a higher prevalence of 0.04% to 5%. CP is an inflammatory
disease characterized by the progressive conversion of pancreatic parenchyma to fibrous tissue. The most frequent causes are
excessive alcohol consumption, cholelithiasis, autoimmune or
individual genetic predisposition, and anatomic variants such
as pancreas divisum.
In up to 20% of the patients the reasons or predisposing
factors are not identifiable. The peak of presentation of the
disease occurs in patients between 35 and 55 years of age (4).
Abdominal pain is the main symptom of CP leading to
inability to work, early retirement, and addiction to analgesics.
Severe pain attacks are the leading causes for hospitalization.
The natural course is characterized by a consecutive loss of
pancreatic parenchyma by fibrosis leading to exocrine insufficiency with maldigestion and finally in advanced stages
endocrine insufficiency.
The clinical course and histological morphological changes
that characterize the disease are extremely variable. Overall the
life expectancy is shortened by 10 to 20 years. The mortality is
increased 3.6-fold, as compared with a population without
CP (2). The annual treatment costs are approximately $17,000
per patient (2). Due to improvements in the treatment 20% to
50% of the patients live more than 20 years with chronic
inflammation of the pancreas (5,6).
Besides pain, exocrine and endocrine malfunction, mechanical
complications occur such as stricture of the bile duct, duodenal
stenosis (7), or the formation of pancreatic pseudocysts. The
process of continuing organ destruction cannot be interrupted
by abstinence from alcohol consumption, which seems to be
the causative agent in most cases. Despite thousands of reports
that have been published in the last decades dealing with this
disease, pathogenesis and pathophysiology of CP are poorly
understood and the clinical course is unpredictable. Therefore
adequate treatment of CP and its complications remain a
major challenge (8,9).
definition of cp
The classification of CP as a separate disease was described in
1946 by Comfort et al. (10). Before, the term CP has been used
for a variety of pancreatic diseases without a generally
accepted definition (11,12). Since then, different classifications of CP have been presented. According to the Marseille
Classification, CP is characterized by histological changes
persisting after the etiologic agent has been removed (13).
The Cambridge Classification (1983) defined CP as an
natural course of cp
In the past the main rationale for conservative approaches
derives from the assumption, that most patients with longstanding CP will become pain free due to a progressive
burning out of the organ (15). Recently it was shown that
the natural course of CP is characterized by progressive loss
of pancreatic function by fibrosis of the parenchyma with
consecutive endocrine and exocrine insufficiency supplementary to pain (12,16,17). After an initial period without
noticeable pain, the disease progresses into the next stage
characterized by pain and exocrine, later endocrine insufficiency. In the third stage the burn-out pancreas with global
insufficiency is found, and pain might subside. The pancreatic parenchyma is irreversibly converted to fibrous tissue
with diabetes and steatorrhea (18).
At time of onset of CP 8% of the patient had a at least moderate endocrine insufficiency, whereas in long-term follow-up
approximately 80% had endocrine insufficiency (19,20). Studies
revealed that it takes 10 to 20 years of a progressive inflammatory process to lead to exocrine insufficiency by destroying the
pancreatic parenchyma (21). Ten years after onset of CP, 50%
to 93% of the patients with CP were still suffering from
abdominal pain (17,2022). At least 50% to 68% of the patients
with CP need surgery for management of complications or for
intractable pain (5,23).
Reduction of alcohol intake did not influence the course of
pain in chronic alcoholic pancreatitis, but continued alcohol
abuse was associated with significantly lower survival rates
(24,25). Patients that quit drinking showed improvement in
exocrine function (20,24). Endocrine insufficiency did not
alter the course of pain. For the individual patient the course
of the disease is unpredictable (20,25).
451
etiology pathomorphological
findings in cp
Long-term alcohol intake is associated with an increased risk
of developing CP. High caloric intake of protein and fat, smoking, and lack of vitamins and trace elements have been
described as additional, predisposing risk factors (12).
Ammann and colleagues suggested that acute pancreatitis and
chronic alcoholic pancreatitis are different stages of the same
disease (17,24). CP represents the remaining damage after episodes of severe acute pancreatitis (26,27). Alcohol consumption is the leading cause of CP in western countries (7090%)
(2,4,11,14). The acinar cells are directly damaged by alcohol. A
change in microcirculatory perfusion and alterations of the
epithelial permeability lead to an imbalance in the pancreatic
juice or decreased fluids or bicarbonate secretion. Parenchymal
necrosis with hemorrhage of the pancreas may induce perilobular fibrosis that leads to intralobular fibrosis, ductal
obstruction, and periductal inflammation. Altered amounts of
lithostatin in the pancreatic juice can lead to formation of the
protein plugs and stones in ducts and ductuli (11,27,28).
Pathomorphological findings in CP such as inflammatory
infiltration of the pancreatic tissue, fibrosis, atrophy of the acinar
cells, calcifications, pancreatic duct stricture, and pseudocysts
can be found isolated, segmental, or diffuse throughout the
whole organ (11,12,27,28). Histomorphologically different
forms of CP can be distinguished.
The most common form, the calcifying CP is characterized
by recurrent bouts of clinically acute pancreatitis with abdominal pain and development of intraductal calculi, protein
plugs, and parenchyma calcifications (2,12). Radiographically
(ERCP) these impose as chain of lakes. These alterations of
various degrees in different stages of the disease lead to pancreatic duct stenosis and consecutively to prestenotic dilatations. Additionally epithelial alterations, inflammatory
periductal infiltrations, parenchymal atrophy, necrosis, and
fibrosis can be found (12,18,26,27,29,30).
Obstructive CP is often painless and caused by blockage of
the main pancreatic duct due to tumor or an inflammatory
process (post-acute pancreatitis) that leads to an atrophy of
the pancreatic tissue and a prestenotic dilatation. No alteration
of the ductal epithelium is found (12,18,26,30). Pancreatic
duct stones are uncommon. Periductal fibrosis and inflammatory infiltration are mainly found around the larger ducts and
in the pancreatic head. Diffuse fibrotic changes occur throughout the organ without lobular topography. Pancreatic main
duct stenosis may be caused by papillary stenosis (tumor) or
inflammation, duodenal diverticula, pancreatic tumors, congenital or acquired duct abnormalities (pancreas divisum), or
rarely by traumatic pancreatic duct injuries. Small duct pancreatitis is an extremely rare form of CP that is defined as a
throughout fibrous, inflammatory tissue with a main duct
diameter of 3 mm, (31) .
The autoimmune pancreatitis is characterized by the absence
of typical risk factors for developing CP or hereditary factors.
In the past this subtype was named primary inflammatory sclerosis of the pancreas, non-alcoholic duct destructive pancreatitis, or lymphoplasmacytic sclerosing pancreatitis (17,18,32).
The term autoimmune pancreatitis was introduced by Yoshida
452
pathogenesis of pain in cp
Pain is the cardinal symptom in patients with CP. Together
with the often ongoing consumption of alcohol it is most difficultly to treat. The permanent pain reduces the quality of life,
leads to addiction of analgesics, and unemployment or early
retirement.
CP cannot be cured; therefore the aim of treatment is directed
against symptoms (e.g. pain) and complications. Pain in CP is
still only fragmentarily understood and a multifactorial nature
is assumed, including inflammation, duct obstruction, high
pancreatic tissue pressure, fibrotic encasement of sensory
nerves, and a neuropathy characterized by both increased
numbers and sizes of intrapancreatic sensory nerves and by
inflammatory injury to the nerve sheaths allowing exposure of
the neural elements to toxic substances. The pain is often
localized in the upper part of the abdomen and is frequently
nocturnal; sometimes it radiates to the back. Development of
pain in the course of the disease is seen in 85% of the patients
(43). It is described to be deep, penetrating, and debilitating
and may increase after eating (44). In the initial stage of the
disease the pain is intermittent and recurrent; later it is persistent. The painless pancreatitis is found rarely in alcoholinduced pancreatitis (<10%), while pain-free periods are seen
in late-onset idiopathic pancreatitis. Pain pattern and histopathologic/radiologic findings have to be correlated in consideration of therapy especially surgery. Histological picture
CHRONIC PANCREATITIS
and diameter of the main pancreatic duct in CT scan,
MRI/MRCP, and ERCP are necessary for optimal planning of
the operation. Small duct disease requires other procedures
compared to obstruction of the main pancreatic duct and
inflammatory mass in the pancreatic head. The assessment of
pain is very difficult. Most trials in CP use classifications for
description of pre- and postoperative pain or outcome, such as
excellent (no pain), good (better), fair (nil), poor (worse) (45),
therefore no comparison between different trials is possible.
Pain relief is more common in patients that quit drinking. The
underlying mechanism for pain in CP is poorly understood.
Different concepts have been hypothesized, but none of them
can completely explain the pain in this disease. Present hypotheses include increased pressure on the ductal system and
parenchyma by obstruction, neuritis, ischemia of the pancreatic
tissue and intra- and extrapancreatic causes such as pseudocysts
and CBDs or duodenal stenosis. The impact of the mentioned
factors for the pathogenesis of the pain remains unclear and
may vary between the patients. A higher intraductal pressure
was measured in patients with CP compared to controls (46).
The reason for increased pressure can be postinflammatory
scarring of the pancreatic (main and side) ducts, pancreatic
duct stones or strictures, or hemosuccus pancreaticus that
leads to obstruction. Other reasons are pancreatic abscess,
ascites, bile duct stenosis, or duodenal stenosis. The patients
that were found to have a reduced intraductal pressure had a
better pain relief compared to patients with higher intraductal pressure in the follow-up (46,47). Additionally it had
been reported that phenotypic modification of primary sensory neurons may play a role in production of persisting pain
(48). Focal release and uptake of mediators in the peptidergic
nerves were changed by initial pancreatic inflammation. Previous trials revealed that number and diameter of the pancreatic nerves, as well as activity are significantly increased in CP
(49,50). A correlation between pain and expression of growthassociated protein (43) and level of methionineenkephalin
was detected (50). It is hypothesized that the increases in pressure facilitate the intox of pain mediators into the nerves and
result in a neuritis and therefore causing the pain in CP.
Another hypothesis is that pancreatic ischemia is responsible
for the pain. The ischemia activates the xanthine oxygenase,
leading to the production of toxic oxygen metabolites. An
increased level of cytochrome P450 in CP was found in several
trials (51,52), but treatment with an inhibitor of the xanthine
oxygenase did not reduce the pain.
complications of cp
In the course of CP, several complications with less or more
life-threatening potential may occur. In 12% of the patients
that underwent surgery for CP, duodenal obstruction was
detected; additionally it was found to be associated with CBD
stenosis (53). Duodenal obstruction can also occur secondarily
to pancreatic pseudocysts (54). The patients typically suffer
from nausea, vomiting, upper abdominal pain, and weight
loss. If duodenal obstruction does not resolve within 1 to
2 weeks of conservative therapy, an irreversible duodenal
obstruction should be considered and therefore interventional/
surgical treatment is indicated.
453
454
CHRONIC PANCREATITIS
duodenum or CBD, intractable pain, pseudoaneurysm, or
vascular erosion that cannot be controlled by radiological
intervention, large pancreatic pseudocysts that cannot be endoscopically controlled, especially in conjunction with ductal
pathology, and neither conservatively nor interventionally
tractable internal pancreatic fistula (8,9,8789).
The indication for surgical interventions in CP has seen its
ups and downs over the last decades. Due to optimized surgical
procedures, improvements in intensive care and in selection of
the patients, the perioperative risk was reduced and the outcome has improved. In preoperative diagnostic it is a major
challenge to differentiate a malignant tumor from an inflammatory mass in the pancreatic head (2). For sufficient histopathological examination it is necessary to provide an adequate
specimen to exclude malignancy; only resections or limited
resections and extended drainage procedures can provide this
(8). In approximately 10% of the patients with pancreatic carcinoma even in experienced centers the initial diagnose of
malignancy is based on the histological specimen at the time of
operation. An optimal surgical intervention should manage the
problems and complications of the CP (Fig. 48.1). Additionally
it should guarantee a low relapse rate, preserve a maximum of
endocrine and exocrine function, and most importantly,
restore quality of life (8).
Drainage
Cysto(gastro-)jejunostomy
Pancreaticojejunostomy (Partington-Rochelle)
Drainage and resection of pancreatic tail (Puestow-Mercadier)
Left-resection of the pancreas (DuVal)
Extended drainage (limited excision of pancreatic head (Frey)
Duodenum preserving resection of pancreatic head (Beger)
Pylorus-preserving partial duodenopancreatectomy
Partial duodenopancreatectomy (Whipple)
Pancreatectomy
Resection
Figure 48.1 Surgical armamentarium for the treatment of chronic pancreatitis.
455
456
duodenum-preserving resection
of the pancreatic head
In order to combine the advantages of drainage procedures
and pancreatoduodenectomy the duodenum-preserving
resection was developed. The technique was first described by
Beger in 1980 (107).
The aim of this procedure was the prevention of sacrificing
undiseased organ and achieving optimal control of the symptoms of the pancreatitis, especially pain. Due to minimizing the
loss of normal pancreatic tissue this procedure is aiming for a
better pancreatic function (108).
This Beger procedure consists of a subtotal resection of the
pancreatic head following transection of the pancreas above
the portal vein. In CP with an inflammatory tumor of the
pancreatic head, the transection is the most challenging part
of the operation due to displacement or compression of the
mesenterico-portal vein axis (Fig. 48.2).
The body of the pancreas is drained by an end-to-end or
end-to-side pancreatojejunostomy using a Roux-en-Y loop.
The resection cavity is drained by the same jejunal loop drains
by a side to side anastomosis to the rim of the resection cavity
of the pancreatic head.
An other advantage of this procedure is that the gastroduodenal passage and CBD continuity may be preserved (102,109).
Extensive resection of the pancreatic head with decompression
of the bile duct and the duodenum will allow adequate management even in cases of distal CBD stenosis or segmental
duodenal obstruction The identification of the intrapancreatic course of the distal bile duct can be facilitated by insertion of a metal probe into the CBD through a proximal
choledochotomy (110).
The Beger procedure provides long-term pain relief in 75%
to 95% of the patients (102,103,106,111115). The mortality
rate ranges from 0% to 3% in experienced centers
(111,112,116). The morbidity rate was found to be 15% to
32% (75,108,112).
In a randomized trial Bergers procedure was superior in
terms of pain relief as compared with pylorus-preserving partial
pancreatoduodenectomy (75). No significant differences in pain
relief were found in randomized trails comparing duodenumpreserving resection and partial pancreatoduodenectomy or
CHRONIC PANCREATITIS
pylorus-preserving partial pancreatoduodenectomy after longterm follow up (117).
A modification of the Beger procedure was presented by
Frey in 1985. The Frey procedure (115,116,118) combines a
longitudinal pancreaticojejunostomy according to Partington
and Rochelle (99) with a local excision of the pancreatic head.
It is marked by leaving a rim of pancreatic tissue across the
portal vein and superior mesenteric vein (Fig. 48.3). Therefore
this operation is easier to learn and perform; additionally only
one pancreatojejunostomy is necessary.
The drainage of the resection cavity of pancreatic head,
body, and tail is performed with a longitudinal pancreatojejunostomy using a Roux-en-Y loop. The Frey procedure can be
performed without mortality (<1%) and low morbidity
(939%) (7,106,112). In these patients, 56% were free of pain,
and 32% had substantial pain relief. The main complications are
hemorrhage, pancreatic fistula (05%), and intra-abdominal
abscess. After 5 years 78% suffered from exocrine and 60%
from endocrine; 44% were professionally rehabilitated.
By preserving the duodenum, the physiological gastroduodenal passage and the continuity of the CBD are sustained.
Additionally exocrine and endocrine pancreatic functions are
preserved and the procedure is able to control complications of
adjacent organs such as CBD stenosis, duodenal stenosis, and
internal pancreatic fistulas comparable to the Beger procedure
(118,119).
The Hamburg procedure is a modification of the Frey procedure and was proposed by Izbicki and coworkers. The extent
of pancreatic head excision can be modified up to a subtotal
excision including the uncinate process combined with a
longitudinal V-shaped excision of the ventral aspect of the
pancreas into the pancreatic duct (Fig. 48.4). If ductal irregularities are present in the pancreatic body and tail, the operation
can be extended as a drainage operation much in the way of a
PartingtonRochelle procedure into the pancreatic tail.
Therefore the major advantage of this procedure is that the
extent of the resection can be customized to the individual
morphology of the pancreas (113).
In a recently published trial, the mortality and morbidity of
the Hamburg procedure were 0% and 19.6%, respectively;
457
Perioperative mortality
Perioperative morbidity
30-mo follow-up
VAS
Frequency of pain attacks
Pain medications
Inability to work
Pain score
7-yr follow-up
VAS
Frequency of Pain attacks
Pain medications
Inability to work
Pain score
Late mortality
Late mortality(chronic
pancreatitis associated)
Endocrine insufficiency
Exocrine insufficiency
Reoperation
Professional rehabilitation
Frey procedure
Pyloruspreserving
pancreatoduodenectomy
3%
19%
0%
53%
12
12.5
0
0
6.1
10
12.5
0
50
18.1
20
25
0
0
17.75
20%
3%
25
25
0
0
18.75
15%
0%
61%
86%
8%
42%
65%
96%
0%
39%
Beger procedure
Frey procedure
0%
32%
0%
22%
12
0
0
0
3
16
0
0
0
4
20
25
0
0
11.25
24%
3%
20
25
0
0
11.25
24%
6%
56%
88%
8%
59%
60%
78%
12%
38%
458
CHRONIC PANCREATITIS
references
salvage procedures
Due to improvement of surgical technique and selection of
patients, pancreatic surgery for CP yields excellent results. In
some cases recurrence develops; most frequently in the remnant of the pancreatic head indicating either insufficient surgical resection of the head of the pancreas or aggressive disease.
In these patients re-do pancreas head resections are indicated. The procedures that should be considered are the partial
pancreatoduodenectomy (Whipple procedure, PPPD) and in
selected patients (i.e. re-recurrence) even total splenopancreatoduodenectomy. This procedure is indicated in patients that
underwent partial pancreatoduodenectomy, and additional
interventional nerve blocks or surgical denervation fail to
achieve definitive pain relief.
In patients that previously underwent duodenum-preserving
resection of the pancreatic head or partial pancreatoduodenectomy with recurrence of the CP in the body or tail a V-shape
drainage procedure is indicated.
conclusion
The aim of treatment of CP is mainly pain relief and improvement in the quality of life, which still poses a major challenge
today. Duodenum-preserving pancreatic head resection is the
ideal procedure for treatment of CP. If ductal pathology is
present in the pancreatic body or tail the procedure can be
combined with longitudinal duct drainage in various degrees
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and offer the best short-term outcome, while the long-term
results of PPPD are comparable. In small duct pancreatitis
(duct diameter <3 mm), a V-shape excision is the therapy of
choice. Pancreatic surgery bears many pitfalls and potential
complications and is technically demanding. It should be left
to experts in high-volume hospitals in order to minimize
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49 Pancreatic injury
history
diagnosis
Clinical Presentation
The diagnosis of penetrating pancreatic injury is usually made
intraoperatively and does not pose any significant diagnostic
problems. However, the diagnosis in blunt trauma is often
challenging. A missed or delayed diagnosis of pancreatic injury
increases morbidity and mortality (15). Because of its retroperitoneal location and infrequent occurrence, timely diagnosis of blunt pancreatic injury requires a high index of suspicion
and is a challenging task even to the most experienced surgeon. Clinical signs are often vague and nonspecific. Even significant pancreatic injuries may present initially with minimal
epigastric pain, with signs of peritonitis developing many
hours or even days after the injury. The cornerstone of early
diagnosis is a combination of serial physical examinations,
laboratory tests, and imaging studies.
epidemiology
Pancreatic trauma remains fairly uncommon. The overall incidence in blunt trauma is reported to be 0.2% and in penetrating trauma about 1% (49). However, it is likely that some
injuries, especially after blunt trauma may remain undiagnosed. Penetrating trauma accounts for the majority of injuries
(7080%), with gunshot wounds being the most common
mechanism (72%) (8). The location of the injury is evenly
distributed among the head/neck and body of the pancreas
(about 40% each), with the tail being less frequently injured
(about 20%) (8,10). Because of the retroperitoneal location of
the pancreas, significant force is mandated to lead to its injury.
This fact, in combination with the proximity of the pancreas
to vital structures, makes isolated pancreatic injuries rare.
Overall, about 60% of patients with blunt trauma and about
90% with penetrating trauma have associated intra-abdominal injuries (7,1115). Pancreatic trauma should be considered as a marker of other intra-abdominal injuries. The most
commonly associated injuries in blunt trauma are of the spleen
(34%), liver (26%), and duodenum (6%). In penetrating
trauma, first is the stomach (53%), followed by the liver (51%)
(7). Associated intra-abdominal vascular injuries are of major
concern since they are the most common cause of early
mortality. More than 75% of penetrating injuries to the head
of the pancreas are associated with a major vascular injury (8).
injury grading
There are numerous classification systems for pancreatic injuries. The most widely accepted grading system is the one proposed by the Organ Injury Scaling Committee of the American
Association for the Surgery of Trauma (OIS-AAST) in 1990
(Table 49.1) (16). This classification scheme takes into account
the type of injury (hematoma or laceration), the presence or
absence of structural duct involvement, and the location of
pancreatic injury (proximal or distal to superior mesenteric
vein). OIS-AAST grades I and II are considered as low-grade
and grades IIIV as high-grade pancreatic injuries (17). The
classification may be based on computed tomography (CT)
and intraoperative or autopsy findings. It is useful in the evaluation and management of patients with pancreatic injuries,
and it is an excellent research tool for the comparison of the
safety and efficacy of the various therapeutic approaches (15).
Laboratory Investigations
Unfortunately, no laboratory test is either sensitive or specific
enough in evaluating suspected pancreatic injuries. Serum
amylase levels have long been used as a useful marker and may
assist in the diagnosis (18,19). Takishima et al. found a timedependent increase of serum amylase in patients suffering
blunt pancreatic trauma (20). Elevated serum amylase was
present in all cases when the samples were collected more than
3 hours after the injury. Therefore, serum amylase on admission may be particularly unreliable and should be followed
serially. Additionally, no relation between the grade of pancreatic injury and the level of hyperamylasemia was found (20).
The sensitivity and specificity of serum amylase in detecting
pancreatic trauma range from 48% to 89% and 64% to 81%,
respectively (Table 49.2). When used as a screening tool after
blunt abdominal trauma, a normal serum amylase has a negative predictive value of 93% to 98% (2024). Various other
injuries, such as brain injuries, salivary gland, duodenal, and
small bowel trauma may be associated with increased serum
amylase levels (2528). The determination of amylase isoenzymes does not improve the sensitivity of specificity.
Radiologic Investigations
Plain abdominal films and ultrasonography are of limited
value in the diagnostic work-up of patients with suspected
pancreatic injury. Contrast-enhanced helical CT is considered
as the imaging study of choice for these patients (Fig. 49.1). Its
accuracy increases in parallel with the interval between the CT
study and the injury. In suspicious injuries a repeat CT scan at
least 6 to 8 hours after the initial investigation is recommended.
The timing of the intravenous contrast bolus, as well as the
experience of the radiologist involved affects the diagnostic
precision (29,30). The overall sensitivity and specificity of CT
for identification of pancreatic injuries of all grades is reported
463
Type of injury
Hematoma
Laceration
II
Hematoma
Laceration
III
Laceration
IV
Laceration
Laceration
Description of injury
Minor contusion without duct injury
Superficial laceration without duct
injury
Major contusion without duct injury
or tissue loss
Major laceration without duct injury
or tissue loss
Distal transection or parenchymal
injury with duct injury
Proximal transection or parenchymal
injury with duct injury
Massive destruction of pancreatic
head
Amylase levels
CT
MRCP
ERCP
Sensitivity
(%)
Specificity
(%)
Level of evidence
(references)
4889
80
>95
>95
6481
80
>95
>95
III (2024)
III (10,3133)
IIIIV (3739)
IIIIV (40,41)
Figure 49.1 Grade IV pancreatic injury (white circle) and concomitant grade IV
liver injury after blunt abdominal trauma.
464
PANCREATIC INJURY
(A)
(B)
Figure 49.3 (A,B) Opening of the lesser sac allows exposure and evalutaion of the anterior surface of the body and tail of the pancreas. Kocher maneuver allows
evaluation of the pancreatic head. Source : From Ref. 83.
465
management
The rarity of these injuries precludes the development of
evidence-based guidelines. Expert opinions and small series
reports (levels III and IV evidence) constitute the major
source of the knowledge gained throughout the years.
Nonoperative Management (NOM)
Selective NOM might have a place in the management of carefully selected patients with blunt abdominal trauma. Only
hemodynamically stable patients without evidence of peritonitis are potential candidates for NOM. Experience of NOM in
pediatric population showed that this approach is safe and
effective. Keller et al. (58) in a National Pediatric Trauma Registry study reviewed 154 pancreatic injuries in children, 80%
with low-grade and 20% with high-grade injuries. NOM was
successful in about half of high-grade injuries and about 80%
of low-grade injuries. The frequency of NOM increased significantly over the last year of the study. However, pediatric
pancreatic trauma is different from adult trauma because of
the much lower risk of pancreatic duct injury in children (less
than 1% in children, about 15% in adults). Subsequent experience in adult blunt trauma patients confirmed the safety of
this approach (5862). In a recent study there were no failures
of NOM in grade I and 17.3% failure in grade II pancreatic
injuries (61). In summary, NOM is safe for low grade injuries
and may be acceptable in selected high-grade injuries. Early
evaluation by means of ERCP or MRCP helps to visualize the
integrity of the pancreatic duct. In addition ERCP might be
used for stent placement, which can be an excellent adjunctive
tool to NOM (63). The downside to NOM is the development
of a pseudocyst or fistulae and occasionally severe pancreatitis
(64). Most of these complications are treatable by percutanous
CT-guided drainage.
There is no evidence that the use of somatostatin analogs,
such as octreotide, increases the success rate of NOM, although
they might have a role in the treatment of posttraumatic pancreatic fistulae (65).
Operative Management
The surgical treatment plan of pancreatic injury should be
determined by the overall condition of the patient, the
grade and location of pancreatic injury, the concomitant
injuries, and the experience of the surgeon. The strengths
of management recommendations for pancreatic trauma
are all of level C or D.
466
Low-grade injuries discovered intraoperatively are best managed with sparse debridement of nonviable tissue, hemostasis,
and wide external drainage with closed suction drains.
Although some authors advocate repair of the pancreatic capsule (66), this may lead to further parenchymal damage and
pseudocyst formation and should only be done to control
bleeding. Application of topical hemostatics on the pancreatic
laceration may facilitate hemostasis and reduce the risk of
postoperative leaks.
When dealing with high-grade injuries (AAST-OIS grades
III, IV, and V), the choice of procedure depends on the general
condition of the patient and the location of duct injury, i.e., in
the head, neck, or tail of the pancreas.
Distal ductal injuries (AAST-OIS grade III) are best treated
by distal pancreatectomy (67,68) often en bloc with the
spleen. Spleen-preserving distal pancreatectomy should be
considered in hemodynamically stable patients especially in
children (6972). Splenic preservation is technically more
challenging and may result in increased blood loss. After completion of the distal pancreatectomy, the main pancreatic duct
is identified if possible and is suture-ligated with nonabsorbable suture. With the main duct ligated, the proximal parenchyma should be closed with a mattress sutures or a TA
stapling device. Extensive pancreatic resection to the right
side of the superior mesenteric vessels may lead to diabetes or
exocrine insufficiency. In these cases, the distal pancreas may
be preserved and anastomosed to a Roux-en-Y jejunal loop
(Fig. 49.5). Closed suction drains should be placed around the
remaining pancreas and left upper quadrant if the spleen has
been removed.
PANCREATIC INJURY
Proximal ductal injuries and injuries to the head of the pancreas
(AAST-OIS grade IV) are more challenging. In the presence of
hemodynamic instability or major associated injuries, or if the
surgeon has no experience with complex pancreatic surgery, no
attempts should be made to evaluate the integrity of the duct or
perform major resections. In these cases, the safest option is
hemostasis and liberal external drainage (50,68). Damage control with packing and temporary abdominal closure may be
necessary. In destructive injuries to the head of the pancreas or
the duodenum, a pancreaticoduodenectomy may be necessary.
It should only be performed as a primary procedure in hemodynamically stable patients by an experienced surgeon. In
severely compromised patients the surgeon should opt for
damage control and a two-stage procedure (7375). Primarily,
damage control surgery should be performed to control the
hemorrhage and any intestinal spillage. Major associated vascular injuries may be managed by ligation or temporary arterial shunts reinforced by abdominal packing. Complex
gastrointestinal injuries may be stapled off and the common
bile duct exteriorly drained. The abdominal wall is temporarily closed and the patient is transferred to the intensive care
unit for stabilization. The definitive Whipples procedure
should be deferred for 24 to 48 hours after restoration of the
hemodynamic status, coagulability, and normalization of body
temperature. The reconstruction, including pancreatico-jejunostomy or pancreatico-gastrostomy (76,77), choledochojejunostomy, and gastro-enterostomy, is similar to that in
elective cases. Insertion of a jejunal feeding tube beyond the
ligament of Treitz is strongly recommended to allow feeding in
prolonged complicated cases. Overall, pancreaticoduodenectomy is rarely indicated in trauma. In a review at our center
over 7.5 years, only 16 of 214 (7.4%) patients with pancreatic
injuries required pancreaticoduodenectomy (73).
outcomes
Mortality
Many patients with pancreatic injury die from associated
exsanguinating injuries. The overall pancreas-related mortality is lower than 1% and is usually the result of sepsis and
organ failure. In pancreatico-duodenal resection the overall
mortality is about 30% to 40% (7,73).
Complications
Pancreas-related local complications occur in about 25% of
patients. The complication rate depends on the severity of
pancreatic injury and associated injuries. The most common
complications include pancreatic fistulae, peripancreatic
fluid collection, local sepsis, pseudocysts, and pancreatitis.
Most of these complications can successfully be managed
non-operatively, either expectantly or with percutaneous
drainage or endoscopic stenting of the duct.
Pancreatic Leaks and Fistulae
Early pancreatic leaks are the most common complications
after surgery for pancreatic trauma and occur in 10% to 35% of
patients (7,78). The amylase levels of this fluid should be determined to confirm the pancreatic origin. The prognosis is excellent and the vast majority close spontaneously within days or
467
summary
Pancreatic injuries remain fairly uncommon with penetrating
trauma accounting for most cases. The diagnosis of isolated
pancreatic injury due to blunt trauma may be missed on the
initial evaluation and this delay increases morbidity and mortality. The diagnosis in these cases can be made timely by a
high index of suspicion, serial clinical examinations, serial
amylase levels, and repeat CT scan evaluation. All penetrating
injuries to the pancreas require surgical interventions but a
significant number of isolated injuries due to blunt trauma
can safely be managed non-operatively, provided that the
main pancreatic duct is intact and the patient is hemodynamically stable and has no signs of peritonitis. The type of operative management of the pancreatic injury depends on the
severity and site of the injury, associated injuries, hemodynamic condition of the patient, and the experience of the surgeon. The majority of injuries can be managed by hemostasis
and closed suction drainage. Distal injuries are best managed
by distal pancreatectomy, with or without splenic preservation. Proximal injuries may be managed with hemostasis and
drainage or extended distal pancreatectomy. In many pancreatic head injuries, if the duodenum is not severely damaged,
hemostasis and external drainage may be sufficient. Pancreaticoduodenectomy is very rarely indicated and should be
reserved only for destructive injuries to the head of pancreas
or the duodenum. Damage control procedures should be considered in hemodynamically unstable, coagulopathic patients.
Pancreas-related complications are common after severe
trauma but they can usually be managed successfully with
non-operative methods.
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50 Pancreas transplantation
Khalid Khwaja
Over the past four decades, the field of pancreas transplantation has seen much evolution, both through refinement in surgical techniques and improvement in immunosuppressive
strategies. Pancreas transplantation is primarily performed in
uremic, type I diabetics in conjunction with a kidney transplant, and when successful, results in freedom from exogenous
insulin therapy, amelioration, or even reversal, of diabetesassociated complications and improved quality of life. Pancreas transplants, contrary to other organ transplants, are not
considered essential to patient survival. For each individual
recipient, the potential benefit of a pancreas transplant must
be carefully weighed against the risk of a major surgical operation and lifelong immunosuppression.
The first successful pancreas transplant was performed at
the University of Minnesota in 1966 (1). Early outcomes were
poor, largely due to technical and infectious complications and
the lack of effective and safe immunosuppressive regimens.
Over the next decade, the efforts of investigators at several centers in Europe and North America resulted in refinement of
surgical techniques and improvement in results. With the
introduction of cyclosporine into clinical practice, the field of
pancreas transplantation blossomed in the 1980s and outcomes became comparable to those of other transplanted
organs. To date, over 20,000 pancreas transplants have been
performed worldwide, as reported by the International Pancreas Transplant Registry and about 75% of these have been in
the United States (2). In 2006 alone, 1386 pancreas transplants
were performed in the United States, with approximately 4000
people waiting for pancreas transplants at the end of that year
(Fig. 50.1) (3).
470
PANCREAS TRANSPLANTATION
SPK
PAK
PTA
All pancreas
3000
2000
1000
SPK
PAK
PTA
All pancreas
1600
Number of transplants
1200
800
400
0
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
surgical techniques
Procurement
The various methods for recovery of the pancreas from the
deceased donor have been well described (2628). Often, multiple recovery teams are present, and careful coordination
between them is of paramount importance. Exposure is
through a long midline or cruciate incision. The infrarenal and
supraceliac aorta are controlled and looped and the pancreas is
inspected through the lesser sac. The gland is assessed for quality, in particular, presence of edema, injury, fibrosis, and fat
content. Pancreas dissection can be performed in the warm
(prior to crossclamp) or in the cold (after crossclamp);
other surgeons prefer some form of en bloc recovery technique, with separation of the pancreas from the liver ex situ
(29,30). The supraceliac aorta is clamped and the infrarenal
aorta flushed with preservation solution. Various solutions are
available and in the United States, typically University of Wisconsin (UW) or HistidineTryptophanKetoglutarate (HTK)
solutions are used; however, recent studies suggest that the rate
of posttransplant pancreatitis and graft failure is higher with
HTK use (31,32). After flush, the pancreas is mobilized, using
the spleen as a handle. The duodenum is maintained intact
with the gland and the mesenteric root stapled and divided
471
Figure 50.3 A pancreas allograft procured from a deceased donor, with the
duodenum and spleen intact.
backtable preparation
Figure 50.4 A procured pancreas allograft. The portal vein (PV), superior
mesenteric artery (SMA), and splenic artery (SA) are preserved with the graft.
The duodenal ends and the root of the small bowel mesentery are transected
with a stapling device.
recipient operations
The recipient operation varies with respect to graft placement
(intra- vs. extraperitoneal), venous drainage (systemic vs. portal), and exocrine drainage (bladder vs. enteric). Most grafts are
placed intraperitoneally, although a few centers prefer extraperitoneal placement, similar to the approach used for kidney
transplantation (34,35). Intraperitoneal placement allows placement of the kidney through the same incision in SPK transplants and may be associated with less wound problems (36).
472
PANCREAS TRANSPLANTATION
Figure 50.8 Pancreas transplant with portal venous drainage and enteric anastomosis. The graft PV is anastomosed, end-to-side, to the recipient superior
mesenteric vein. The graft duodenum points cephalad.
473
Figure 50.9 Pancreas transplant with systemic venous drainage and exocrine
drainage into the bladder. The graft duodenum points caudad.
474
Surgical Complications
Early surgical complications are particularly relevant after
pancreas transplantation as they often lead to graft loss. Common, pancreas-specific complications are thrombosis, hemorrhage, infection/pancreatitis, and anastomotic leak. Graft
thrombosis accounts for over 70% of technical failures (44)
and can be arterial or venous. The incidence varies with transplant category and technique and ranges from 5% to 11%
(2,44). Risk factors for thrombosis include older donor age,
cerebrovascular cause of donor death, prolonged preservation
time, retransplantation, segmental grafts, and non-standard
vascular reconstruction (49). Rarely, with early surgical intervention, a graft may be salvaged after thrombosis (50). Due to
improved antibiotic prophylaxis, better surgical techniques
and more targeted immunosuppression, the incidence of
perigraft infections is decreasing (2,44). Most infections will
occur in the first few weeks posttransplant and are treated
aggressively with antibiotics, antifungals, and surgical washout
if necessary. Anastomotic leak rates are around 5% to 10% and
tend to be higher with bladder-drained grafts (51,52). The
most important risk factor for leaks is preservation time; when
it exceeds 24 hours, leak rates as high as 25% have been
reported (53). Bladder leaks can often be managed with drainage alone, whereas enteric leaks usually require aggressive surgical intervention.
outcomes
Historically, SPK transplant recipients have enjoyed much better pancreas graft survival than PAK and SPK recipients (54).
Over the last decade, the 1-year survival for solitary grafts has
been steadily improving. Current 1-year graft survivals for
SPK, PAK, and PTA transplants are 86%, 79%, and 80%,
respectively (Fig. 50.10) (3). At 10 years, 51% of SPK recipients
still have functioning grafts, compared to only 28% of PAK
recipients and 24% of PTA recipients (55). Chronic rejection
and death with a functioning graft are responsible for most
cases of late graft loss (56).
Patient survival is similar for the three categories, and ranges
from 95% to 97% at 1 year and 64% to 71% at 10 years (Fig.
50.11) (3). Recent studies have clearly demonstrated a survival
advantage with SPK transplants (5759). However, one analysis of registry data suggested that survival after pancreas transplant was worse with solitary pancreas transplants, when
compared to waitlisted people who received conventional
therapy for diabetes (58). Some patients were registered on
several waitlists and counted more than once, and patients
who dropped off the list for medical reasons were censored,
biasing the outcomes of this study. When these differences
were accounted for, there was no difference in survival at
4 years between waitlisted patients and those receiving PAK or
PTA transplants (level of evidence: III) (59).
PANCREAS TRANSPLANTATION
SPK
100%
PTA
PAK
80%
60%
40%
immunosuppression
20%
0%
1-Year
3-Year
5-Year
10-Year
Figure 50.10 Unadjusted pancreas graft survival by transplant type. Data from
2007 OPTN/SRTR Annual Report. Accessed from www.ustransplant.org
December 2008.
SPK
100%
PTA
PAK
80%
60%
40%
20%
0%
1-Year
3-Year
5-Year
10-Year
Up to 80% of pancreas recipients receive some form of induction therapy at the time of transplant, usually a T-cell depleting agent such as thymoglobulin (77). Standard maintenance
regimen consists of a calcineurin inhibitor (tacrolimus or
cyclosporine), an antimetabolite (mycophenolate mofetil or
sirolimus), and steroids. Outcomes with tacrolimus-based
therapy are better overall (78,79) but one must be wary of the
potential of nephrotoxicity with this agent (80). Steroid avoidance and steroid withdrawal protocols are also increasingly
used, with good short-term results (81).
Acute rejection rates in the first year after pancreas transplant are currently less than 25% for SPK transplants and
somewhat higher for solitary transplants (78). A rise in serum
amylase or lipase, a fall in urinary amylase output (for bladderdrained grafts), and hyperglycemia are suggestive of acute
rejection, and should prompt a biopsy. The histologic features
for diagnosis and grading acute pancreas allograft rejection
were recently standardized (82).
conclusions
Combined kidney and pancreas transplant is an effective
option for uremic patients with type I diabetes. A select group
of type I diabetics, who have normal renal function, may benefit from a solitary pancreas transplant. In the current era,
graft survivals are comparable to those of other solid organ
transplants. There is much enthusiasm over islet cell transplantation as a less invasive alternative, but, at present, the
results are not as durable as those of whole organ transplant
(83). No doubt, both fields will continue to evolve, with
ongoing advances in techniques and immunosuppression.
references
1. Kelly WD, Lillehei RC, Merkel FK, et al. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy.
Surgery 1966; 61: 82737
2. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United
States (US) and non-US cases as reported to the United Network for
Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant 2005; 19: 43355
3. Leichtman AB, Cohen D, Keith D, et al. Kidney and pancreas transplantation in the United States, 19972006: the HRSA Breakthrough Collaboratives and the 58 DSA Challenge. Am J Transplant 2008; 8(4 Pt 2): 94657.
4. Finne P, Reunanen A, Stenman S, et al. Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA 2005; 294(14): 17827
5. Nishimura R, Dorman JS, Bosnyak Z, et al. Incidence of ESRD and survival after renal replacement therapy in patients with type 1 diabetes: a
report from the Allegheny County Registry. Am J Kidney Dis. 200; 42(1):
11724.
6. Foley RN, Collins AJ. End-stage renal disease in the United States: an
update from the United States Renal Data System. J Am Soc Nephrol 2007;
18(10): 26448.
7. Farney AC, Cho E, Schweitzer EJ, et al. Simultaneous cadaver pancreas
living-donor kidney transplantation: a new approach for the type 1 diabetic uremic patient. Ann Surg 2000; 232(5): 696703.
475
476
PANCREAS TRANSPLANTATION
56. Humar A, Khwaja K, Ramcharan T, et al. Chronic rejection: the next
major challenge for pancreas transplant recipients. Transplantation 2003;
76(6): 91823.
57. Ojo AO, Meier-Kriesche HU, Hanson JA, et al. The impact of simultaneous pancreas-kidney transplantation on long-term patient survival.
Transplantation 2001; 71(1): 8290.
58. Venstrom JM, McBride MA, Rother KI, et al. Survival after pancreas
transplantation in patients with diabetes and preserved kidney function.
JAMA 2003; 290(21): 281723.
59. Gruessner RW, Sutherland DE, Gruessner AC. Mortality assessment for
pancreas transplants. Am J Transplant 2004; 4(12): 201826.
60. The Diabetes Control and Complications Trial Research Group. the effect
of intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N Engl J
Med 1993; 329: 97786
61. Fioretto P, Steffes MW, Sutherland DER, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998;
339; 6975.
62. Coppelli A, Giannarelli R, Boggi U, et al. Disappearance of nephrotic syndrome in type 1 diabetic patients following pancreas transplant alone.
Transplantation 2006; 81(7): 10678.
63. Konigsrainer A, Miller K, Steurer W, et al. Does pancreas transplantation
influence the course of diabetic retinopathy? Diabetologia 1991; 34(S1):
S868.
64. Koznarova R, Saudek F, Sosna T, et al. Beneficial effect of pancreas and
kidney transplantation on advanced diabetic retinopathy. Cell Transplant
2000; 9: 9038.
65. Giannarelli R, Copelli A, Sartini MS, et al. Early improvement of unstable
diabetic retinopathy after solitary pancreas transplantation. Diabetes
Care 2002; 25: 23589.
66. Ramsey RC, Goetz FC, Sutherland DE, et al. Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes
mellitus. N Engl J Med 1998; 318: 20814.
67. Navarro X, Sutherland DE, Kennedy WR. Long-term effects of pancreatic
transplantation on diabetic neuropathy. Ann Neurol 1997; 42: 72736.
68. Allen RD, Al-Harbi IS, Morris JG, et al. Diabetic neuropathy after pancreas transplantation: determinants of recovery. Transplantation 1997; 63:
8308.
69. Jukema J, Wouter MD, Smets YF, et al. Impact of simultaneous pancreas
and kidney transplantation on progression of coronary atherosclerosis in
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477
51
introduction
Advances in surgical technique have led various treatment
options for patients with hepatobiliary and pancreatic disorders. There have also been advances in the understanding of
pathogenesis and clinical behavior of specific diseases. This
chapter addresses the common hepatobiliary and pancreatic
disorders with a focus on surgical treatment modalities.
biliary atresia ba
Classification
BA is an obstructive condition of the bile ducts. It is of
unknown etiology but results from a progressive obliterative
process of variable extent. It has a worldwide incidence of
1 in 5000 to 18,000 live births, and it is more common in
girls than in boys (1,2). Two clinical forms are described:
acquired and embryonic (3). The acquired form accounts
for 80% of affected infants. They are asymptomatic and
anicteric at birth and develop jaundice in the first postnatal
weeks. These otherwise normal infants are born with a patent biliary system which undergoes progressive inflammation and fibro-obliteration initiated by a perinatal insult.
Infants with the embryonic form have no jaundice-free
interval and suffer from one or more congenital anomalies,
such as interruption of the suprarenal segment of the inferior vena cava with azygous continuation, preduodenal portal vein, midline symmetric liver, intestinal malrotation,
situs anomalies, bronchial anomalies, and polysplenia or
asplenia (2,4).
Pathology
BA can be classified by using macroscopic appearance and
cholangiography findings according to three main categories. Types I, II, and III are defined as atresia at the site of the
common bile duct, at the site of the hepatic duct, and up to
the porta hepatis, respectively. Type III is most common. A
patent duct that can be anastomosed to the intestine at the
porta hepatis is present in 5% of cases. In more than 90% of
cases, no normal ductal structures are seen at the porta
hepatis (5).
Early in the course the liver is enlarged. There are portal
tract edema, bile duct proliferation, portal and periductal
inflammation, and associated areas of hepatic cell injury.
This process develops into end stage cirrhosis. The pathologic changes are generally considered to be panductal,
affecting intrahepatic as well as extrahepatic structures (68).
The degree of damage present in the intrahepatic biliary system is responsible for much of the morbidity after hepatic
portoenterostomy (HPE). Paucity or absence of intralobular
bile ducts along with architectural disturbances, even in
jaundice-free infants after successful HPE, has been observed
by some (9).
478
Clinical Features
Signs and symptoms include jaundice, clay-colored stools, and
hepatomegaly. In infancy, jaundice that persists beyond
2 weeks is no longer considered physiologic. The differential
for neonatal cholestasis is presented in Table 51.1. The first
step in diagnosis in an infant is to identify conjugated hyperbilirubinemia with prolonged jaundice, pale stools, or dark
urine. A conjugated bilirubin greater than 20% of an elevated
total serum bilirubin is diagnostic of homeostasis. Table 51.2
lists the diagnostic evaluation appropriate for the homeostatic
neonate. Several authors consider liver biopsy to be the most
reliable test for establishing the diagnosis (10,11). Liver biopsy
can correctly predict extra hepatic biliary obstruction in more
than 90% of cases (1,12). Ultrasound is safe and noninvasive
and should be performed in all jaundiced infants as in initial
evaluation.
Treatment
The surgical procedure of choice is the HPE, first described by
Kasai in 1959 (13). The procedure has three components: (1)
abdominal exploration and cholangiography to confirm the
diagnosis, (2) dissection of the porta hepatis and transection
of biliary tissue remnants at the portal plate, and (3) establishment of biliary drainage through the construction of a 40 to
50 cm Roux-en-Y jejunal conduit. Success in obtaining bile
flow is better if HPE is done when the patient is between 60
and 90 days old. The sequential use of HPE followed by liver
transplantation is the standard surgical paradigm followed
around the world (1416).
Outcomes
Left untreated, an infant with BA has a life expectancy of
approximately 1 year. Following a Kasai procedure, 5-year survival rates with native liver have ranged between 48% and 60%.
With the sequential treatment of a Kasai portoenterostomy and
secondary liver transplant, if required, overall survival rate is
approximately 90% (17). Outcomes of BA following Kasai HPE
and liver transplant from various centers are summarized in
Table 51.3. Survival with the native liver after the Kasai operation is approximately 30% at 10 years and 14% to 23% at
20 years (1821). The largest North American long-term experience with HPE demonstrated survival with the native liver of
35% at 10 years and 21% at 20 years (22). A recent series of 755
BA patients listed for liver transplantation from North America
reported a 3-year graft survival rate of 88% and a patient survival rate of 80% (23). Thus the current use of HPE followed by
liver transplantation in children who subsequently develop
cirrhosis provides excellent long-term survival for a disease that
is fatal without surgery. Complications include cholangitis,
cessation of bile flow, portal hypertension, intrahepatic cysts,
hepatopulmonary syndrome, and others.
choledochal cyst
Classification
Choledochal cysts are congenital anomalies of the biliary tract
manifested by cystic dilatation of the extra hepatic biliary tree.
479
Number of
patients
Median age
at HPE
Survival with
native liver
1381
6170 days
93
54 days
104
271
61 days
57 days
148
54 days
Overall survival
of patients
5 years: 75.5% (actual)
480
gallbladder disease
Cholelithiasis
The prevalence of gallstones in children varies according to
geography and age. The predominant factors in gallstone formation are biliary stasis, excess bilirubin pigment, and lithogenic bile. Hemolytic disorders, fasting and TPN, ileal
resection/disease, cystic fibrosis, Down syndrome, childhood
cancer, bone marrow transplantation, cardiac transplantation,
spinal surgery, dystrophia myotonica, and chronic intestinal
pseudo-obstruction have all been associated with increased
incidence of cholelithiasis in children (40).
Gallstones in infants occasionally resolve spontaneously.
Early surgery can be deferred in the asymptomatic infant with
gallbladder calculi. Management of asymptomatic cholelithiasis in older children is controversial. In children without
hemolytic disorders, a conservative approach is recommended
(41). Cholecystectomy is the standard treatment for symptomatic or complicated gallbladder stones.
Hemolytic Cholelithiasis
In the past, the usual cause of gallstones in children was hemolytic disease. Hereditary spherocytosis, sickle cell anemia, and
thalassemia are the most common hemolytic disorders resulting in the development of gallstones. In patients with spherocytosis, ultrasound is indicated prior to splenectomy. If stones
are present, cholecystectomy is performed. In sickle cell disease, only symptomatic patients require cholecystectomy,
which should be preformed electively rather than emergently
during a hemolytic crisis (42).
Congenital Deformities
Congenital deformities include a variety of abnormal configurations and locations of the gallbladder, such as gallbladder
agenesis, duplication, bilobation, floating gallbladder, diverticula, and ectopia. They are usually of no clinical relevance; if
hepatoblastoma
Incidence
Hepatoblastoma is the most common malignant hepatic
tumor. Liver cancers constitute 0.5% to 2% of all pediatric solid
tumors and about 5% of abdominal tumors in childhood (43).
Hepatoblastomas are the most common primary hepatic
tumors of childhood constituting 43% to 64% of all hepatic
neoplasms in one large series (4345). Approximately twothirds of all liver masses occurring in children are malignant.
Eighty percent of 123 children in the United States registered
with malignant liver tumors in 2000 had hepatoblastoma and
they accounted for 91% of primary hepatic malignancies in
children less than 5 years of age (46). There are approximately
50 to 70 new cases per year in the United States with a male to
female ratio of 1.7:1 (47). The median age at diagnosis is
about 18 months, and most cases occur before age 2 to
3 years (48).
Hepatoblastoma may occur in siblings (4951). It is most
strongly associated with familial polyposis (52,53), Gardners
syndrome (54), and BeckwithWiedemann syndrome (55,56).
Pathology
The five histologic subtypes observed in hepatoblastoma are
fetal, embryonal, mixed mesenchymal, macrotubular, and
anaplastic or small cell. The importance of subtyping in hepatoblastoma is the association between prognostic risk and
subtype (57,58). Patients with small cell undifferentiated
tend to do worse. Figure 51.1 illustrates imaging and pathology of a child with Beckwith-Wiedemann syndrome with
hepatoblastoma.
Clinical Features
The most common presenting sign of hepatoblastoma is an
asymptomatic abdominal mass. A mild anemia with a markedly elevated platelet count is observed in most patients at
diagnosis. The cause is probably secondary to abnormal cytokine release. In an abstract from the 1993 Annual Meeting of
the American Society of Clinical Oncology, Van Tournet et al.
stated that measurement of serum alpha-fetoprotein is well
established as an initial tumor marker in the diagnosis of hepatoblastoma and a means of monitoring the therapeutic
response. The normal level in most laboratories is less than 20
ng/ml whereas the AFP level at diagnosis in hepatoblastoma
patients can range from normal to 7.7 106 ng/ml. It is estimated that the AFP is elevated in 84% to 91% of patients with
hepatoblastoma (58). In comparison, the mean in pediatric
patients with HCC was about 200,000 ng/ml (59).
Imaging
The first imaging study is usually an abdominal ultrasound.
Computed tomography (CT) is useful to identify pulmonary
metastases, identify diffuse hepatic involvement, and determine respectability. MRI is useful for evaluating hepatic lesions
and their relationship to vascular structures (60). It can show
the hepatic veins, the vena cava, and bile ducts.
Staging
Most studies to date have used the clinical grouping defined by
the Childrens Cancer Group and the Pediatric Oncology
Group, which is presented in Table 51.4.
Treatment
Most studies support the effectiveness of systemic chemotherapy combined with complete surgical resection of the primary
hepatic tumor (61,62). Survival depends on removal of the primary liver tumor in most cases. The first clinical decision is
whether to initial neoadjuvant chemotherapy or proceed with
resection. A completely resected tumor without the presence of
metastatic disease is deemed stage I. If after resection pathology
shows pure fetal histology, close observation ensues. For all
other histologies and for stage II disease, four cycles of combination cisplatin, 5-fluorouracil, and incrusting are given. For a
tumor deemed unrespectable at diagnosis (stage III) or a
patient with metastatic disease (stage IV), current therapy consists of four cycles of chemotherapy with either resection or
liver transplantation after cycle 4 followed by two more cycles.
Extensive tumors usually shrink with chemotherapy, facilitating resection, whereas chemotherapy might be lessened or
avoided in some patients by resection at diagnosis. About 46%
of hepatic malignancies are resectable at diagnosis (59).
Outcome
Overall survival of 60% to 70% is achievable with non-stage
IV hepatoblastoma except for with the very aggressive small
cell variant. Approximately 50% of patients who present with
pulmonary metastasis are curable. If gross disease remains in
the primary site, survival falls to zero. Some patients with
microscopic residual tumor are curable with continued chemotherapy and may benefit from external-beam radiotherapy
to the primary hepatic site. In a multivariate analysis, factors
that have been independent predictors of worsened prognosis
include high TNM stage, unresectable tumor, bilobar involvement and multifocality, AFP less than 100 ng/ml or more than
105 ng/ml, distant metastases, embryonal versus fetal histology,
and vascular invasion (63).
Incidence
HCC accounts for 23% of pediatric liver tumors (64). The
incidence is bimodal with an early peak that occurs before
5 years and a second peak that occurs between 13 and 15 years.
HCC is the most common hepatic malignancy of adolescence
(65). There is a male predominance of 1.3 to 3.2:1. Hepatitis B
and C correlate with the incidence of HCC. In Asia 85% of
these patients (adults and children) are hepatitis B surface
antigen positive, whereas this is found in only 10% to 25% of
patients in the United States. The relative risk for the development of HCC is 250:1 for patients with chronic active hepatitis
compared with patients without hepatitis surface antigen positivity (66). Other conditions associated with the development of
HCC include cirrhosis, 1-antitrypsin deficiency, tyrosinemia,
aflatoxin ingestion, hemochromatosis, hepatic venous obstruction, androgen and estrogen exposure, Alagille syndrome, and
thorotrast administration (67).
481
(A)
(B)
(C)
(D)
(E)
Figure 51.1 Ten-month-old female with BeckwithWiedemann syndrome. (A,B) The hepatoblastoma is centered on the middle hepatic vein, with an extension
into the right hepatic vein (arrow in A) and an encasement of the left hepatic vein (arrow in B). (C,D) Preoperative chemotherapy resulted in shrinkage of the
tumor, with apparent involvement of a clear plane between the tumor and the right hepatic vein (arrow in C); panel D demonstrates the tumor encasing the left
portal vein. An attempted extended left hepatic lobectomy was abandoned because of the presence of an occult tumor involvement of the right hepatic vein noted
at surgery. (E) The patient underwent hepatic transplantation. Source: Reprinted from Ref. (104).
Pathology
HCCs are highly invasive and often multicentric at diagnosis,
with frequent hemorrhage and necrosis. Invasiveness, especially
vascular invasion, is a hallmark of these tumors. Extrahepatic
dissemination to portal lymph nodes, lungs, and bones is
frequent at diagnosis and strongly affects survival.
482
Clinical Features
Children and adolescents with HCC frequently present (68)
with palpable abdominal masses (40%), but many are asymptomatic at diagnosis. Pain is common (38%) and may occur in
the absence of an obvious mass. Constitutional disturbances
such a as anorexia, malaise, nausea and vomiting, and significant
Stage III
Stage IV
Complete resection
Purely fetal histology with a low
mitotic index
All other stage I tumors
Gross total resection with
microscopic residuals or total
resection with preoperative or
intraoperative rupture
Unresectable tumors as
determined by the attending
surgeon, partially resected
tumors with macroscopic
residual, or any tumor with
lymph node involvement
Measurable metastatic disease to
lungs or other organs
pancreas
Congenital Anomalies
Ectopic Pancreatic Rests
The incidence of ectopic pancreatic rests in autopsy ranges
from 1% to 2% (76) and is frequently encountered along foregut derivatives, such as the stomach and duodenum, as well as
jejunum, ileum, and colon (77). They represent the most common anomaly of the gastric antrum and may cause a gastric
outlet obstruction (78). Their origin is unknown, but one possible explanation suggests an aberrant epithelialmesenchymal
interaction, leading to trans-differentiation of heterotrophic
embryonic epithelium into pancreatic epithelium. Ectopic rests
are usually asymptomatic and found incidentally at laparotomy.
Pancreas Divisum
Failure of the duct of Wirsung and the duct of Santorini to
unite from the dorsal and ventral pancreas during development
results in the anatomic variant known as pancreas divisum. In
this disorder the duct of Wirsung is very small, and the duct of
Santorini becomes the major ductal system and communicates
with the duodenum through the minor papilla. If the orifice of
the accessory papilla is stenotic, pancreatitis can occur. The
goal of treatment is to establish adequate drainage of the duct
of Santorini. Several reports show that adequate drainage can
be obtained with accessory papilla sphincteroplasty (83).
Acute Pancreatitis
The causes of acute pancreatitis include trauma, biliary tract
stone disease, choledochal cyst, ductal developmental anomalies, drugs, such as retrovirals, diuretics, anticonvulsants, as well
as some chemotherapeutic agents, metabolic derangements,
and infections. In children, trauma is the most common cause.
Pancreas divisum is an anomaly present in 10% of the population, resulting from failure of the dorsal duct to fuse with the
ventral duct. This relative obstruction may cause recurring
episodes of pancreatitis (84). These patients should undergo a
sphincteroplasty of the minor papilla. The pathogenesis
entails the inappropriate activation of proenzymes, leading to
autodigestion of the pancreas.
Acute pancreatitis usually presents with the acute onset of
midepigastric pain associated with back pain, severe vomiting,
and low-grade fever (85,86). In severe cases of necrotizing or
hemorrhagic pancreatitis, hemorrhage may dissect from the
pancreas along tissue plans appearing as ecchymosis either in
the flanks (GreyTurner sign) or at the umbilicus (Cullens
sign). Lipase levels have been proposed as a more specific test of
pancreatic tissue damage, although intestinal perforation does
cause an elevation of lipase throughout reabsorption via the
peritoneum. Lipase is produced only in the pancreas and its
measurement is particularly helpful for distinguishing pancreatic trauma from salivary trauma (87). CT scan offers better
resolution than other modalities to determine size of pancreas,
degree of edema, and the presence of fluid collections (88). It
483
484
KEY POINTS
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487
Index
AAST. See American Association for Surgery
of Trauma
Abdominal compartment syndrome, 274
Abdominal pain, 451
Ablative techniques, 5758
ABO-incompatible liver, 291
ACC. See Acinar cell carcinoma
Acinar cell carcinoma, 432
pancreatic lesions, 107
ACS. See Abdominal compartment
syndrome
Acute and chronic liver failure
auxiliary liver transplantation
auxiliary whole orthotopic liver
transplantation, 294295
immunosuppression, 295
outcome of, 295
donor selection
ABO-incompatible liver, 291
donation after cardiac death, 290291
donors with infection, 290
donors with malignancy, 290
elderly donors, 289290
hepatitis B core antibody positive
donors, 290
hepatitis C infection donors, 290
split-liver, 290
steatosis and abnormal liver
function, 289
future perspectives
hepatocyte transplantation, 297
immune tolerance, 297
liver support devices, 295, 297
orthotopic liver transplantation
immunosuppression, 292293
operative technique of, 292
outcomes in, 293294
post-operative management, 292293
recipient selection
with acute liver failure, 288
end-stage liver disease, 288
with HIV, 288289
with viral hepatitis, 288
retrieval of deceased donor liver graft
donation after cardiac death
retrieval, 292
standard retrieval, 291
splitting of deceased donor liver graft, 292
Acute cholangitis, gallstone disease, 374
Acute cholecystitis
bile duct injuries, 360362
gallstone disease, 373
Acute pancreatitis
congenital anomalies, 483484
early management of, 439441
etiology of, 439
gallstone disease, 374375
laparoscopy, 443
489
INDEX
Benign cystic diseases
aspiration sclerotherapy, 301303
polycystic liver disease, 303304
rare lesions, 305
simple biliary hepatic cysts, 301
Benign disease, 24
Benign inflammatory pseudotumors, 370
Benign solid tumors
adult hemangioma, 262
capillary hemangioma, 262
cavernous hemangioma
imaging features of, 263
management of, 263
pathology of, 262
classification of, 262
congenital hepatic fibrosis, 267
focal nodular hyperplasia
imaging features of, 264
management of, 264
pathology of, 263
telangiectatic, 263
hepatocellular adenoma
imaging features of, 265
management of, 265
pathology of, 264265
hepatocellular adenomatosis
management of, 266267
pathology of, 265266
nodular regenerative hyperplasia, 266
pseudolipoma
hereditary hemorrhagic
telangiectasia, 268
heterotopic tissue, 268
inflammatory pseudotumor, 268
miscellaneous rare benign solid liver
lesions, 268
peliosis hepatic, 267268
Benzimidazole, 321
Bevacizumab, 140, 176, 220
Bile duct
hamartomas, 305
ultrasound applications, 3941
Bile duct injuries
noniatrogenic bile duct strictures
benign inflammatory
pseudotumors, 370
biliary strictures secondary to
pancreatitis, 369370
calculous disease, 370
sclerosing cholangitis, 370
patient-related factors
acute cholecystitis, 360362
congenital abnormalities, 362363
procedure-related factors
critical view technique, 365
misidentification concepts, 363365
technical problems, 365
surgeon/hospital-related factors
laparoscopic equipment, 366
learning curve effect, 366
psychology of human error, 366
Bile ducts and liver, surgical anatomy
490
anatomical hepatectomies, 56
anatomy of biliary exposure, 1213
arterial blood supply of, 1112
biliary anatomy, 1011
biliary tract, 6
caudate lobe, surgical approach, 6
cystic duct, 910
early application of functional anatomy, 1
extrahepatic biliary anatomy, 89
falciform ligament, 14
gallbladder, 910, 14
hepatic veins, 13
intrahepatic biliary anatomy, 78
ligamentum venosum, 14
morphological anatomy, 1
portal system, 1314
radiological anatomy of, 13
segmental anatomy of, 15
Bile fistula, 367
Bile leak, hepatectomy
incidence, 65
prevention, 65
risk factors, 6566
Bile pigment stone, 373
Biliary adenoma, 267
Biliary atresia
classification, 478
clinical features, 478
outcomes, 478
pathology, 478
surgical treatment, 478
Biliary colic, 373
Biliary decompression
nonoperative technique, 402
operative technique, 402
Biliary drainage, 333334
Biliary dyspepsia, 375
Biliary hamartoma, 266267
Biliary injuries
avoidance of, 366367
classification of, 360
iatrogenic, 360
incidence
laparoscopic versus open
cholecystectomy, 360
population-based studies, 360
management of
intraoperative recognition, 367368
operative technique, 368369
preoperative preparation, 368
types of injuries, 368
outcome of treatment, 369
post-transplantation, 369
Biliary stricture, 356
after hepatectomy
incidence of, 66
management of, 66
Bladder drainage, 473474
Bland embolization, 216218
Bleeding, hepatectomy
incidence, 63
investigation and treatment, 65
presentation, 65
prevention, 6365
Body habitus, 363
Borderline tumors, 385
Brachytherapy, malignant biliary
obstruction, 349350
Breast cancer, 54
noncolorectal, nonneuroendocrine
metastases, 166
British Society of Gastroenterology, 346
BSG. See British Society of Gastroenterology
BuddChiari syndrome, 280
CA19-9. See Carbohydrate antigen 19-9
Cambridge Classification of Chronic
Pancreatitis, 451
Capecitabine, 173
Capillary hemangioma, 262
Carbamates, 321
Carbohydrate antigen 19-9, 382
Carcinoid symptom severity scale, 157
Carcinoid tumors, 154
Carcinoma
fibrolamellar, 104
gallbladder, 104
hepatocellular, 104
Carolis disease, 357
Caspofungin, 259
Caudal pancreatic artery, 20
Caudate lobe, surgical approach, 6
Caval injury, 276
Cavernous hemangioma
imaging features of, 263
management of, 263
pathology of, 262
CCA. See Cholangiocarcinoma
CECT. See Contrast-enhanced
computerized tomography
Central pancreatectomy, 85
Cetuximab, 137, 176
CgA. See chromogranin A
Charcots Triad of symptoms, 374
Chemical ablation, 195
Chemical splanchnicectomy, 403404
Chemo-embolization, 216218
Chemotherapeutic agents
capecitabine, 173
irinotecan, 135
oxaliplatin, 135
Chemotherapeutic regimens, 173
Chemotherapy
neuroendocrine tumors, 161
non-functional islet cell tumors, 428
Chemotherapy-associated hepatotoxicity
diagnosis, 176177
monoclonal antibodies, 176
nonalcoholic fatty liver disease
sinusoidal obstruction
syndrome, 174176
steatohepatitis, 174
steatosis, 173174
preoperative chemotherapy, 178
INDEX
prevention, 177
Chemotherapy-associated nonalcoholic
fatty liver disease
diagnosis of, 173
sinusoidal obstruction syndrome, 174176
steatohepatitis, 174
steatosis, 173174
CHF. See Congenital hepatic fibrosis
ChildTurcottePugh Score, 289
Chlorozotocin, 428
Cholangiocarcinoma
liver and biliary tract lesions, 104
liver transplantation
neoadjuvant chemoradiotherapy,
229231
organ allocation, 231
Cholecystenteric fistula, 374
Choledochal cysts
adulthood
clinical presentation, 354
complications, 355
diagnosis, 354355
etiology and classification, 354
incidence and pathophysiology, 354
treatment, 355358
classification, 479
clinical features, 480
imaging, 480
outcomes, 480
pathology, 479480
surgical treatment, 480
Choledochoduodenostomy, 91
Choledocholithiasis, 370
Choledochotomy, 9091
Cholelithiasis, 480
Cholestatic neonate, diagnostic evaluation
in, 479
Cholesterol stones, 373
chromogranin A, 154
Chronic pancreatitis
classification of, 451
comparison of different surgical
approaches, 457458
complications of, 453454
congenital anomalies, 484
conservative treatment, 454
definition of, 451
duodenum-preserving resection
Beger procedure, 456457
Berne procedure, 457
Hamburg procedure, 457
quality of life, 458
etiology pathomorphological
findings, 452
indications for surgical
intervention, 454455
interventional treatment, 454
natural course of, 451
pathogenesis of pain, 452453
rationale for drainage
procedures, 455456
rationale for resectional procedures, 456
salvage procedures, 459
lithotripsy, 377
surgical management
laparoscopic common bile duct stone
removal, 378
open choledocholithotomy, 377
Computed tomography
choledochal cyst, 355
colorectal liver metastases, 148149
hydatid cyst, 311
liver and biliary tract lesions
cholangiocarcinoma, 104
cross-sectional anatomy, 100
fibrolamellar carcinoma, 104
focal nodular hyperplasia, 102
gallbladder carcinoma, 104
hepatic hemangioma, 102
hepatocellular adenoma, 102, 104
hepatocellular carcinoma, 104
metastatic cancer to liver, 104
liver metastases, 109110
localization of insulinomas, 415
neuroendocrine tumors, 155
pancreatic ductal adenocarcinoma,
382383
pancreatic injuries, 463
pancreatic lesions
acinar cell carcinoma, 107
cross-sectional anatomy, 100
metastatic cancer to pancreas, 107
pancreatic adenocarcinoma, 107
pancreatic neuroendocrine tumors, 106
solid pseudopapillary tumor, 106107
scanning, radiological anatomy of liver, 13
Congenital abnormalities, bile duct injuries,
362363
Congenital anomalies
acute pancreatitis, 483484
adenocarcinoma, 484
annular pancreas, 483
chronic pancreatitis, 484
ectopic pancreatic rests, 483
pancreas divisum, 483
pancreatic abscess, 484
pancreatic pseudocyst, 484
persistent hyperinsulinemic
hypoglycemia of infancy, 484
Congenital deformities, 480481
Congenital hepatic fibrosis, 267
CONKO-1, randomized controlled
trail, 391392
Contrast-enhanced computerized
tomography, 192
Contrast-enhanced ultrasound, liver
metastases, 109
Conventional Milan Criteria, 193
Covered stents, 349
CP. See Central pancreatectomy; Chronic
pancreatitis
CRLM. See Colorectal liver metastases
Cross-sectional imaging. See CT imaging,
MRI characteristics
CRS. See Clinical risk score
Cryoablation, neuroendocrine tumors, 160
491
INDEX
Cryotherapy, 126
thermal ablation, 180181
Cryptogenic abscess, 256
CT. See Computed tomography
Curative surgical resection, 394
Cyst aspiration, 301
Cyst fluid analysis, 411
Cystic dilatation. See Choledochal cyst
Cystic fibrosis, 380381
Cystic lesions, 3637
Cystic metastases, 113
Cystic pancreatic neoplasms, 41
Cystic tumors
clinical scenarios
presentation and diagnostic
evaluation, 407
treatment, 412
diagnostic evaluation, 411
pathologic sub-types and clinical
behavior
intraductal papillary mucinous
neoplasm, 409410
mucinous cystic neoplasm, 410411
pancreatic pseudocyst, 407
serous cystadenoma, 407409
treatment recommendations
intraductal papillary mucinous
neoplasm, 412
mucinous cystic neoplasm, 412
DCCT. See Diabetes Control and
Complication Trial
DCD. See Donation after cardiac death
DDLT. See Deceased donor liver
transplantation
Deceased donor liver graft
retrieval of
donation after cardiac death
retrieval, 292
standard retrieval, 291
splitting of, 292
Deceased donor liver transplantation,
208213
Delayed gastric emptying, 81, 389
Detectable metastases, 401
Dexamethasone, 136
DGE. See Delayed gastric emptying
Diabetes Control and Complication
Trial, 475
Diabetic nephropathy, 475
Diagnostic laparoscopy
palliation of pancreas cancer, 401402
pancreatic ductal adenocarcinoma,
383, 385
Diagnostic radiography, 402
Diarrhea, 417, 421
Diet, 380
Diffuse liver disease
liver, 36
pancreas, 41
Diffusion-weighted MR imaging, 111
Direct cholangioscopy, 346
endoscopic therapy, 347
492
INDEX
donors with infection, 290
donors with malignancy, 290
elderly donors, 289290
hepatitis B core antibody positive
donors, 290
hepatitis C infection donors, 290
split-liver, 290
steatosis and abnormal liver
function, 289
Extensive locoregional disease, 401
External beam radiotherapy, 230
Extracorporal shockwave lithotripsy, 454
Extrahepatic biliary anatomy, 89
Extrahepatic cholangiocarcinoma
operative procedures
combined liver and portal vein
resection, 339340
distal cholangiocarcinoma, 336337
hepatobiliary resection for hilar
cholangiocarcinoma, 337339
hepatopancreatoduodenectomy, 340
pancreatoduodenectomy, 336337
preoperative management
biliary drainage, 333334
portal vein embolization, 334
staging of cholangiocarcinoma, 333
synbiotics treatments with bile
replacement, 334336
surgical anatomy of bile duct, 333
Extrahepatic disease, 181183
Extrahepatic portal hypertension, 453
[18F] 2-fluoro-2-deoxyglucose, 111112
Familial pancreatic cancer syndrome, 380
Familial predisposition, 380
FAST. See Focused Assessment for
Sonographic examination of
Trauma patient
FDA. See Food and Drug Administration
FDG. See [18F] 2-fluoro-2-deoxyglucose;
Fluorine-18-labeled
fluoro-deoxyglucose
Fertile cyst, 315
Fibrolamellar carcinoma, 104
Fine needle aspiration, 383, 440
FISH. See Fluorescent in situ hybridization
FLC. See Fibrolamellar carcinoma
Floxuridine, 136137
FLR. See Future liver remnant
Fluorescent in situ hybridization, 229
Fluorine-18-labeled fluoro-deoxyglucose, 329
Fluorouracil, 135
5-Fluorouracil, 5859
FNA. See Fine needle aspiration
FNH. See Focal nodular hyperplasia
FNH-like lesions, 264
Focal fatty variants, 267
Focal hepatic lesions
ultrasound applications
cystic lesions, 3637
solid liver lesions, 3739
Focal nodular hyperplasia
imaging features of, 264
Gallstone
acute cholangitis, 374
acute cholecystitis, 373
acute pancreatitis, 374375
biliary colic, 373
biliary dyspepsia, 375
cholecystenteric fistula, 374
classification of, 373
empyema, 373374
gallstone ileus, 374
ileus, 374
Mirrizis syndrome, 375
mucocele, 374
non-surgical management
analgesia for biliary colic/
cholecystitis, 375
drug dissolution therapy, 375
percutaneous cholecystostomy, 375
obstructive jaundice, 374
surgical management, cholecystectomy
laparoscopic cholecystectomy, 376
open cholecystectomy, 375376
operative technique, 376377
Gastric cancer, noncolorectal,
nonneuroendocrine
metastases, 167168
Gastric decompression
nonoperative technique, 402403
operative technique, 403
Gastric outlet obstruction, 401402
Gastrinomas
management of, 419
precise localization of, 417
preoperative evaluation, 418
sensitivity of invasive and non-invasive
imaging studies, 418
symptoms of, 417
Gastrointestinal cancers, 55
Gastrojejunostomy, 402
isoperistaltic, 403
palliative, 403
Gelfoam, 216
Genitourinary tumors, 55
Giant cell tumors, 435
Giant hemangiomas, 37
-Glucuronidase, 242
Glucagonomas, 419420
Grade A fistulas, 389
Grade B fistulas, 389
Grade C fistulas, 389390
Great pancreatic artery, 20
Gynecological tumors, 166
HAE. See Hepatic artery embolization
HAI. See Hepatic arterial infusion
HALT. See Heterotopic auxiliary liver
transplantation
HAS. See Hepatic hemangiosarcoma
HBV. See Hepatitis B Virus
HCC. See Hepatocellular carcinoma
Head and neck tumors, 168
HEHE. See Hepatic epithelioid
hemangioendothelioma
493
INDEX
Hemangioma, 37
adult, 262
Hemolytic cholelithiasis, 480
Hemorrhage, 273274
Hepatectomy, 56
bile leak
consequences of, 66
incidence, 65
management of, 66
presentation, 66
prevention, 65
risk factors, 6566
biliary stricture
incidence of, 66
management of, 66
bleeding
incidence, 63
investigation and treatment, 65
presentation, 65
prevention, 6365
cardiac complications, 69
hepatic insufficiency
incidence, 66
optimization of venous drainage, 67
portal vein embolization, 67
prevention, 67
treatment, 6768
intra-abdominal infection
abdominal drainage, 68
factors affecting, 68
pain relief, 6869
renal failure
consequences of, 6970
etiology of, 69
renal impairment, 70
respiratory complications, 6869
wound complications, 70
Hepatic abscess. See Liver abscess
Hepatic arterial infusion, 136137
Hepatic arterial infusional
chemotherapy, 59
Hepatic artery embolization, 427
neuroendocrine tumors, 156158
Hepatic cryoablation, 160
Hepatic epithelioid
hemangioendothelioma, 233235
Hepatic hemangioma, 102
Hepatic hemangiosarcoma, 237238
Hepatic infantile hemangioendothelioma,
235237
Hepatic metastasectomy
adjuvant chemotherapy, 5859
colorectal metastases, 53
neuroendocrine metastases, 53
noncolorectal metastases, 5455
nonneuroendocrine metastases, 5455
patient selection
colorectal metastases, 55
neuroendocrine tumors, 56
noncolorectal tumors, 56
nonneuroendocrine tumors, 56
resection techniques
ablative techniques, 5758
494
Hepatocellular adenoma
imaging features of, 265
liver and biliary tract lesions, 102, 104
management of, 265
pathology of, 264265
Hepatocellular adenomatosis
management of, 266267
pathology of, 265266
Hepatocellular carcinoma
advanced stage, 195
diagnosis, 192
early stages
chemical ablation, 195
liver resection, 193195
liver transplant, 195
thermal ablation, 195
intermediate stage, 195
liver and biliary tract lesions, 104
liver surgery, in elderly patients, 4850
liver transplantation
in Asia, 208
pretransplant neoadjuvant
therapy, 211212
recurrence treatment, 212213
selection criteria and outcomes,
209211
local regional therapies
arterial embolization, 216
bland embolization, 216218
chemo-embolization, 216218
drug-eluting microspheres, 218
percutaneous chemical/thermal
ablation, 218219
radio-embolization, 218
pediatric hepato-pancreato-biliary
disorders
clinical features, 482483
incidence, 481
outcomes, 483
pathology, 482
surgical treatment, 483
staging systems, 192
systemic therapies
advanced cirrhosis treatment, 220
anti-angiogenic therapies, 219220
cisPlatin, interferon, adriamycin, and
5-fluorouracil, 219
future developments, 220221
historical background, 219
treatment options, 192193
ultrasound applications, 38
variceal bleeding, 281
Hepatocyte transplantation, 297
Hepatopancreatoduodenectomy, 340
Hepatopulmonary syndrome, 285
Hepatotomy, 275276
Hereditary chronic pancreatitis, 452
Hereditary hemorrhagic
telangiectasia, 268
Hereditary pancreatitis, 380
Hereditary tumor syndromes, 380
Heterotopic auxiliary liver
transplantation, 295
INDEX
Heterotopic tissue, 268
HHT. See Hereditary hemorrhagic
telangiectasia
5-HIAA. See 5-Hydroxyindoleacetic acid
High-affinity somatostatin receptors, 424
High-grade pancreatic injuries, 466
HIHE. See Hepatic infantile
hemangioendothelioma
Hilar cholangiocarcinoma
anatomic right trisectionectomy, 339
intrahepatic cholangiojejunostomy, 339
left trisectionectomy, 338
left-sided hepatectomy, 337
liver transplantation
neoadjuvant chemoradiotherapy,
229231
organ allocation, 231
right hepatectomy, 338339
right trisectionectomy, 338
Hilar strictures, malignant biliary
obstruction
disease modifying treatment, 349
unilateral vs. bilateral, 349
HistidineTryptophanKetoglutarate, 471
Hockey stick incision, 25
HPD. See Hepatopancreatoduodenectomy
HPE. See Hepatic portoenterostomy
HPS. See Hepatopulmonary syndrome
HT. See Hepatocyte transplantation
HTK. See HistidineTryptophan
Ketoglutarate
5-HTP. See 5-Hydroxytryptophan
Human error, psychology of, 366
Hydatid cyst, 102
biological basis of surgery, 308
complications
infection, 313
rupture, 313314
conservative procedures, 316317
diagnostic imaging
angiography, 313
computed tomography, 311
magnetic resonance imaging, 311
radioisotope imaging, 313
ultrasonography, 311
intraoperative approach, 315316
laparoscopy, 320
medical therapy, 321
pathological basis of surgery, 308
puncture aspiration injection
reaspiration, 320321
radical procedures, 317320
serology of, 313
structure of, 308310
topography, 314315
treatment, 315
5-Hydroxyindoleacetic acid, 154
5-Hydroxytryptophan, 424
Hyperglycemia, 471
Hypersplenism, 280
Hypervascular metastases, 113
Hypoechoic halo, 38
Hypoechoic liver, 39
495
INDEX
Left lateral sectionectomy, 3233
Left trisectionectomy
hepatic resection, 32
hilar cholangiocarcinoma, 338
Left-sided hepatectomy, 337
Lexipafant, 440
LGSW. See Liver gunshot wounds
Ligasure device, 94
Lipase, 483
Lipoma, 267
Lithotripsy, 377
Liver
and bile ducts, surgical anatomy
anatomical hepatectomies, 56
anatomy of biliary exposure, 1213
arterial blood supply of, 1112
biliary anatomy, 1011
biliary tract, 6
caudate lobe, surgical approach, 6
cystic duct, 910
early application of functional
anatomy, 1
extrahepatic biliary anatomy, 89
falciform ligament, 14
gallbladder, 910, 14
hepatic veins, 13
intrahepatic biliary anatomy, 78
ligamentum venosum, 14
morphological anatomy, 1
portal system, 1314
radiological anatomy of, 13
segmental anatomy of, 15
and biliary tract lesions, CT and MRI
imaging
cholangiocarcinoma, 104
cross-sectional anatomy, 100
fibrolamellar carcinoma, 104
focal nodular hyperplasia, 102
gallbladder carcinoma, 104
hepatic hemangioma, 102
hepatocellular adenoma, 102, 104
hepatocellular carcinoma, 104
metastatic cancer to liver, 104
hydatid cyst
biological basis of surgery, 308
complications, 313314
conservative procedures, 316317
diagnostic imaging, 311, 313
intraoperative approach, 315316
laparoscopy, 320
medical therapy, 321
pathological basis of surgery, 308
puncture aspiration injection
reaspiration, 320321
radical procedures, 317320
serology of, 313
structure of, 308310
topography, 314315
treatment, 315
ultrasound applications
diffuse liver disease, 36
focal hepatic lesions, 3639
Liver abscess, 356
496
amebic abscess
diagnosis of, 253254
epidemiology of, 253
outcomes of, 255
pathogenesis of, 253
treatment of, 254255
fungal abscess, 258259
pyogenic abscess
diagnosis of, 256257
epidemiology of, 255
microbiology of, 256
outcomes of, 258
pathogenesis of, 255256
treatment of, 257258
Liver biopsy, 478
Liver Cancer Study Group of Japan, 223
Liver failure, 48
Liver gunshot wounds, 274275
Liver metastases
computed tomography, 109110
contrast-enhanced ultrasound, 109
detection, 114115
imaging findings
cystic metastases, 113
hypervascular metastases, 113
intrabiliary metastases, 113
pitfalls and limitations, 113
magnetic resonance imaging, 110111
perfusion imaging, 112
positron emission
tomography, 111112
preoperative staging, 115116
ultrasound techniques, 109
Liver resection
laparoscopically discovered gallbladder
cancer, 203204
stages of hepatocellular carcinoma,
193195
types of, 122
Liver support devices, 295, 297
Liver surgery, elderly patients
age-related liver changes, 4647
colorectal liver metastases, 4748
financial cost, 50
hepatocellular carcinoma, 4850
surgical risk evaluation, 47
Liver transplantation
for acute and chronic liver failure
auxiliary liver transplantation, 294295
donor selection, 289291
future perspectives, 295, 297
orthotopic liver transplantation,
292294
recipient selection, 288289
retrieval of deceased donor liver
graft, 291292
splitting of deceased donor liver
graft, 292
in Asia, 208209
hepatocellular carcinoma
pretransplant neoadjuvant
therapy, 211212
recurrence treatment, 212213
INDEX
liver and biliary tract lesions
cholangiocarcinoma, 104
cross-sectional anatomy, 100
fibrolamellar carcinoma, 104
focal nodular hyperplasia, 102
gallbladder carcinoma, 104
hepatic hemangioma, 102
hepatocellular adenoma, 102, 104
hepatocellular carcinoma, 104
metastatic cancer to liver, 104
liver metastases, 110111
neuroendocrine tumors, 155
pancreatic lesions
acinar cell carcinoma, 107
cross-sectional anatomy, 100
metastatic cancer to pancreas, 107
pancreatic adenocarcinoma, 107
pancreatic neuroendocrine tumors, 106
solid pseudopapillary tumor, 106107
Malignant biliary obstruction
causes of, 343
covered vs. uncovered stents, 349
CT scanning, 343
direct cholangioscopy, 346
endoscopic therapy, 347
methods of therapy, 347
percutaneous drainage of
jaundice, 348
endoscopic intervention, 344
endoscopic retrograde
cholangio-pancreatography, 344346
ERCP vs. PTC vs. surgery, 348
hilar strictures
disease modifying treatment, 349
unilateral vs. bilateral, 349
MR scanning, 343344
operative vs. nonoperative palliation
of, 404
plastic vs. metal, 348349
radiological diagnostic imaging, 343
radiotherapy
brachytherapy, 349350
photodynamic therapy, 350
ultrasound, 343
Malignant disease, 24
Malignant gastroduodenal obstruction, 404
Malignant insulinomas, 416
MarseilleRome classification of chronic
pancreatitis, 451
Mass-forming type of intrahepatic
cholangiocarcinoma, 223
Mayo Clinic protocol, 230
MCN. See Mucinous cystic neoplasm
MCT. See Microwave coagulation
MdCT. See Multidetector computed
tomography
Mebendazol, 321
Medullary carcinoma, 436
Melanoma, 5455
noncolorectal, nonneuroendocrine
metastases, 169
Memorial Sloan-Kettering
Cancer Center, 201
497
INDEX
Noncolorectal, nonneuroendocrine
metastases (Continued)
sarcoma, 168169
Noncolorectal tumors, 56
Non-functional islet cell tumors, 421422
clinical presentation of, 422423
curative resection and survival, 426
curative surgery treatment
for metastatic disease, 426427
for the primary tumor, 425426
extent of disease and localization, 423424
location of, 422
prognosis, 428
surgical palliation and survival, 427
treatment
chemotherapy, 428
octreotide, 428
palliative surgery, 427
radiation therapy, 428
Non-functioning islet cell tumors, 414
Noniatrogenic bile duct strictures
benign inflammatory pseudotumors, 370
biliary strictures secondary to
pancreatitis, 369370
calculous disease, 370
sclerosing cholangitis, 370
Nonneuroendocrine metastases, 5455
Nonneuroendocrine tumors, 56
Non-operative management of liver
injury, 272273
Nonparasitic simple hepatic cysts, 102
Nonresectable metastatic disease
intra-arterial chemotherapy, 125126
management of, 124
systemic chemotherapy, 124125
NOTES. See Natural orifice transabdominal
endoscopic surgery
NRH. See Nodular regenerative
hyperplasia
Nutrition, 440
Obesity, 363
Obstructive chronic pancreatitis, 452
Obstructive jaundice, 334, 374, 401
Octreotide, 84
non-functional islet cell tumors, 428
Octreotide acetate, 420
Ocular melanoma, 55
OGTP. See osteoclast-like giant cell tumor
of pancreas
OIS-AAST. See Organ Injury Scaling
Committee of the American
Association for the Surgery of
Trauma
Okuda Classification, 192
OLT. See Orthotopic liver transplant
Open cholecystectomy
common bile duct stones, 377
gallstone disease, 375376
Organ Injury Scaling Committee of the
American Association for the
Surgery of Trauma, 463464
Oriental cholangiohepatitis, 370
498
INDEX
somatostatinomas, 421
VIPomas, 420421
non-functioning islet cell tumors
clinical presentation of, 422423
curative resection and survival, 426
curative surgery treatment, 425427
extent of disease and localization,
423424
location of, 422
prognosis, 428
surgical palliation and survival, 427
treatment, 427428
Pancreatic exocrine secretions, 474
Pancreatic fistula, 81
Pancreatic fluid, 389
Pancreatic inflammation, 439
Pancreatic injury
diagnosis
clinical presentation, 463
intraoperative exposure
and evaluation, 464465
intraoperative pancreatography, 465466
laboratory investigations, 463
radiologic investigations, 463464
epidemiology of, 463
injury grading, 463
nonoperative management, 466
operative management
distal ductal injuries, 466
high-grade injuries, 466
low-grade injuries, 466
proximal ductal injuries, 467
outcomes
complications, 467
late stricture, 468
mortality, 467
pancreatic insufficiency, 468
pancreatic leaks and fistulae, 467
peripancreatic fluid collection, 467468
pseudocysts, 467468
Pancreatic ischemia, 453
Pancreatic leaks, 467
Pancreatic lesions, CT and MRI imaging
acinar cell carcinoma, 107
cross-sectional anatomy, 100
metastatic cancer to pancreas, 107
pancreatic adenocarcinoma, 107
pancreatic neuroendocrine tumors, 106
solid pseudopapillary tumor, 106107
Pancreatic lymphoma, 434
Pancreatic main duct stenosis, 452
Pancreatic neoplasms, 4142. See also
Non-functioning islet cell tumors
Pancreatic neuroendocrine tumors, 435
pancreatic lesions, 106
Pancreatic polypeptideoma, 423
Pancreatic pseudocyst, 407
congenital anomalies, 484
Pancreatic pseudocysts, 91
Pancreatic resections
distal pancreatectomy, 7374
duodenum-preserving pancreatic head
resection, 7576
enucleation, 7677
metastasis resections, 7879
multivisceral resections, 78
recurrence resections, 78
segmental resections, 76
total pancreatectomy, 7475
vessel resections, 7778
Whipple resection, 73
Pancreatic trauma, 463
Pancreaticopleural fistulas, 453
Pancreaticenteric anastomosis, 386387
Pancreatitis, choledochal cyst, 356
Pancreatoduodenectomy vs.
pylorus-preserving
pancreatoduodenectomy, 336337
Panitumumab, 137
Parasympathetic innervation, 22
Partial pancreaticoduodenectomy, 73
Partial surgical shunts, 283
Patient-related factors, bile duct injury
acute cholecystitis, 360362
congenital abnormalities, 362363
Paucity, 478
PBD. See Preoperative biliary drainage
PCLD. See Polycystic liver disease
PDAC. See Pancreatic ductal
adenocarcinoma
PDT. See Photodynamic therapy
Pediatric hepato-pancreato-biliary
disorders
biliary atresia, 478
choledochal cysts, 479480
congenital anomalies, 483484
gallbladder disease, 480481
hepatoblastoma, 481
hepatocellular carcinoma, 481483
PEI. See Percutaneous ethanol injection
Peliosis hepatic, 267268
Percutaneous catheter drainage, 443444
Percutaneous chemical/thermal
ablation, 218219
Percutaneous cholangio-drainage, 385
Percutaneous cholecystostomy, 375
Percutaneous drainage of jaundice, 348
Percutaneous ethanol injection, 184
Percutaneous necrosectomy, 443, 446
Percutaneous transhepatic biliary
drainage, 247248
Percutaneous transhepatic
cholangiography, 348, 367
Perfusion imaging, 112
Perihepatic packing, 275
Peripancreatic fluid collection, 467468
Peritoneal drainage, 84
Peroral cholangioscopy, 333
Persistent hyperinsulinemic hypoglycemia
of infancy, 484
PET. See Positron emission tomography
PET-CT. See Positron emission tomography
with CT
Pharmacologic therapy, 282283
PHHI. See Persistent hyperinsulinemic
hypoglycemia of infancy
499
INDEX
Ppower Doppler, 36
ppPD. See Pylorus-preserving
pancreatoduodenectomy
Preoperative biliary drainage, 385
Primary pancreatic lymphoma, 434
Primary prophylaxis, 281282
Primary resection therapy, 194
Primary sclerosing cholangitis
cholangiocarcinoma, 324325
diagnosis of, 324
endoscopic treatment, 325
medical treatment, 325
natural history of, 324
surgical management, 325327
Procedure-related factors, bile duct injury
critical view technique, 365
misidentification concepts, 363365
technical problems, 365
Procurement surgical technique, 471472
Prophylactic octreotide, 84
Proton pump inhibitors, 417
Proximal ductal pancreatic injuries, 467
PSC. See Primary sclerosing cholangitis
Pseudocysts, 467468
Pseudolipoma
hereditary hemorrhagic telangiectasia, 268
heterotopic tissue, 268
inflammatory pseudotumor, 268
miscellaneous rare benign solid liver
lesions, 268
peliosis hepatic, 267268
PTA. See Pancreas transplant alone
PTC. See Percutaneous trans-hepatic
cholangiography
PTCD. See Percutaneous cholangio-drainage
Pulmonary syndromes, 280281
Puncture aspiration injection reaspiration,
320321
PVE. See Portal vein embolization
Pylorus-preserving
pancreaticoduodenectomy, 84,
385386
Pyogenic liver abscess
diagnosis of, 256257
epidemiology of, 255
microbiology of, 256
outcomes of, 258
pathogenesis of, 255256
treatment of, 257258
Pyrexia, 440
Radiation therapy, 428
Radiochemotherapy, 391
Radio-embolization, 218
Radiofrequency ablation, 126
thermal ablation, 181183
Radioisotope imaging, hydatid cyst, 313
Radiolabeled metaiodobenzylguanidine, 155
Radionuclide therapy, neuroendocrine
tumors, 161
Randomized controlled trail
operative vs. nonoperative palliation
malignant biliary obstruction, 404
500
malignant gastroduodenal
obstruction, 404
pancreatic ductal adenocarcinoma
CONKO-1, 391392
ESPAC-1, 391393
Rapamycin, 235
Rare benign cystic lesions, 305
Rare benign solid liver lesions, 268
Rare tumors
acinar cell carcinoma, 432
adenosquamous carcinoma, 432434
autoimmune pancreatitis, 436437
giant cell tumors, 435
medullary carcinoma, 436
metastatic disease, pancreas, 434435
pancreatic lymphoma, 434
renal cell carcinoma, 434
solid pseudopapillary neoplasm, 432
Von HippelLindau syndrome, 435
Rare vascular liver tumors
hepatic epithelioid
hemangioendothelioma, 233235
hepatic hemangiosarcoma, 237238
hepatic infantile
hemangioendothelioma, 235237
nodular regenerative hyperplasia, 239
RCC. See Renal cell carcinoma
Recurrence resections, 78
Recurrent metastatic disease, 129130
Recurrent pyogenic cholangitis
acute management, 246247
clinical presentation, 244245
complications, 250
definitive management, 247
definitive surgery, 248250
hematological and biochemical
investigations, 245246
minimal access approach, 247248
pathogenesis of, 242243
pathology of, 243244
Recurrent variceal bleeding, 282
Refractory bleeding, 275
Regenerative nodules, 266
Regional chemotherapy, 136137
Renal cell cancer, 166167, 434
Repeat liver resection, 129130
Resectable liver disease, systemic therapy,
140141
Resectable tumors, 385
Resection of contiguous structures, 8485
Respiratory tract, 168
Retroperitoneal laparostomy, 447
RFA. See Radiofrequency ablation
Right hemihepatectomy, 3031
Right hepatectomy, 338
Right trisectionectomy
hepatic resection, 31
hilar cholangiocarcinoma, 338339
Routine arteriography, 416
RPC. See Recurrent pyogenic cholangitis
Sarcoma, 54
noncolorectal, nonneuroendocrine
metastases, 168169
INDEX
Surgeon/hospital-related factors (Continued)
learning curve effect, 366
psychology of human error, 366
Surgical resection, pancreatic ductal
adenocarcinoma, 385387
extended lymphadenectomy, 387
extended resections, 387
pancreaticenteric anastomosis, 386387
standard vs. pylorus-preserving
pancreatoduodenectomy, 385386
Surgical shunts, 283284
Sympathetic innervation, 22
Symptom palliation, 401
Symptomatic hepatocellular carcinoma, 192
Synchronous liver metastases
neoadjuvant chemotherapy, 130131
surgery, 131
Systemic chemobiologic therapy, 137138
Systemic chemotherapy
nonresectable metastatic disease, 124125
unresectable liver disease, 135136
Systemic therapies
advanced cirrhosis treatment, 220
anti-angiogenic therapies, 219220
cisPlatin, interferon, adriamycin, and
5-fluorouracil, 219
future developments, 220221
historical background, 219
unresectable liver disease, 140141
Systemic venous drainage, 472473
TACE. See Transarterial chemo-embolization;
Trans-catheter arterial
chemo-embolization
TachoSil, 65
Telangiectatic focal nodular hyperplasia, 263
Tenting injuries, 366367
TFNH. See Telangiectatic focal nodular
hyperplasia
Therapeutic packing, 275
Thermal ablation
CLOCC study, 184
cryotherapy, 180181
edge cryotherapy, 181
limitations of, 180
microwave ablation, 183184
percutaneous ethanol injection, 184
radiofrequency ablation, 181183
stages of hepatocellular carcinoma, 195
Thermal injuries, 366367
TIPS. See Transjugular intrahepatic
portosystemic shunt
501
Second Edition
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